WO2020210670A1

WO2020210670A1 - Compositions and methods for cancer immunotherapy

Info

Publication number: WO2020210670A1
Application number: PCT/US2020/027725
Authority: WO
Inventors: Paul C. Tumeh
Original assignee: Biograph 55, Inc.
Priority date: 2019-04-12
Filing date: 2020-04-10
Publication date: 2020-10-15

Abstract

Provided herein are analytical methods to be applied to samples, diagnostic methods, methods of determining a therapeutic regimens, and methods of treating cancer in a subject comprising compositions described herein.

Description

COMPOSITIONS AND METHODS FOR CANCER IMMUNOTHERAPY

CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 62/833,460, filed April 12^th, 2019, which is incorporated by reference herein in its entirety.

BACKGROUND

[0002] Cancer is a leading cause of death throughout the world. One approach to cancer treatment is cancer immunotherapy. Cancer immunotherapy involves the use of compositions and methods to elicit or enhance an individual's immune system against cancerous cells.

BRIEF SUMMARY

[0003] Disclosed herein are methods comprising administering to a subject, a therapeutically effective amount of a proliferation-inducing ligand (APRIL) inhibitor.

[0004] Disclosed herein are pharmaceutical compositions. In some embodiments, a pharmaceutical composition can comprise an APRIL inhibitor or a salt thereof; and a B-cell activating factor receptor (BAFF-R) inhibitor or a salt thereof. In some embodiments, a BAFF-R inhibitor or a salt thereof can comprise an antibody, single chain antibody molecule, or an active fragment thereof. In some embodiments, a BAFF-R inhibitor or a salt thereof can comprise an antibody or an active fragment thereof. In some embodiments, an antibody or an active fragment thereof can be a monoclonal antibody or an active fragment thereof or a polyclonal antibody or an active fragment thereof. In some

embodiments, an antibody or an active fragment thereof can be humanized. In some embodiments, an antibody or an active fragment thereof can be an IgG, IgE, IgM, IgD, IgA or IgY. In some embodiments, an antibody or an active fragment thereof can be a recombinant protein. In some embodiments, a BAFF-R inhibitor or a salt thereof can comprise a heavy chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NO: 29. In some embodiments, a BAFF-R inhibitor or a salt thereof can comprise a light chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NO: 30. In some embodiments, a BAFF-R inhibitor or a salt thereof can comprise a light chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 24-27; 84 or 85. In some embodiments, a BAFF-R inhibitor or a salt thereof can comprise a heavy chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 21-23 or 28. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a third antibody, third single chain antibody molecule, or an active fragment thereof. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a third antibody or an active fragment thereof. In some embodiments, a third antibody or an active fragment thereof can comprise a monoclonal antibody or an active fragment thereof or a polyclonal antibody or an active fragment thereof. In some embodiments, a third antibody or an active fragment thereof can be humanized. In some embodiments, a third antibody or an active fragment thereof can be an IgG, IgE, IgM, IgD, IgA or IgY. In some embodiments, a third antibody or an active fragment thereof can be a recombinant protein. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a heavy chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 217-224; 227-229 or 231. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a light chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: : 225-226; 230 or 22. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a light chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: SEQ ID NO: 179; 181; 185-187; or 195-206. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a heavy chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 178; 180; 182-184; 188-194; or 207-216. In some embodiments, an APRIL inhibitor or a salt thereof can be a biosimilar product to a reference product, wherein a reference product can comprise atacicept or a salt of any one thereof, and any combination thereof. In some embodiments, an APRIL inhibitor or a salt thereof, or a BAFF-R inhibitor or a salt thereof can be a bispecific antibody. In some embodiments, a pharmaceutical composition further can comprise a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition can be in unit dose form. In some embodiments, a composition further can comprise an addition agent. In some embodiments, an additional agent can comprise a BAFF inhibitor or a salt thereof. In some embodiments, a BAFF inhibitor or a salt thereof can comprise an antibody, single chain antibody molecule, or an active fragment thereof. Further comprised herein are methods of administering a pharmaceutical composition to a subject. In some embodiments, an APRIL inhibitor or a salt thereof and a BAFF-R inhibitor or a salt thereof can be administered concurrently. In some embodiments, an APRIL inhibitor or a salt thereof and a BAFF-R inhibitor or a salt thereof can be administered together in a single composition. In some embodiments, an APRIL inhibitor or a salt thereof and a BAFF-R inhibitor or a salt thereof can be administered sequentially. In some embodiments, an APRIL inhibitor or a salt thereof can be

administered first and a BAFF-R inhibitor or a salt thereof can be administered second. In some embodiments, a BAFF-R inhibitor or a salt thereof can be administered first and an APRIL inhibitor or a salt thereof can be administered second. In some embodiments a subject can have a cancer or can be suspected of having a cancer. In some embodiments a cancer can comprise leukemia, melanoma, prostate cancer, bladder cancer, osteosarcoma, cervical cancer, liver cancer, multiple myeloma, testicular, renal cancer or a combination thereof. In some embodiments a cancer was at least partially refractive to an administration. In some embodiments a subject was previously treated with a checkpoint inhibitor or a salt thereof, and a cancer was at least partially refractive to a checkpoint inhibitor or a salt thereof. In some embodiments, an administering can be intra-arterially, intravenously, intramuscularly, orally, subcutaneously, via inhalation, or any combination thereof. In some embodiments a method can comprise a method of treating a cancer. In some embodiments, prior to an administering, an expression level of APRIL can be assessed. In some embodiments, an expression level of APRIL can be compared to a reference. In some embodiments, an expression level of APRIL can be above a reference. In some embodiments, a reference can be derived from a non disease sample. In some embodiments, a reference can be derived from a disease sample. In some embodiments, a disease sample can be from a subject having a disease. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be in remission. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be progressing. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be stable. In some embodiments, a disease sample can comprise a cancer sample. Further disclosed are methods of making a pharmaceutical composition comprising: contacting an APRIL inhibitor or salt thereof of and a B-cell activating factor receptor (BAFF-R) inhibitor or a salt thereof. In some embodiments, a pharmaceutical composition described herein can be in a form of a tablet, a capsule, a gel, or a liquid formulation.

[0005] Disclosed herein are pharmaceutical compositions. In some embodiments, a pharmaceutical composition can comprise an APRIL inhibitor or a salt thereof; and a checkpoint inhibitor or a salt thereof. In some embodiments, a checkpoint inhibitor or a salt thereof can be a PD-1 inhibitor, PD-L1 inhibitor or PD-L2 inhibitor. In some embodiments, a checkpoint inhibitor or a salt thereof can comprise a second antibody, second single chain antibody molecule, or an active fragment thereof. In some embodiments, a checkpoint inhibitor or a salt thereof can comprise a second antibody or an active fragment thereof. In some embodiments, a second antibody or an active fragment thereof can be a monoclonal antibody or an active fragment thereof or a polyclonal antibody or an active fragment thereof. In some embodiments, a second antibody or an active fragment thereof can be humanized. In some embodiments, a second antibody or an active fragment thereof can be an IgG, IgE, IgM, IgD, IgA or IgY. In some embodiments, a second antibody or an active fragment thereof can be a recombinant protein. In some embodiments, a checkpoint inhibitor or a salt thereof can comprise a heavy chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 17; 19; 165; 167; 169; 171 or 173. In some embodiments, a checkpoint inhibitor or a salt thereof can comprise a light chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: : 18; 20; 166; 168; 170; 172 or 174. In some embodiments, a checkpoint inhibitor inhibits PD-1, PD-L1, PD-L2, CTLA-4, A2AR, B7- H3, B7-H4, BTLA, IDO, KIR, LAG3, TIM-3, VISTA, CD160, TIGIT or PSGL-1. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a third antibody, third single chain antibody molecule, or an active fragment thereof. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a third antibody or an active fragment thereof. In some embodiments, a third antibody or an active fragment thereof can comprise a monoclonal antibody or an active fragment thereof or a polyclonal antibody or an active fragment thereof. In some embodiments, a third antibody or an active fragment thereof can be humanized. In some embodiments, a third antibody or an active fragment thereof can be an IgG, IgE,

IgM, IgD, IgA or IgY. In some embodiments, a third antibody or an active fragment thereof can be a recombinant protein. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a heavy chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 217-224; 227-229 or 231. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a light chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: : 225-226; 230 or 22. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a light chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: SEQ ID NO: 179; 181; 185-187; or 195-206. In some embodiments, an APRIL inhibitor or a salt thereof can comprise a heavy chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 178; 180; 182-184; 188-194; or 207-216. In some embodiments, an APRIL inhibitor or a salt thereof can be a biosimilar product to a reference product, wherein a reference product can comprise atacicept or a salt of any one thereof, and any combination thereof. In some embodiments, an APRIL inhibitor or a salt thereof, or a checkpoint inhibitor or a salt thereof can be a bispecific antibody. In some embodiments, a pharmaceutical composition further can comprise a pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition can be in unit dose form. In some embodiments, a composition further can comprise an addition agent. In some embodiments, an additional agent can comprise a BAFF inhibitor or a salt thereof. In some embodiments, a BAFF inhibitor or a salt thereof can comprise an antibody, single chain antibody molecule, or an active fragment thereof. Further comprised herein are methods of administering a pharmaceutical composition to a subject. In some embodiments, an APRIL inhibitor or a salt thereof and a checkpoint inhibitor or a salt thereof are administered concurrently. In some embodiments, a salt thereof and a checkpoint inhibitor or a salt thereof are administered together in a single composition. In some embodiments, an APRIL inhibitor or a salt thereof and a checkpoint inhibitor or a salt thereof are administered sequentially. In some

embodiments, an APRIL inhibitor or a salt thereof can first be administered and a checkpoint inhibitor or a salt thereof can be administered second. In some embodiments, a checkpoint inhibitor or a salt thereof can first be administered and an APRIL inhibitor or a salt thereof can be administered second. In some embodiments a subject can have a cancer or can be suspected of having a cancer. In some embodiments a cancer can comprise leukemia, melanoma, prostate cancer, bladder cancer, osteosarcoma, cervical cancer, liver cancer, multiple myeloma, testicular, renal cancer or a combination thereof. In some embodiments a cancer was at least partially refractive to an administration. In some embodiments a subject was previously treated with a checkpoint inhibitor or a salt thereof, and a cancer was at least partially refractive to a checkpoint inhibitor or a salt thereof. In some embodiments, an administering can be intra arterially, intravenously, intramuscularly, orally, subcutaneously, via inhalation, or any combination thereof. In some embodiments a method can comprise a method of treating a cancer. In some

embodiments, prior to an administering, an expression level of APRIL can be assessed. In some embodiments, an expression level of APRIL can be compared to a reference. In some embodiments, an expression level of APRIL can be above a reference. In some embodiments, a reference can be derived from a non disease sample. In some embodiments, a reference can be derived from a disease sample. In some embodiments, a disease sample can be from a subject having a disease. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be in remission. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be progressing. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be stable. In some embodiments, a disease sample can comprise a cancer sample. Further disclosed are methods of making a pharmaceutical composition comprising: contacting an APRIL inhibitor or salt thereof of and a checkpoint inhibitor or a salt thereof. In some embodiments, a pharmaceutical composition described herein can be in a form of a tablet, a capsule, a gel, or a liquid formulation.

[0006] Disclosed herein are bispecific antibodies. In some embodiments, a bispecific antibody can comprise a first domain, wherein a first domain specifically binds APRIL or a portion thereof; and a second domain, wherein a second domain specifically binds PD1, PDL1 or BAFF-R. In some embodiments, a first domain can comprise a heavy chain variable region, light chain variable region, light chain or heavy chain of atacicept. In some embodiments, a first domain can comprise at least 80% or 90% sequence identity to any one of SEQ ID NOS: 178 - 232. In some embodiments, a second domain can comprise a heavy chain variable region, light chain variable region, light chain or heavy chain of nivolumab, docetaxel, pembrolizumab, pidilizumab, BGB-A31, MEDI0680, AMP -224, MEDI0680, PDR001, Cemiplimab or a combination thereof. In some embodiments, a second domain can comprise at least 80% or 90% sequence identity to any one of SEQ ID NOS: 17-20; 165-174; 21-30; 84 or 85. Further comprised herein are methods of administering a bispecific antibody to a subject. In some embodiments a subject can have a cancer or can be suspected of having a cancer. In some embodiments a cancer can comprise leukemia, melanoma, prostate cancer, bladder cancer, osteosarcoma, cervical cancer, liver cancer, multiple myeloma, testicular, renal cancer or a combination thereof. In some embodiments a cancer was at least partially refractive to an administration. In some embodiments a subject was previously treated with a checkpoint inhibitor or a salt thereof, and a cancer was at least partially refractive to a checkpoint inhibitor or a salt thereof. In some embodiments, an administering can be intra arterially, intravenously, intramuscularly, orally, subcutaneously, via inhalation, or any combination thereof. In some embodiments a method can comprise a method of treating a cancer. In some

embodiments, prior to an administering, an expression level of APRIL can be assessed. In some embodiments, an expression level of APRIL can be compared to a reference. In some embodiments, an expression level of APRIL can be above a reference. In some embodiments, a reference can be derived from a non disease sample. In some embodiments, a reference can be derived from a disease sample. In some embodiments, a disease sample can be from a subject having a disease. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be in remission. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be progressing. In some embodiments, a disease sample can be from a subject having a disease, wherein a disease can be stable. In some embodiments, a disease sample can comprise a cancer sample.

[0007] Disclosed herein are methods of administering to a subject, a single therapy or a combination therapy based on an expression of APRIL in a sample obtained from a subject. In some embodiments, a single therapy can be administered if an expression of APRIL is below a threshold. In some embodiments, a subject can be responsive to a single therapy. In some embodiments, a single therapy can comprise a BAFF inhibitor, BAFF-R inhibitor, checkpoint inhibiter or an APRIL inhibitor. In some embodiments, a combination therapy can be administered if an expression of APRIL is above a threshold. In some embodiments, a subject can be responsive to a combination therapy and nonresponsive to a single therapy. In some embodiments, a combination therapy can comprise two or more of a BAFF inhibitor, BAFF-R inhibitor, checkpoint inhibiter or an APRIL inhibitor.

[0008] Disclosed herein are methods comprising: detecting a level of APRIL in a sample obtained from a subject having cancer or suspected of having a cancer, wherein a detecting can be performed at least twice; and determining disease status based on a detecting. In some embodiments, APRIL expression can be below a reference level. In some embodiments, a disease status can be stable. In some embodiments, APRIL expression can be above a reference level. In some embodiments, a disease status can be progressive.

[0009] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure can comprise other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.

INCORPORATION BY REFERENCE

[0010] All publications, patents, patent applications, and NCBI accession numbers mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference, and as if set forth in their entireties. In the event of a conflict between a term as used herein and the term as defined in the incorporated reference, the definition of this disclosure controls.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also“figure” and“FIG.” herein), of which:

[0012] FIG. 1A-FIG.1Q show APRIL expression in anti-PD-1 treated melanoma patients before and during treatment. FIG. 1A - FIG. ID shows patient 1. FIG. IE - FIG. 1H shows patient 2. FIG. II - FIG. 1L shows patient 3. FIG. 1M - FIG. lO shows patient 4. FIG. IP - FIG. IQ shows patient 5.

[0013] FIG. 2A - FIG. 2D show APRIL expression intensity in anti-PD-1 treated melanoma patients before and during treatment. FIG. 2A shows patient 1. FIG. 2B shows patient 2. FIG. 2C shows patient 3. FIG. 2D shows patient 4. FIG. 2E shows patient 5. [0014] FIG. 3 depicts a graph showing APRIL expression intensity in anti -PD- 1 treated melanoma patients before and during treatment.

[0015] FIG. 4 shows a computer control system.

[0016] FIG. 5A - FIG. 5T show expression of APRIL (FIG. 5A, FIG. 5B, FIG. 5C, FIG. 5D, FIG. 5E), BAFF (FIG. 5F, FIG. 5G, FIG. 5H, FIG. 51, FIG. 5J), BCMA (FIG. 5K, FIG. 5L, FIG. 5M,

FIG. 5N, FIG. 50), and BCMA/BAFF-R/CD 138 (FIG. 5P, FIG. 5Q, FIG. 5R, FIG. 5S, FIG. 5T) expression in sample (T cell inflamed tumor) from a patient with type II resistance pre treatment and post treatment with anti -PD 1 and did not respond to treatment.

[0017] FIG. 6A - FIG. 6B show expression of APRIL+ cells innervated by CD 138+ cell at baseline (FIG. 6A) and BAFF-R+ tertiary follicle structures present 150 days into treatment with anti -PD 1 and did not respond to treatment (FIG. 6B) in sample (T cell inflamed tumor) from a patient with type II resistance.

[0018] FIG. 7 shows baseline BAFF and APRIL expression according to treatment outcome.

Baseline FFPE Melanoma samples from anti -PD- 1 -treated patients were stained by multiplex fluorescence immunohistochemistry for APRIL, BAFF, BAFFR, BCMA, CD 138, and IgA. The density of BAFF+ (FIG. 7A) or APRIL+ (FIG. 7B) expression was determined as the number of positively stained cells per area of tissue analyzed. The densities were plotted according to treatment outcome (Responders (N=13) or Progressors (N=28) (Type-I (N=13) or Type-II (N=15))).

[0019] FIG. 8 shows BAFF and APRIL covariate in metastatic melanoma. FFPE Melanoma samples (N=75) from anti-PD-1 -treated patients were stained by multiplex fluorescence immunohistochemistry for APRIL, BAFF, BAFFR, BCMA, CD 138, and IgA. The density of BAFF+ or APRTL+ expression was determined as the number of positively stained cells per area of tissue analyzed. FIG. 8A shows APRIL and BAFF densities plotted together on an XY Plot. A Spearman nonparametric correlation was determined using GraphPad Prism Software. FIG. 8B and FIG. 8E show representative staining of APRIL on metastatic melanoma tissue (DAPI staining of cell nuclei). FIG. 8C and FIG. 8E show representative staining of BAFF, and FIG. 8D and FIG. 8G show a combination image of APRIL and BAFF.

[0020] FIG. 9 A and FIG. 9B shows BAFF system signaling is associated with Type II Resistance. FFPE Melanoma samples (N=75) from anti-PD-1 -treated patients were stained by multiplex fluorescence immunohistochemistry for BAFF, IgA, and APRIL (FIG. 9A), and for BCMA, CD 138, and BAFFR (FIG. 9B). The density of cell (sub)population was determined as the number of positively stained cells per area of tissue analyzed. A heat map was generated to determine the relative abundance of each (sub)population according to treatment outcome.

[0021] FIG. 10 shows the relationship between APRIL expression and CD138+BCMA+ cell density. FFPE Melanoma samples (N=75) from anti-PD-1 -treated patients were stained by multiplex fluorescence immunohistochemistry for APRIL, BAFF, BAFFR, BCMA, CD 138, and IgA. The density of APRIL+ or CD138+BCMA+ expression was determined as the number of positively stained cells per area of tissue analyzed. APRIL and CD138+BCMA+ densities were plotted together on an XY Plot. A Spearman nonparametric correlation was determined using GraphPad Prism Software.

[0022] FIG. 11 shows the differences in gene signature between APRIL and a housekeeping gene. The relationship between APRIL expression and a housekeeping gene signature (39 genes) was examined by analyzing TCGA RNA-seq gene expression data in 11,574 cancer samples using Spearman’s Rho correlation. Numerical values are shown on a heatmap of Spearman’s Rank Correlation with p < 0.05.

[0023] FIG. 12 shows the differences in gene signature between APRIL and a T-cell inflamed gene signature. The relationship between APRIL expression and a T-cell inflamed gene signature (39 genes) was examined by analyzing TCGA RNA-seq gene expression data in 11,574 cancer samples using Spearman’s Rho correlation. Numerical values are shown on a heatmap of Spearman’s Rank Correlation with p < 0.05.

DETAILED DESCRIPTION

[0024] As used herein, the singular forms“a”,“an”, and“the” include plural references unless the context clearly dictates otherwise. Any reference to“or” herein may be intended to encompass“and/or” unless otherwise stated.

[0025] As used herein, the term“about” may mean the referenced numeric indication plus or minus 15% of that referenced numeric indication.

[0026] The term“fragment,” as used herein, may be a portion of a sequence, a subset that may be shorter than a full-length sequence. A fragment may be a portion of a gene. A fragment may be a portion of a peptide or protein. A fragment may be a portion of an amino acid sequence. A fragment may be a portion of an oligonucleotide sequence. A fragment may be less than about: 20, 30, 40, 50 amino acids in length. A fragment may be less than about: 20, 30, 40, 50 oligonucleotides in length.

[0027] The term“homology,” as used herein, may be to calculations of "homology" or“percent homology” between two or more nucleotide or amino acid sequences that can be determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first sequence). The nucleotides at corresponding positions may then be compared, and the percent identity between the two sequences may be a function of the number of identical positions shared by the sequences (i.e., % homology = (# of identical positions/total # of positions) x 100). For example, a position in the first sequence may be occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent homology between the two sequences may be a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. In some embodiments, the length of a sequence aligned for comparison purposes may be at least about: 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 95%, of the length of the reference sequence. A BLAST® search may determine homology between two sequences. The two sequences can be genes, nucleotides sequences, protein sequences, peptide sequences, amino acid sequences, or fragments thereof. The actual comparison of the two sequences can be accomplished by well-known methods, for example, using a mathematical algorithm. A non-limiting example of such a mathematical algorithm may be described in Karlin, S. and Altschul, S., Proc. Natl. Acad. Sci. USA, 90- 5873-5877 (1993). Such an algorithm may be incorporated into the NBLAST and XBLAST programs (version 2.0), as described in Altschul, S. et al., Nucleic Acids Res., 25:3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, any relevant parameters of the respective programs (e.g., NBLAST) can be used. For example, parameters for sequence comparison can be set at score= 100, word length= 12, or can be varied (e.g. , W=5 or W=20). Other examples include the algorithm of Myers and Miller, CABIOS (1989), ADVANCE, ADAM, BLAT, and FASTA. In another embodiment, the percent identity between two amino acid sequences can be accomplished using, for example, the GAP program in the GCG software package (Accelrys, Cambridge, UK). The term“length homology” can mean percent length identity between the length of a particular polypeptide and the length of another polypeptide.“Length homology” can in some instances be calculated by dividing the number of amino acids in a first peptide chain by the number of amino acids in a second peptide chain and multiplying the result by 100%. Chain amino acids can be those forming the backbone of the peptide.

[0028] The term "microenvironment," as used herein, may refer to the tumor microenvironment as a whole or to an individual subset of cells within the microenvironment. Exemplary cells within the tumor microenvironment may include but not limited to Tumor Infiltrating Lymphocytes (TILs), leukocytes, macrophages, and/or other cells of the immune system, and/or stromal cells, and/or fibroblasts (e.g., cancer or tumor associated fibroblasts).

[0029] The phrase“pharmaceutically acceptable” may be employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0030] The phrase“pharmaceutically acceptable excipient” or“pharmaceutically acceptable carrier” as used herein may refer to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Some examples of materials which may serve as pharmaceutically acceptable carriers may include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; or (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0031] In some embodiments, the term“prevent” or“preventing” as related to a disease or disorder may refer to a compound or composition that, in a statistical sample, may reduce the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or may delay the onset or may reduce the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0032] The terms“treat,”“treating” or“treatment,” as used herein, may include at least partially: alleviating, abating or ameliorating a disease or condition symptom; preventing an additional symptom; ameliorating or preventing the underlying causes of symptom; inhibiting the disease or condition, e.g., at least partially arresting the development of the disease or condition; relieving the disease or condition; causing regression of the disease or condition; relieving a condition caused by the disease or condition; or stopping a symptom of the disease or condition either prophylactically and/or therapeutically. Treatment may include stopping the growth of a cancer, shrinking the mass of a cancer, slowing the growth of a cancer shrinking the volume of a cancer, or prolonging the life span of a subject when compared to an otherwise substantially identical subject who may not be treated.

[0033] Included in the present disclosure may be salts, including pharmaceutically acceptable salts, of the compositions described herein. The compounds or compositions of the present disclosure that may possess a sufficiently acidic, a sufficiently basic, or both functional groups, may react with any of a number of inorganic bases, inorganic acids, or organic acids, to form a salt. Alternatively, compositions containing compounds that are inherently charged, such as those with quaternary nitrogen, may form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.

[0034] As used herein,“agent” or“biologically active agent” may refer to a biological,

pharmaceutical, or chemical compound or a salt of any of these. Non-limiting examples may include a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, antibody fragment, a vitamin derivative, a carbohydrate, a toxin, or a

chemotherapeutic compound. Various compounds may be synthesized, for example, small molecules and oligomers (e.g., oligopeptides and oligonucleotides), or synthetic organic compounds based on various core structures. In addition, various natural sources may provide compounds for screening, such as plant or animal extracts, and the like.

[0035] As used herein, an“immunotherapeutic agent” may refer to an agent that may be used on or used to modify an immune mechanism or immune response.

[0036] As used herein, a“pharmaceutical agent” may refer to an agent or a therapy that may be used to prevent, diagnose, treat, or cure a disease, or combinations thereof.

[0037] Activity of a protein, as used herein, may refer to a transcript level of mRNA transcribed from a gene that codes for said protein, expression level of said protein, nature of an expressed protein, such as folding, ability of said protein to interact with other proteins in a tumor microenvironment, and ability of said protein to interact with downstream or upstream signaling molecules in a signaling cascade of which said protein is a member.

[0038] The methods and compositions described herein can include the use of amorphous forms as well as crystalline forms or polymorphs. In some embodiments disclosed herein, compounds may be in a form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity may be included in the scope of the present disclosure. In addition, the compounds described herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein may also considered to be disclosed herein.

[0039] As used herein, a“biosimilar” or a“biosimilar product” may refer to a biological product that can be licensed based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from a reference product. Only minor differences in clinically inactive components may be allowable in biosimilar products. A“biosimilar” of an approved reference product/biological drug refers to a biologic product that is similar to a reference product based upon data derived from (a) analytical studies that demonstrate that a biological product is highly similar to a reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including an assessment of toxicity); and/or (c) a clinical study or studies (including an assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which a reference product can be licensed and intended to be used and for which licensure is sought for a biological product. In some embodiments, a biosimilar biological product and reference product can utilize a same mechanism or mechanisms of action for a condition or conditions of use prescribed, recommended, or suggested in a proposed labeling, but only to an extent a mechanism or mechanisms of action are known for a reference product. In some

embodiments, a condition or conditions of use prescribed, recommended, or suggested in a labeling proposed for a biological product have been previously approved for a reference product. In some embodiments, a route of administration, a dosage form, and/or a strength of a biological product can be the same as those of a reference product. In some embodiments, a facility in which a biological product can be manufactured, processed, packed, or held may meet standards designed to assure that a biological product continues to be safe, pure, and potent. In some embodiments, a reference product may be approved in at least one of the U.S., Europe, or Japan. In some embodiments, a response rate of human subjects administered a biosimilar product can be 50%-150% of a response rate of human subjects administered a reference product. For example, a response rate of human subjects administered a biosimilar product can be 50%-100%, 50%-l 10%, 50%-120%, 50%-130%, 50%-140%, 50%-150%, 60%-100%, 60%- 110%, 60%-120%, 60%-130%, 60%-140%, 60%-150%, 70%-100%, 70%-l 10%, 70%- 120%, 70%-130%, 70%-140%, 70%-150%, 80%-100%, 80%-l 10%, 80%-120%, 80%-130%, 80%- 140%, 80%-150%, 90%-100%, 90%-l 10%, 90%-120%, 90%-130%, 90%-140%, 90%-150%, 100%- 110%, 100%- 120%, 100%- 130%, 100%- 140%, 100%- 150%, 110%- 120%, 110%- 130%, 110%- 140%, 110%- 150%, 120%- 130%, 120%- 140%, 120%- 150%, 130%- 140%, 130%- 150%, or 140%- 150% of a response rate of human subjects administered a reference product. In some embodiments, a biosimilar product and a reference product can utilize a same mechanism or mechanisms of action for a condition or conditions of use prescribed, recommended, or suggested in a proposed labeling, but only to an extent a mechanism or mechanisms are known for a reference product.

[0040] A polypeptide disclosed herein may have one or more modifications, such as a post- translational modification (e.g., glycosylation, phosphorylation, etc.) or any other modification (e.g., pegylation, etc.). A polypeptide may contain one or more non-naturally-occurring amino acids (e.g., such as an amino acid with a side chain modification).

[0041] To obtain approval for biosimilar drugs, studies and data of structure, function, animal toxicity, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical safety and efficacy may be needed.

[0042] A biosimilar may also be known as a follow-on biologic or a subsequent entry biologic. In some embodiments, a biosimilar product may be highly similar to the reference product notwithstanding minor different in clinically inactive components.

[0043] In some embodiments, an expression construct for a proposed product may encode the same primary amino acid sequence as its reference product. Minor modifications may be present. Minor modifications may include N- or C-terminal truncations or alterations.

[0044] In some embodiments, a method described herein may comprise administering a therapeutically effective amount of an antibody or a fragment thereof.

[0045] As used herein, a“interchangeable biological product” may refer to biosimilar to an FDA- approved reference product and meets additional standards for interchangeability. In some embodiments, an interchangeable biological product can, for example, produce the same clinical result as a reference product in any given patient. In some embodiments, an interchangeable product may contain the same amount of the same active ingredients, may possess comparable pharmacokinetic properties, may have the same clinically significant characteristics, and may be administered in the same way as a reference compound. In some embodiments, an interchangeable product can be a biosimilar product that meets additional standards for interchangeability. In some embodiments, an interchangeable product can produce the same clinical result as a reference product in all of a reference product’s licensed conditions of use. In some embodiments, an interchangeable product can be substituted for a reference product by a pharmacist without the intervention of a health care provider who prescribed a reference product. In some embodiments, when administered more than once to an individual, a risk in terms of safety or diminished efficacy of alternating or switching between use of a biological product and a reference product can be no greater than a risk of using a reference product without such alternation or switch. In some embodiments, an interchangeable product can be a regulatory agency approved product. In some embodiments, a response rate of human subjects administered an interchangeable product can be 80%-120% of a response rate of human subjects administered a reference product. For example, a response rate of human subjects administered an interchangeable product can be 80%-100%, 80%-110%, 80%-120%, 90%-100%, 90%- 110%, 90%-120%, 100%-110%, 100%-120%, or 110%-120 of a response rate of human subjects administered a reference product.

[0046] In some embodiments, a method of the current disclosure can comprise administering a therapeutically effective amount of a diagnostic to a patient who has been administered an FDA approved diagnostic.

Methods

[0047] In some cases, disclosed herein are methods of detecting APRIL in a subject. In some embodiments, APRIL expression correlates with disease progression. In some embodiments, subjects that initially show a partial response to treatment developed an acquired resistance as APRIL expression increases increased. In some embodiments, an expression of APRIL in tumors or a tumor

microenvironment above control can indicate resistance to checkpoint inhibitor treatment, for example anti-PDl treatment and disease progression. In some embodiments, a detection of APRIL above a threshold in a tumor or tumor microenvironment can indicate resistance to a single therapy. In some embodiments, a detection of APRIL below a threshold in a tumor or tumor microenvironment can indicate a subject responsive to a single therapy. In some embodiments, disclosed herein can be a pharmaceutical composition comprising an APRIL inhibitor or a salt thereof; and a B-cell activating factor receptor (BAFF-R) inhibitor or a salt thereof. In some embodiments, disclosed herein can be a pharmaceutical composition comprising an APRIL inhibitor or a salt thereof; and a B-cell activating factor (BAFF) inhibitor or a salt thereof. In some embodiments, disclosed herein can be a pharmaceutical composition comprising: an APRIL inhibitor or a salt thereof; and a checkpoint inhibitor or a salt thereof.

[0048] In some embodiments, a tumor disclosed herein can be a“cold” tumor. In some

embodiments, a cold may not respond to single agent treatment. In some embodiments, a tumor disclosed herein can be a“hot” tumor. In some embodiments, a hot may comprise a high density of CD8 cells or CD138+ cells. In some embodiments, a hot tumor may be expected to respond to single agent therapy. In some embodiments, a hot tumor may have an increased level of BAFF and/or APRIL. In some embodiments, a hot tumor with an increased level of BAFF or APRIL may not respond to a single agent treatment. In some embodiments, following treatment with a single agent, a hot tumor may increase expression of BAFF and/or APRIL. In some embodiments, a hot tumor with an increased expression of BAFF and/or APRIL may respond to a combination treatment disclosed herein. In some embodiments, a tumor expressing an increased level of BAFF and /or APRIL responds to a treatment comprising APRIL inhibitor and/or BAFF inhibitor and/or BAFF-R inhibitor and a checkpoint inhibitor.

[0049] In some embodiments, an APRIL inhibitor may comprise an antibody, a small molecule, a protein, a peptide, an aptamer, an enzyme, or any combination thereof. In some embodiments, an APRIL inhibitor may comprise an antibody, an antigen binding fragment thereof, an APRIL binding domain, or any combination thereof. In some embodiments, an APRIL inhibitor can comprise a mouse antibody. In some embodiments, an APRIL inhibitor may comprise a rat antibody. In some embodiments, an APRIL inhibitor may comprise a human antibody. In some embodiments, an APRIL inhibitor may comprise a humanized antibody. In some embodiments, an APRIL inhibitor may comprise a light chain region, a heavy chain region, or a combination thereof. In some embodiments, an light chain region may comprise any one of CDR1, CDR2, CDR3, or any combination thereof. In some embodiments, an heavying chain may comprise any one of CDR1, CDR2, CDR3, or any combination thereof. In some embodiments, an APRIL inhibitor may comprise one or more antibody framework regions. In some embodiments, one or more of a framework region may be humanized.

[0050] In some embodiments, an APRIL inhibitor may have a sequence of SEQ ID NOS: 178-236, a fragment of any of these, a sequence having at least about: 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more sequence homology to any of these, or any combination thereof. (Table 1). In some embodiments, an APRIL inhibitor may be a biosimilar, wherein a biosimilar may be truncated and may have less than 100% length of a reference compound. In some embodiments, a biosimilar that comprises less than 100% length of a reference compound may still have a remaining sequence that can comprise at least about 90% or more sequence identity to a corresponding part of a reference sequence.

Table 1

[0051] In some embodiments, a method of the current disclosure may comprise administering a therapeutically effective amount of an immunotherapeutic agent or a salt thereof, wherein an

immunotherapeutic agent or a salt thereof may inhibit a biological cascade selected from a group consisting of: a B-cell activating factor receptor cascade, a transmembrane activator and calcium- modulator and cyclophilin ligand interactor receptor cascade, a B-cell maturation antigen receptor cascade, and any combination thereof; wherein an immunotherapeutic agent may be co-administered with a checkpoint inhibitor.

[0052] In some embodiments, a method of the current disclosure may comprise treating a subject in need thereof, comprising: administering a therapeutically effective amount of an immunotherapeutic agent or a salt thereof, wherein an immunotherapeutic agent or a salt thereof may inhibit a biological cascade selected from a group consisting of: a B-cell activating factor receptor cascade, a transmembrane activator, calcium-modulator, cyclophilin ligand interactor receptor cascade, a B-cell maturation antigen receptor cascade, and any combination thereof; and administering a checkpoint inhibitor. In some embodiments, an immunotherapeutic agent can comprise an APRIL inhibitor.

[0053] In some embodiments, a method of treatment of the current disclosure may result in at least partial remission of a cancer or a tumor. After administration of a composition described herein, progression of a cancer or a tumor may be delayed. Methods described herein may delay progression of a cancer or a tumor. After administration of a composition, a mass of a cancer or a tumor may be reduced, or a volume of a cancer or a tumor may be reduced. A method described herein may prolong a lifespan, an expected lifespan, or a life of a subject.

[0054] In one aspect, the present disclosure can provide a method of treating a subject in need thereof. In some embodiments, a method may comprise: administering a therapeutically effective amount of at least one APRIL inhibitor or B-cell activating factor (BAFF) inhibitor and/or at least one B-cell activating factor receptor (BAFF-R) inhibitor, or a salt thereof; and/or administering a therapeutically effective amount of at least one checkpoint inhibitor or a salt thereof. In some embodiments, a subject may have been diagnosed with a cancer or a tumor. In some embodiments, a method can comprise a method of treating a cancer or a tumor in a subject. In some embodiments, a subject may not have previously undergone treatment for a cancer or a tumor. In some embodiments, a subject may have previously or may be currently undergoing treatment for a cancer or a tumor. In some embodiments, a subject may have previously undergone treatment with surgery or radiation, and a subject may be in remission. In some embodiments, a subject may have previously undergone treatment with surgery, radiation, an anticancer agent, or any combination thereof, and a cancer or a tumor may have been at least partially refractive to a treatment. In some embodiments, a subject may have been previously treated with surgery, radiation therapy, an anticancer agent, and any combination thereof, and a cancer or a tumor may have re-occurred in a subject following a period of remission, wherein a period of remission may be at least about: 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0055] In some embodiments, a subject may have been previously treated with a checkpoint inhibitor or a salt thereof, and a cancer or a tumor may have been at least partially refractive to a checkpoint inhibitor or a salt thereof. In some embodiments, a subject may have been previously treated with a checkpoint inhibitor or a salt thereof, and a cancer or a tumor may have re-occurred in a subject following a period of remission, wherein a period of a remission may have been at least about: 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. In some embodiments, a checkpoint inhibitor or a salt thereof may be administered sequentially with a BAFF inhibitor or a salt thereof and/or BAFF-R inhibitor or a salt thereof and/or an APRIL inhibitor or a salt thereof. In some embodiments, a checkpoint inhibitor or a salt thereof may be administered concurrently with a BAFF inhibitor and/or APRIL inhibitor and/or BAFF-R inhibitor or a salt thereof. In some embodiments, a checkpoint inhibitor may be selected from an agent that binds to anti-programmed cell death protein 1 (PD-1), anti -programmed death ligand 1 (PD-L1), anti -programmed death ligand 2 (PD-L2), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), cluster of differentiation 276 (B7-H3), V-set domain-containing T-cell activation inhibitor 1 (B7-H4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG3), Indoleamine-pyrrole 2,3 -dioxygenase (IDO), a salt of any one thereof, and any combination thereof. In some embodiments, a composition disclosed herein can be administered with IL-6 or an antihistamine. In some embodiments, a

compositions disclosed herein can be administered with a third agent. In some embodiments, a third agent can be administered together with a composition disclosed herein, subsequently, or before a composition disclosed herein.

[0056] In some embodiments, a BAFF-inhibitor may comprise a sequence of any of SEQ ID Nos. 1- 16, 150-163, a fragment of any of SEQ ID Nos. 1-19, 150-163 or a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence homology to any of SEQ ID Nos. 1-19, 150-163. In some embodiments, a BAFF-R inhibitor may comprise a sequence of any of SEQ ID Nos. 21-30, 74-85, a fragment of any of SEQ ID Nos. 21-30, 84, 85, or a sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence homology to any of SEQ ID Nos. 21-30, 74-85. In some embodiments, a checkpoint inhibitor may comprise a sequence of any of SEQ ID NOs: 17-20, 165-174 (see Table 4B), a fragment of any of SEQ ID Nos: 17-20, 165-174 a sequence having at least about: 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence homology to a sequence of any of SEQ ID Nos: 17-20, 165-174 or any combination thereof. [0057] In some embodiments, a BAFF-R inhibitor can comprise VAY736. VAY736 can comprise a fully human combinatorial antibody library (HuCAL)-derived monoclonal antibody targeting BAFF-R. In some examples, a heavy chain CDR1 of VAY736 can comprise an amino acid sequence of

GDSVSSNSAAWG (SEQ ID NO: 74). In some embodiments, a heavy chain CDR2 of VAY736 can comprise an amino acid sequence of RIYYRSKWYNSYAVSVKS (SEQ ID NO: 75). In some embodiments, a heavy chain CDR3 of VAY736 can comprise an amino acid sequence of

YDWVPKIGVFD S (SEQ ID NO: 76). In some embodiments, a light chain CDR1 of VAY736 can comprise an amino acid sequence of RASQFISSSYLS (SEQ ID NO: 77). In some embodiments, a light chain CDR2 of VAY736 can have an amino acid sequence of LLIYGSSSRAT (SEQ ID NO: 78). In some embodiments, a light chain CDR3 of VAY736 can comprise an amino acid sequence of

QQLYSSPM (SEQ ID NO: 79). In some embodiments, a heavy chain variable region of VAY736 can comprise an amino acid sequence of:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYA V S VKSRITINPDTSKN QF SLQLN S VTPEDTA VYY CARYDWVPKIGVFD SW GQGTLVTV S S (SEQ ID NO: 80). In some embodiments, a light chain variable region of VAY736 can comprise an amino acid sequence of:

DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFSG SGSGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRT (SEQ ID NO: 81). In some embodiments, a heavy chain of VAY736 can comprise an amino acid sequence of:

QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWGWIRQSPGRGLEWLGRIYYRSKWYNSYA VSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARYDWVPKIGVFDWGQGTLVTVSSASTKGP SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV PSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMIS RTPEVTCVVVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVV S VLTVLHQDWLNG KEYKCKV SNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQV SLTCLVKGFYPSDIAVEW ESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GK (SEQ ID NO: 82). In some embodiments, a light chain variable region of VAY736 can have an amino acid sequence of:

DIVLTQSPATLSLSPGERATLSCRASQFISSSYLSWYQQKPGQAPRLLIYGSSSRATGVPARFSGSG SGTDFTLTISSLEPEDFAVYYCQQLYSSPMTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 83).

[0058] In some embodiments, a BAFF inhibitor can comprise an entire length or a fraction of any one of sequences SEQ ID Nos. 1-16 or 150-163. In some embodiments, a BAFF inhibitor, in some examples, can comprise a sequence that can be about 50% to about 99% homologous to an entire length of or a fraction of an entire length of any of SEQ ID Nos. 1-16 or 150-163. In some cases, a BAFF inhibitor can comprise a sequence that can be about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% homologous to an entire length of or a fraction of an entire length of any of SEQ ID Nos. 1-16 or 150-163.

[0059] A BAFF inhibitor may comprise an antibody, a small molecule, a protein, a peptide, an aptamer, an enzyme, or any combination thereof. In some embodiments, A BAFF inhibitor may comprise an antibody, an antigen binding fragment thereof, a BAFF binding domain, or any combination thereof. In some embodiments, a BAFF inhibitor may comprise a mouse antibody. In some embodiments, a BAFF inhibitor may comprise a rat antibody. In some embodiments, a BAFF inhibitor may comprise a human antibody. In some embodiments, a BAFF inhibitor may comprise a humanized antibody. In some embodiments, a BAFF inhibitor may comprise a light chain region, a heavy chain region, or a combination thereof. In some embodiments, a light chain region may comprise any one of CDR1, CDR2, CDR3, or any combination thereof. In some embodiments, a heavy chain may comprise any one of CDR1, CDR2, CDR3, or any combination thereof. In some embodiments, a BAFF inhibitor may comprise one or more antibody framework regions. In some embodiments, one or more framework regions may be humanized.

[0060] A BAFF inhibitor may comprise a sequence having at least about: 80%, 85%, 90%, 95%, or 99% sequence homology to a light chain CDR1, light chain CDR2, light chain CDR3, heavy chain CDR1, heavy chain CDR2, heavy chain CDR3, or any combination thereof of one of the following: tabalumab, atacicept, BAFF/IL-17 bispecific antibody, ardenermin, briobacept, blisibimod, or belimumab.

[0061] A BAFF inhibitor may comprise a sequence having at least about: 80%, 85%, 90%, 95%, or 99% sequence homology to at least a portion of a variable region of one of the following: tabalumab, atacicept, BAFF/IL-17 bispecific antibody, ardenermin, briobacept, blisibimod, or belimumab.

[0062] A BAFF inhibitor may comprise a sequence having at least about: 80%, 85%, 90%, 95%, or 99% sequence homology to at least a portion of an antibody binding domain of one of the following:

tabalumab, atacicept, BAFF/IL-17 bispecific antibody, ardenermin, briobacept, blisibimod, or belimumab.

[0063] A BAFF, BLyS, TALL-1, THANK, neutrokine-a, or zTNF inhibitor may comprise a light chain sequence, a heavy chain sequence, wherein a light chain can comprise CDR1, 2, and 3 and a heavy chain region can comprise CDR1, CDR2, CDR3. Exemplary heavy chain, light chain, and CDR sequences are provided in Table 2A. Table 2B further comprises sequences of anti-BAFF-R antibodies. Contemplated are sequences that have about 75%, 80%, 85%, 90%, 96%, 97%, 98%, 99%, or more homology to heavy chain, light chain, and CDR sequences of Table 2A or Table 2B.

[0064] Table 2A

[0065] In some embodiments, a sequence of a composition described herein may comprise at least about: 100% homology, 95% homology, 90% homology, 85% homology, 80% homology, 75% homology, 70% homology, 65% homology, 60% homology, 55% homology, 50% homology, to an entire length or a fraction of an entire length of a reference sequence, or a sequence listed in Table 2A or Table 2B.

[0066] Table 2B

[0067] In some embodiments, a BAFF or a BAFF-R inhibitor can comprise an aptamer comprising 100% homology, 95% homology, 90% homology, 85% homology, 80% homology, 75% homology, 70% homology, 65% homology, 60% homology, 55% homology, 50% homology, to an entire length or a fraction of an entire length of Aptamer 1 (SEQ ID NO: 175) 5'-GGG AGG ACG AUG CGG GAG GCU CAA CAA UGA UAG AGC CCG CAA UGU UGA UAG UUG UGC CCA GUC UGC AGA CGA CUC GCC CGA-3'; Aptamer 2 (SEQ ID NO: 176) 5'-GGG AGG ACG AUG CGG AUA ACU AUU GUG CUA GAG GGC UUA UUU AUG UGA GCC GGU UGA UAG UUG CGC AGA CGA CUC GCC CGA-3'; or Aptamer 3 (SEQ ID NO: 177) 5'-GGG AGG ACG AUG CGG AUC CUC CGA AGG UCG CGC CAA CGU CAC ACA UUA AGC UUU UGU UCG UCU GCA GAC GAC UCG CCC GA-3'.

[0068] In some cases, a BAFF-R protein can comprise an amino acid sequence substantially the same as described in Table 2C.

[0069] Table 2C

[0070] In some cases, a BAFF protein can comprise an amino acid sequence substantially the same as described in Table 3.

G0071Ί Table 3

_

[0072] In some embodiments, a BAFF protein described herein may comprise at least about: 100% identity, 95% identity, 90% identity, 85% identity, 80% identity, 75% identity, 70% identity, 65% identity, 60% identity, 55% identity, 50% identity, of a reference sequence, or a sequence listed in Table

3.

[0073] In some cases, a BAFF protein can be expressed from one or more coding regions from chromosome 13. In some cases, a BAFF protein can be expressed from one or more coding regions of a polynucleotide sequence of SEQ ID NO. 35 depicted in Table 4A.

[0074] Table 4A

[0075] In some embodiments, a checkpoint inhibitor may comprise an antibody, a small molecule, a protein, a peptide, an aptamer, an enzyme, or any combination thereof. A checkpoint inhibitor or a salt thereof may be a PD-1 inhibitor or a salt thereof. In some embodiments, a PD-1 inhibitor or a salt thereof may comprise nivolumab (Opdivo®, CAS number 946414-94-4), pembrolizumab (Keytruda ®, CAS number 1374853-91-4), pidilizumab (CT-011, CAS number 1036730-42-3), BGB-A31, MEDI0680 (AMP-514), AMP-224, PDR001 (Spartalizumab®, Cas number 1935694-88-4), Cemiplimab (Libtayo®, CAS number 1801342-60-8), a salt of any one thereof, or any combination thereof. The PD-1 inhibitor or a salt thereof may be selected from a group consisting of nivolumab (Opdivo®, CAS number 946414-94- 4), pembrolizumab (Keytruda ®, CAS number 1374853-91-4), pidilizumab (CT-011, CAS number 1036730-42-3), BGB-A31, MEDI0680 (AMP-514), a salt of any one thereof, and any combination thereof. In some embodiments, a PD-1 inhibitor may be nivolumab or a salt thereof. In some

embodiments, a PD-1 inhibitor may be pembrolizumab (Keytruda ®, CAS number 1374853-91-4) or a salt thereof. In some embodiments, a PD-1 inhibitor may be pidilizumab (CT-011, CAS number 1036730- 42-3) or a salt thereof. In some embodiments, a PD-1 inhibitor may be BGB-A31 or a salt thereof. In some embodiments, a PD-1 inhibitor may be MEDI0680 (AMP-514) or a salt thereof. In some embodiments, a PD-1 inhibitor can be an immunoadhesin ( e.g ., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, a PD-1 inhibitor can be AMP-224. In some embodiments, a PD-L1 inhibitor can be anti-PD-Ll antibody. In some embodiments, an anti-PD-Ll binding antagonist can be YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105. MDX-1105, also known as BMS-936559, can be an anti-PD-Ll antibody described in

US2009/0055944A1. Antibody YW243.55.S70 (heavy and light chain variable region sequences shown in SEQ ID Nos. 20 and 21, respectively) can be an anti-PD-Ll described in US 2010/0203056. [0076] MDX-1106, also known as MDX-1106-04, Nivolumab, ONO-4538 or BMS-936558,arean anti-PD-1 antibody described in US 2009/0217401. Merck 3745, also known as MK-3475 or SCH- 900475, Lambrolizumab, or Pembrolizumab, can be an anti-PD-1 antibody described in US

2011/0008369. Pidilizumab (CT-011; Cure Tech) can be a humanized IgGlk monoclonal antibody that binds to PD-1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in US 2011/0117085. In other embodiments, an anti-PD-1 antibody can be pembrolizumab. AMP-224 (B7- DCIg; Amplimmune; e.g., disclosed in US 2011/0223188 and US 2013/0017199), can be a PD-L2 Fc fusion soluble receptor that blocks an interaction between PD-1 and B7-H1. Other anti-PD-1 antibodies include AMP 514.

[0077] Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD- 1 are disclosed in US 8,008,449 and US 2009/0217401. Pembrolizumab or Lambrolizumab (also referred to as MK-3475; Merck) can be a humanized IgG4 monoclonal antibody that binds to PD-1.

Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in US 8,354,509 and US 2011/0008369.

[0001] MDPL3280A (Genentech / Roche) can be a human Fc optimized IgGl monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1 are disclosed in U.S. Patent No.: 7,943,743 and U.S Publication No.: 2012/0039906. Other anti-PD-L1 binding inhibitors can include YW243.55.S70 (described in US 2010/0203056) and MDX-1105 (also referred to as BMS- 936559, and, e.g, anti- PD-L1 binding agents disclosed in US 2009/0055944).

[0078] In some embodiments, a PD-1 or PD-L1 inhibitor may have a sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 165, SEQ ID NO: 166, SEQ ID NO:

167, SEQ ID NO: 168, SEQ ID NO: 169, SEQ ID NO: 170, SEQ ID NO: 171, SEQ ID NO: 172, SEQ ID NO: 173, SEQ ID NO: 174, a fragment of any of these, a sequence having at least about: 60%, 65%,

70%, 75%, 80%, 85%, 90%, 95%, 99% or more sequence homology to any of these, or any combination thereof. (Table 4B). In some embodiments, a PD-1 or PD-L1 inhibitor may be a biosimilar, wherein a biosimilar may be truncated and may have less than 100% length of a reference compound. In some embodiments, a biosimilar that comprises less than 100% length of a reference compound may still have a remaining sequence that is at least about 90% or more matching a corresponding part of an original reference sequence.

[0079] Table 4B

[0080] In some embodiments, a PD1 or PD-L1 inhibitor or a pharmaceutically acceptable salt thereof can comprise a structure, formula, analogs or derivatives of any one of structures 1-7.

Structure 1.

Structure 2.

Structure 3.

Structure 4.

Structure 5.

Structure 6.

Structure 7.

[0081] In some embodiments, a biosimilar may comprise less than 100% length, less than about 90% length, less than about 80% length, less than about 70% length, less than about 60% length, or less than about 50% length to a reference compound. In some embodiments, a biosimilar may comprise a sequence that can comprise at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or 100% identity to a corresponding part of an original reference sequence.

[0082] In some embodiments, a checkpoint inhibitor or a salt thereof may be a PD-L1 inhibitor or a salt thereof. In some embodiments, a PD-L1 inhibitor or a salt thereof may be selected from a group consisting of atezolizumab (Tecentriq®, CAS number 1380723-44-3), avelumab (Bavencio®, CAS number 1537032-82-8), durvalumab (Imfinzi®, CAS number 1428935-60-7), MDX-1105,

MSB0010718C, a salt of any one thereof, and any combination thereof. In some embodiments, a PD-L1 inhibitor may be atezolizumab (Tecentriq®, CAS number 1380723-44-3) or a salt thereof. In some embodiments, a PD-L1 inhibitor may be avelumab (Bavencio®, CAS number 1537032-82-8) or a salt thereof. In some embodiments, a PD-L1 inhibitor may be durvalumab (Imfinzi®, CAS number 1428935- 60-7) or a salt thereof. In some embodiments, a PD-L1 inhibitor may be MDX-1105 or a salt thereof. In some embodiments, a PD-L 1 inhibitor may be MSB0010718C or a salt thereof.

[0083] In some embodiments, the checkpoint inhibitor may be a CTLA4 inhibitor or a salt thereof.

In some embodiments, a CTLA4 inhibitor or a salt thereof may be selected from the group consisting of ipilimumab (Yervoy®, CAS number 477202-00-9), tremelimumab (ticilimumab, CAS number 745013- 59-6), AGEN1884, a salt of any one thereof, and any combination thereof. In some embodiments, a CTLA4 inhibitor may be ipilimumab (Yervoy®, CAS number 477202-00-9) or a salt thereof. In some embodiments, a CTLA4 inhibitor may be tremelimumab (ticilimumab, CAS number 745013-59-6) or a salt thereof. In some embodiments, a CTLA4 inhibitor may be AGEN 1884 or a salt thereof.

[0084] In some embodiments, a checkpoint inhibitor or a salt thereof may be a LAG3 inhibitor or a salt thereof. In some embodiments, a LAG3 inhibitor may be BMS-986016 or a salt thereof. In some embodiments, a checkpoint inhibitor or a salt thereof may be a TIM3 inhibitor or a salt thereof. In some embodiments, a TIM3 inhibitor or a salt thereof may be selected from the group consisting of MBG453, TSR-022, a salt of any one thereof, and any combination thereof. In some embodiments, a TIM3 inhibitor may be MBG453 or a salt thereof. In some embodiments, a TIM3 inhibitor may be TSR-022 or a salt thereof. [0085] Another aspect of the current disclosure provides a method of treating a subject in need thereof. In some embodiments, a method may comprise administering a therapeutically effective amount of at least one APRIL/BAFF and/or BAFF-R inhibitor or a salt thereof to the subject; and administering at least one immune agonist agent or a salt thereof to the subject. In some embodiments, an immune agonist agent or a salt thereof may be selected from a group consisting of an agent that binds to glucocorticoid- induced tumor necrosis factor receptor-related protein (GITR), cluster of differentiation 134 (0X40), cluster of differentiation 137 (CD137), cluster of differentiation 40 (CD40), Toll-like receptor (TLR), a salt of any one thereof, and any combination thereof.

[0086] In some embodiments, an immune agonist agent may be a GITR agonist or a salt thereof. In some embodiments, a GITR agonist or a salt thereof may be selected from the group consisting of an agent that binds to TRX518, GWN323, MEDI1873, INCAGN01876, a salt of any one thereof, and any combination thereof. In some embodiments, a GITR agonist may be TRX518 or a salt thereof. In some embodiments, a GITR agonist may be GWN323 or a salt thereof. In some embodiments, a GITR agonist may be MEDI1873 or a salt thereof. In some embodiments, a GITR agonist may be INCAGN01876 or a salt thereof.

[0087] In some embodiments, an immune agonist agent may be an 0X40 agonist or a salt thereof. In some embodiments, an 0X40 agonist may be selected from a group consisting of GSK3174998, PF- 04518600, MEDI6469, INCAGN01949, a salt of any one thereof, and any combination thereof. In some embodiments, a 0X40 agonist may be GSK3174998 or a salt thereof. In some embodiments, an 0X40 agonist may be PF-04518600 or a salt thereof. In some embodiments, an 0X40 agonist may be

MEDI6469 or a salt thereof. In some embodiments, an 0X40 agonist may be INCAGN01949 or a salt thereof.

[0088] In some embodiments, the immune agonist agent may be a cluster of differentiation 137 (4- 1BB) agonist or a salt thereof. In some embodiments, a 4- IBB agonist may be urelumab, utomilumab, or a salt of any one thereof. In some embodiments, a 4- IBB agonist may be isurelumab or a salt thereof. In some embodiments, a 4- IBB agonist may be isutomilumab or a salt thereof.

[0089] In some embodiments, an immune agonist agent may be a CD40 agonist or a salt thereof. In some embodiments, a CD40 agonist may be APX005M, CP870893, or a salt thereof. In some embodiments, a CD40 may be APX005M or a salt thereof. In some embodiments, a CD40 may be CP870893 or a salt thereof.

[0090] In some embodiments, an immune agonist agent may be a TLR agonist or a salt thereof. In some embodiments, a TLR agonist may be selected from a group consisting of an agent that binds to TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-13, a salt or any one thereof, and any combination thereof.

[0091] In some embodiments, an immune agonist agent may be a KIR agonist or a salt thereof. In some embodiments, a KIR agonist may be antibody 1-7F9, or a salt thereof. [0092] Yet another aspect of the current disclosure provides a method of treating a subject in need thereof. In some embodiments, a method may comprise: administering a therapeutically effective amount of at least one APRIL/BAFF and/or BAFF-R inhibitor or a salt thereof; and administering at least one vaccine agent or a salt thereof. In some embodiments, a vaccine agent may be selected from the group consisting of: MAGE-3, NY-ESO-1, TRAG-3, p53, at least one or more a-actinin-4 and malic enzymes, carcinoembryonic antigen, HER2, MUC1, survivin, WT-1, PRAME, Survivin-2b, Bacillus Calmette- Guerin, MV AX, at least one or more heat shock proteins, keyhole limpet hemocyanin, interleukin-2, QS21, montanide ISA-51, granulocyte monocyte-colony stimulating factor, GVAX, GI-4000, CDX-1307, IMA910, TroVAX, CRS-207, CA-9, a salt of any one thereof, and any combination thereof.

[0093] An aspect of the current disclosure provides a method of treating a subject in need thereof. In some embodiments, a method may comprise: administering a therapeutically effective amount of at least one APRIL inhibitor, BAFF inhibitor and/or BAFF-R inhibitor or a salt thereof; and administering at least one oncolytic viral based agent or a salt thereof. In some embodiments, a oncolytic viral based agent may be selected from the group consisting of: enadenotucirev, talimogene laherparepvec, reolysin, CG0070, Pexastimogene devacirepvec, cavatak, oncolytic vesicular stomatitis virus, ONCOS-102, a salt of any one thereof, and any combination thereof.

[0094] An aspect of the current disclosure provides a method of treating a subject in need thereof. In some embodiments, a method may comprise: administering a therapeutically effective amount of at least one APRIL inhibitor, BAFF inhibitor and/or BAFF-R inhibitor or a salt thereof; and administering at least one cell-based therapy, any cell derivative thereof, or a salt of any one thereof. In some embodiments, a cell-based therapy may be selected from at least one or more autologous lymphocytes; at least one or more genetically engineered autologous lymphocytes; at least one or more chimeric antigen receptor cells; at least one or more chimeric antigen receptor T-cells; at least one or more dendritic cell based vaccines; a salt of any one thereof; and any combination thereof.

[0095] Another aspect of the current disclosure provides a method of treating a subject in need thereof. In some embodiments, a method may comprise: administering a therapeutically effective amount of at least one APRIL inhibitor, BAFF inhibitor, or BAFF-R inhibitor or a salt thereof; and administering at least one chemotherapeutic agent or a salt thereof. In some embodiments, a chemotherapeutic agent may be an alkylating agent, an antimetabolite agent, a plant alkaloid agent, an antitumor antibiotic, a salt of any one thereof, and any combination thereof.

[0096] One aspect of the current disclosure provides for a method of treating a subject in need thereof. In some embodiments, a method may comprise: administering a therapeutically effective amount of at least one APRIL inhibitor, and/or BAFF-R inhibitor or a salt thereof; and administering at least one targeted therapeutic agent or a salt thereof. In some embodiments, a targeted therapeutic agent may be an agent that inhibits signal transduction, angiogenesis, hormone expression, or any combination thereof. In some embodiments, a BAFF inhibitor and/or BAFF-R inhibitor may prevent binding of BAFF or a BAFF-induced ligand to a BAFF-R; may be a partial antagonist of a BAFF; may be a partial agonist of a BAFF; may be a competitive antagonist of a BAFF-R; may be a non-competitive antagonist of a BAFF-R receptor; or any combination thereof. In some embodiments, a BAFF inhibitor may be an antibody, antigen binding fragment, a bispecific antibody, or a recombinant fusion protein.

[0097] In some embodiments, the BAFF inhibitor antibody may be human, humanized, chimeric, composite, polyclonal or monoclonal. In some embodiments, a BAFF antibody or antigen binding fragment may block interaction of molecules to BAFF. In some embodiments, a BAFF inhibitor may be selected from the group consisting of: tabalumab (CAS number 1143503-67-7), atacicept (CAS number 845264-92-8), RCT-18, BAFF/IL-17 bispecific antibody, ardenermin, briobacept, blisibimod (A-623, CAS number 1236126-45-6), belimumab (Benlystra®, CAS number 356547-88-1), a transmembrane activator and calcium-modulator and cyclophilin ligand interactorcept, a salt of any one thereof, and any combination thereof. In some embodiments, a BAFF inhibitor may be selected from a group consisting of: MEDI-700, NOV-5, rGel/BLyS, a salt of any one thereof, and any combination thereof. In some embodiments, a BAFF inhibitor may be tabalumab (CAS number 1143503-67-7) or a salt thereof. In some embodiments, a BAFF inhibitor may be blisibimod (A-623, CAS number 1236126-45-6) or a salt thereof. In some embodiments, a BAFF inhibitor may be belimumab (Benlystra®, CAS number 356547- 88-1) or a salt thereof. In some embodiments, a BAFF inhibitor may be atacicept (CAS number 845264- 92-8).

[0098] One aspect of the current disclosure provides a method of treating a subject in need thereof.

In some embodiments, a method may comprise: administering a therapeutically effective amount of an immunotherapeutic agent or a salt thereof, wherein an immunotherapeutic agent or a salt thereof may inhibit a biological cascade selected from a group consisting of: a B-cell activating factor receptor cascade, a transmembrane activator and calcium-modulator and cyclophilin ligand interactor receptor cascade, a B-cell maturation antigen receptor cascade, and any combination thereof; wherein an immunotherapeutic agent may be co-administered with a checkpoint inhibitor.

[0099] In some embodiments, a checkpoint inhibitor may be a salt. In some embodiments, a checkpoint inhibitor may be selected from a group consisting of: an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, a salt of any of these, and any combination thereof.

[0100] In some embodiments, vemurafenib (Zelboraf®, CAS number 918504-65-1) or erlotinib (Tarceva®, CAS number 183321-74-6) may be administered. In some embodiments, a method described herein may comprise administering an anti-programmed cell death protein 1 agent or a salt thereof. In some embodiments, an anti-programmed cell death protein 1 agent or a salt thereof may be selected from a group consisting of docetaxel (Taxotere®, CAS number 114977-28-5), nivolumab (Opdivo®, CAS number 946414-94-4), pembrolizumab (Keytruda ®, CAS number 1374853-91-4), a salt of any of these, and any combination thereof. In some embodiments, an agent or a salt thereof may be vemurafenib (Zelboraf®, CAS number 918504-65-1) or erlotinib (Tarceva®, CAS number 183321-74-6). In some embodiments, an anti-programmed cell death protein 1 agent or a salt thereof may be pembrolizumab (Keytruda ®, CAS number 1374853-91-4). In some embodiments, a method may comprise administering an anti-programmed death ligand 1 agent or a salt thereof.

[0101] In some embodiments, an anti-programmed death ligand 1 agent or a salt thereof may be selected from a group consisting of atezolizumab (Tecentriq®, CAS number 1380723-44-3), avelumab (Bavencio®, CAS number 1537032-82-8), durvalumab (Imfinzi®, CAS number 1428935-60-7), a salt of any of these, and any combination thereof. In some embodiments, an immunotherapeutic agent or a salt thereof at least partially may prevent binding of a ligand to a B-cell activating factor receptor; may be a partial antagonist of a B-cell activating factor receptor; may be a partial agonist of a B-cell activating factor receptor; may be a competitive antagonist of a B-cell activating factor receptor; may be a non competitive antagonist of a B-cell activating factor receptor; or any combination thereof. In some embodiments, an immunotherapeutic agent or a salt thereof at least partially may prevent ligand binding to a transmembrane activator and calcium -modulator and cyclophilin ligand interactor receptor; may be a partial antagonist of a transmembrane activator and calcium-modulator and cyclophilin ligand interactor receptor; may be a partial agonist of a transmembrane activator and calcium-modulator and cyclophilin ligand interactor receptor; or any combination thereof.

[0102] In some embodiments, an immunotherapeutic agent or a salt thereof at least partially may prevent ligand binding to a B-cell maturation antigen receptor; may be a partial antagonist of a B-cell maturation antigen receptor; may be a partial agonist of a B-cell maturation antigen receptor; or any combination thereof. In some embodiments, an immunotherapeutic agent may be an antibody or a salt thereof. In some embodiments, an immunotherapeutic agent may be a human or humanized monoclonal antibody or a salt thereof. In some embodiments, an immunotherapeutic agent or a salt thereof may be selected from a group consisting of ardenermin, briobacept, blisibimod (A-623, CAS number 1236126- 45-6), belimumab (Benlystra®, CAS number 356547-88-1), a transmembrane activator and calcium- modulator and cyclophilin ligand interactorcept, tabalumab (CAS number 1143503-67-7), atacicept, RCT-18, a salt of any of these, and any combination thereof.

[0103] In some embodiments, an immunotherapeutic agent or a salt thereof may be selected from a group consisting of MEDI-700, NOV-5, rGel/BLyS, a salt of any of these, and any combination thereof. In some embodiments, an immunotherapeutic agent may be tabalumab (CAS number 1143503-67-7) or a salt thereof. In some embodiments, a immunotherapeutic agent may be blisibimod (A-623, CAS number 1236126-45-6) or a salt thereof. In some embodiments, an immunotherapeutic agent may be belimumab (Benlystra®, CAS number 356547-88-1) or a salt thereof. In some embodiments, an immunotherapeutic agent may be atacicept (CAS number 845264-92-8) or a salt thereof.

[0104] In some embodiments, a method described herein may further comprise monitoring a treatment after an administering. In some embodiments, a treatment may maintain at least partial remission of a cancer or a tumor, wherein a period of remission may be at least about: 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years. In some embodiments, a treatment may comprise, after administering, delaying progression of a cancer or a tumor in a subject. In some embodiments, a treatment may comprise, after administering, regression of a cancer or a tumor.

[0105] In some embodiments, a regression may be a reduction in mass of a cancer or a tumor, a reduction in volume of a cancer or a tumor, or both. In some embodiments, a treatment may comprise prolonging a subject’s life. In some embodiments, a subject may have previously shown at least partial refraction to a monotherapy for a cancer or a tumor. In some embodiments, a subject may have shown refraction to a monotherapy for a cancer or a tumor. In some embodiments, a cancer may have metastasized from a first location of a subject to a second location of a subject. In some embodiments, a cancer at a first location of a body may be less than fully responsive to a monotherapy, and wherein a cancer at a second location of a body may be responsive to a treatment. In some embodiments, a checkpoint inhibitor and an immunotherapeutic agent may be synergistic. In some embodiments, a synergy on a cancer or a tumor may be at least about 10% more than an additive effect.

[0106] In some embodiments, an anti -programmed cell death protein 1 agent, an anti -programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt thereof or any combination thereof, and an immunotherapeutic agent or a salt thereof may be administered concurrently. In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt thereof or any combination thereof, and an immunotherapeutic agent or a salt thereof may be administered sequentially. In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti programmed death ligand 2 agent, or a salt thereof or any combination thereof, and an immunotherapeutic agent or a salt thereof may be administered in different formulations within a same treatment schedule.

[0107] In some embodiments, an anti -programmed cell death protein 1 agent, an anti -programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt thereof or any combination thereof, may be administered at least once a week. In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt thereof or any combination thereof, may be administered at least once a day. In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti programmed death ligand 2 agent, or a salt thereof or any combination thereof, may be administered at least once during a treatment schedule.

[0108] In some embodiments, an immunotherapeutic agent or a salt thereof may be administered at least once a week. In some embodiments, an immunotherapeutic agent or a salt thereof may be administered at least once a day. In some embodiments, an immunotherapeutic agent or a salt thereof may be administered at least once during a treatment schedule. In some embodiments, an immunotherapeutic agent or a salt thereof may be administered in an amount from about 0.1 mg to about 1,000 mg per kg body weight. In some embodiments, an immunotherapeutic agent or a salt thereof may be administered in an amount from about 0.1 mg to about 100 mg per kg body weight. In some embodiments, an immunotherapeutic agent or a salt thereof may be administered in an amount from about 1 mg to about 50 mg per kg body weight.

[0109] In some embodiments, an anti -programmed cell death protein 1 agent, an anti -programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, an APRIL inhibitor or a salt thereof or any combination thereof, may be administered in an amount from about 0.1 mg to about 1,000 mg per kg body weight. In some embodiments, an anti -programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt thereof or any combination thereof, may be administered in an amount from about 1 mg to about 100 mg per kg body weight. In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt of any one thereof, or any combination thereof, may be individually present as a pharmaceutical formulation. In some embodiments, a pharmaceutical formulation may be in unit dose form. In some embodiments, a pharmaceutical formulation may further comprise a pharmaceutically-acceptable excipient.

[0110] In some cases, a method may comprise treating a cancer, wherein a cancer may be prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, melanoma, multiple myeloma, Hodgkin’s lymphoma, ovarian cancer, or any combination thereof.

[0111] In one aspect, the present disclosure provides a method of selecting a therapeutic regimen. In some embodiments, a method may comprise: determining a level of APRIL expression in a sample and based on APRIL expression selecting a single therapy or a combination therapy. In one aspect, the present disclosure provides a method of deterring disease progression. In some embodiments, a method may comprise: determining a level of APRIL expression in a sample before and/or after a subject receive treatment for a cancer.

[0112] In some embodiments, a sample may be obtained from a human from peripheral blood, peripheral venous blood, peripheral arterial blood, peripheral whole blood monocytes, peripheral mononuclear cell enriched monocytes, red blood cell lysate of whole peripheral blood, serum, plasma, tears, hair, sputum, broncho alveoli, cerebrospinal fluid, pericardial fluid, pleural fluid, peritoneal fluid, synovial fluid, vaginal fluid, urethral fluid, pericarditis fluid, pleural effusion fluid, ascites fluid, saliva, sweat, tumor, lymph, lymphatic vessels, lymph node tissue, adenoid tissue, spleen, spleen cells, cancer tissue, or any combination thereof.

[0113] A sample may comprise cells that may be intact, cells that may be dissociated, extracellular products that may be cell-derived, or any combination thereof.

[0114] Extracellular products may be derived from cells that may be dissociated from cells and extracellular in form and may comprise nucleic acids, proteins, lipids, carbohydrates, nanovesicles, microvesicles, glycated end-products, enzymes, chemical products of metabolism, chemical by-products of metabolism, cations, and anions.

Diagnostic Methods [0115] In some embodiments, a method of the current disclosure may comprise selecting a therapeutic regimen. A method of selecting a therapeutic regimen may comprise: determining a presence or absence of APRIL in a cancer or a tumor of a subject or a cancer sample or a tumor sample of a subject; if APRIL expression is below a reference level, selecting a single therapeutic regimen comprising an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti programmed death ligand 2 agent, or a salt thereof or any combination thereof, and an immunotherapeutic agent or a salt thereof; if APRIL expression is above a reference level, selecting a combination therapeutic regimen comprising at least two of an anti-programmed cell death protein 1 agent, an anti programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, APRIL inhibitor, BAFF inhibitor, BAFF-R inhibitor or a salt thereof or any combination thereof. In some embodiments, a reference level can be an expression level of a marker in a sample from a subject not having a cancer. In some embodiments, a reference level can be an expression level of a marker in a sample from a subject who receives treatment and is stable or in remission.

[0116] The method may be a method of treatment, wherein a treatment may comprise: administering a therapeutically effective amount of an immunotherapeutic agent or a salt thereof, wherein an immunotherapeutic agent or a salt thereof inhibits a biological cascade selected from a group consisting of a B-cell activating factor receptor cascade, a transmembrane activator and calcium-modulator and cyclophilin ligand interactor receptor cascade, a B-cell maturation antigen receptor cascade, and any combination thereof; wherein an immunotherapeutic agent may be co-administered with a checkpoint inhibitor.

[0117] The presence of APRIL may be determined by staining, imaging after staining, microscopy, or any combination thereof. In some embodiments, a staining may comprise binding of an antibody to a protein. In some embodiments, a staining may further comprise binding of a second antibody to a first antibody, wherein a second antibody may contain a fluorescence marker. In some embodiments, a presence, absence, or level of APRIL may be determined by: immunoassays, polymerase chain reaction, sequencing, including next generation sequencing, flow cytometry, or any combination thereof. Assay reagents may include: antibody-based reagents, primary antibody+ secondary antibody, detectable label: enzymatic, chromogenic -based, detectable label: enzymatic, fluorescent-based, primary

antibody+oligonucleotide, detectable label: complementary hybridization + PCR amplification, detectable label: complementary hybridization without PCR amplification, RNA-based, DNA-based reagents, or any combination thereof.

[0118] One embodiment provides a diagnostic method wherein a subject can be identified as resistant to an immunotherapy comprising a single agent, such as an immune checkpoint protein inhibitor, by determining expression levels of one or more genes that code for APRIL. One embodiment provides a diagnostic method wherein a subject can be identified as resistant or responsive to an immunotherapy comprising a single agent, such as an immune checkpoint protein inhibitor, by determining expression levels of a gene that code for APRIL, or a variant thereof. In some embodiments, a diagnostic method can be provided wherein a subject can be identified as responsive to a combination therapy comprising an agent that regulates activity of APRIL, BAFF protein or a BAFF receptor, such as APRIL inhibitor, a BAFF inhibitor, a BAFF-receptor (BAFF-R) inhibitor, or a salt thereof, or any combination thereof. In some embodiments, a monitoring method can be provided wherein a subject may be identified as a suitable candidate for continuing treatment with an immunotherapy comprising a single agent or with a combination therapy comprising an immunotherapy and an agent that regulates activity of an APRIL protein, a BAFF protein or a BAFF-receptor protein. In some embodiments, a method described herein can be repeated multiple times to monitor a subject.

[0119] The above mentioned expression levels can be in some instances determined in a biological sample isolated from said patient. In some embodiments, a biological sample, may be from a tumor microenvironment of a subject.

[0120] The expression levels can be determined using any sequencing based techniques, including but not limited to RNA-seq, methods that utilize bisulfite conversion (such as MethylC-seq8 and Reduced Representation Bisulfite Sequencing, or RRBS9), methods that utilize enrichment of methylated DNA (Methylated DNA Immunoprecipitation sequencing, or MeDIP-seqlO, 11 and Methylated DNA Binding Domain sequencing, or MBD-seql2), qPCR can be performed using a Fluidigm Biomark system, serial analysis gene expression technology, targeted RNA sequencing, mRNA sequencing, total RNA-seq. Any other appropriate method can be used to determine expression levels, such as, for example,

immunohistochemistry, immunofluorescence, multiplexed ion beam imaging based methods. MIBI can be a mass spectrometry based imaging platform wherein secondary ion mass spectrometry can be used to image antibodies tagged with isotopically pure elemental metal reporters, instead of antibodies tagged with fluorophores or enzyme reporters that generate colored pigments.

Pharmaceutical Compositions

[0121] Provided herein, in some embodiments, may be compositions comprising a therapeutically effective amount of an immunotherapeutic agent and a checkpoint inhibitor.

[0122] In some embodiments, an inhibitor may refer to an agent or a therapy that may be an agonist, an antagonist, a partial agonist, a partial antagonist, or any combination thereof.

[0123] In some embodiments, an immunotherapeutic agent or a salt thereof may inhibit a biological cascade selected from a group consisting of: a B-cell activating factor receptor cascade, a transmembrane activator and calcium-modulator and cyclophilin ligand interactor receptor cascade, a B-cell maturation antigen receptor cascade, and any combination thereof.

[0124] A checkpoint inhibitor may be an anti-programmed cell death protein 1 agent, an anti programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, a salt of any of these, and any combination thereof.

[0125] An anti-programmed cell death protein 1 (PD-1) agent may be an agent that inhibits or at least partially inhibits the binding of a PD-1 cell surface receptor to a ligand, wherein a ligand may be anti -programmed death ligand 1 (PD-L1) or anti -programmed death ligand 2 (PD-L2). In some embodiments, , inhibition of a binding of a PD-1 receptor to a ligand may activate an immune response.

[0126] An immunotherapeutic agent may be an agent that at least partially blocks a B-cell activating factor (BAFF) receptor cascade.

[0127] In some embodiments, an immunotherapeutic agent or salt thereof may inhibit a B-cell activating factor receptor (BAFF) cascade, a transmembrane activator and calcium-modulator and cyclophilin ligand interactor receptor (TACI) cascade, a B-cell maturation antigen receptor (BCMA) cascade, APRIL or any combination thereof. In some embodiments, an immunotherapeutic agent can be an APRIL inhibitor.

[0128] An immunotherapeutic agent may be a small molecule, an antibody, a partial antibody, or any combination thereof. An immunotherapeutic agent may be an antibody or a salt thereof. In some embodiments, an immunotherapeutic agent may be a human antibody, a humanized monoclonal antibody, or a salt thereof.

[0129] In some embodiments, an immunotherapeutic agent or a salt thereof can be Bion-1301, APRIL/TNFSF13 antibody, ardenermin, briobacept, blisibimod (A-623, CAS number 1236126-45-6), belimumab (Benlystra®, CAS number 356547-88-1), a transmembrane activator and calcium-modulator and cyclophilin ligand interactorcept, MEDI-0700, NOV-5, rGel/BLyS, tabalumab (CAS number 1143503-67-7), atacicept (CAS number 845264-92-8), RCT-18, a salt of any of these, and any combination thereof. An immunotherapeutic agent or a salt thereof may be selected from a group consisting of: MEDI-700, NOV-5, rGel/BLyS, a salt of any of these, and any combination thereof. In some embodiments, an immunotherapeutic agent may be tabalumab (CAS number 1143503-67-7) or a salt thereof. In some embodiments, an immunotherapeutic agent may be LY_2127399 or a salt thereof. In some embodiments, an immunotherapeutic agent may be atacicept (CAS number 845264-92-8) or a salt thereof. In some embodiments, an immunotherapeutic agent may be blisibimod (A-623, CAS number 1236126-45-6) or a salt thereof. In some embodiments, an immunotherapeutic agent may be belimumab (Benlystra®, CAS number 356547-88-1) or a salt thereof. A BAFF/BAFF-R inhibitor may be combined with avelumab (Bavencio®, CAS number 1537032-82-8). A BAFF/BAFF-R inhibitor may be combined with pembrolizumab (Keytruda ®, CAS number 1374853-91-4).

[0130] In some embodiments, a PD-L1 inhibitor may be avelumab (Bavencio®, CAS number 1537032-82-8). In some embodiments, a PD-L1 inhibitor may be Bavencio. In some embodiments, a PD- L1 inhibitor may be atezoluzumab. In some embodiments, a PD-L1 inhibitor may be tecentriq. In some embodiments, a PD-1 inhibitor may be pembrolizumab (Keytruda ®, CAS number 1374853-91-4). In some embodiments, a PD-1 inhibitor may be keytruda. In some embodiments, a PD-1 inhibitor may be MK 3475. In some embodiments, a PD-1 inhibitor may be lambrolizumab. In some embodiments, a PD- 1 inhibitor may be nivolumab (Opdivo®, CAS number 946414-94-4). In some embodiments, a PD-1 inhibitor may be opdivo. In some embodiments, a PD-1 inhibitor may be 0N0 4538. In some embodiments, a PD-1 inhibitor may be BMS 936558. In some embodiments, a PD-1 inhibitor may be MDX_1106.

[0131] An immunotherapeutic agent may be an antibody. An immunotherapeutic agent may be a human monoclonal antibody. An immunotherapeutic agent may be a humanized monoclonal antibody, chimeric antibody, a fully human antibody, or an isolated or purified version of any of the above. An immunotherapeutic agent may be a checkpoint inhibitor, an immune agonist, a vaccine, a virus, or a T- cell .

[0132] Compositions may comprise a therapeutically effective amount of a pharmaceutical agent and an immunotherapeutic agent. Compositions may comprise a therapeutically effective amount of a pharmaceutical agent and an immunotherapeutic agent, wherein an immunotherapeutic agent may be tabalumab (CAS number 1143503-67-7) or a fragment or a salt thereof.

[0133] Compositions may comprise a therapeutically effective amount of a pharmaceutical agent and an immunotherapeutic agent, wherein an immunotherapeutic agent may be briobacept, rGel/BLyS, BLyS radiolabeled, Xencor, NOV-5, ardenermin, anti-BR3, blisibimod (A-623, CAS number 1236126-45-6), belimumab (Benlystra®, CAS number 356547-88-1), IL- 17-bispecific antibody, anti-BLyS/APRIL antibody fusion protein, or a fragment or a salt thereof.

[0134] Compositions may comprise a therapeutically effective amount of a pharmaceutical agent and an immunotherapeutic agent, wherein an immunotherapeutic agent may be florbetapir, solanezumab, scyllo-inositol, gantenerumab, flutafuranol FI 8, cromolyn sodium + ibuprofen, AZTherapies, crenezumab, CAD-106, aducanumab, UB-311, GSK-933776A, BAN-2401, ACI-24, VM-100, SAR- 228810, NGP-555, MRZ-99030, MEDI-1814, LY-3002813, Lu-AF-20513, HSRx 888 + donepezil hydrochloride, Exebryl-1, bisnorcymserine, anti -amyloid beta antibody, Kyowa Hakko Kirin, ALZ-801, Affitope AD-03, AAB-003, (+)-phenserine, TRV-101, RV-03, P-8, NPT440-1, MRK-560, KAL-ABP, IN-NO 1-OX2, IN-N01, CB-301, C12, Pharma Bio, CT-01344, BAN-2502, AZP-2006, anti-beta amyloid, Aerie, anti-amyloid beta programme, anti-amyloid beta antibody-2, anti-amyloid beta antibody, ALZT- Patch, ALZ-201, AGT-160, ADx, ACU-193, ACI-812, ACI-260, ZT-331, ACC-001, tramiprosate, SIB- 1281, ponezumab, PF-4382923, GT3001, GT2501, GT2342, bapineuzumab, AN-1792, ACU-244, V-950, U-101033E, CHF-5022, SeV-2-0401, SEN-1576, SEN-1500, SEN-1269, SEN-1176, RV-02, RV-01, RS- 0406, PX-106, PTI-L07665, PTI-48579, PTI-3001, PTI-2001, PTI-00703, protease nexin-1, SIBIA, phenserine(-)-eseroline phenylcarbamate(-)-phenserine, Pharmaprojects No. 5550, Pharmaprojects No. 4246, DP-74, NU-700, NP-0361, , MPI-442690, MPI-423948MPI-127585, MK-3328, MER-5101, KMS- 88009KMS-88016, INM-176, ESBA-212, EDN-OL1, DP-68, DLX-212, DBT-1339, Cymserine, Nl- phenethylnorcymserine, CLR-01, CaprospinolSP-233, BAN-2203AD-2203, AZD-2995, AZD-2184, ARC-031, amyloid inhibiting peptides, amyloid beta modulator, AMDL receptor antagonist, ALZT-OP2, SPI-008SPI-0090, SPI-019, AGT-3100, AGT-100, Affitope AD-02, Affitope AD-01, ACU-CD0061, ACU-5A5, ACU-347, ACU-193, ABP-102, DRM-106, or a fragment or a salt of any of these. [0135] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries that may facilitate processing of a pharmaceutical composition into preparations that may be used pharmaceutically. Proper formulation may be dependent upon a route of administration chosen. A summary of pharmaceutical compositions may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0136] In some embodiments, compositions and methods of the present disclosure can be utilized to treat an individual in need thereof. In some embodiments, an individual may be a mammal such as a human, or a non-human mammal. In some embodiments, a subject may be a human. In some

embodiments, a human may be an adult male, an adult female, a female child, or a male child. In some embodiments, when administered to an animal, such as a human, a composition or a pharmaceutical composition, may be administered as a pharmaceutical composition comprising, for example, a therapeutically effective amount of an anti-programmed cell death protein 1 agent and an

immunotherapeutic agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers may include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In an embodiment, when such pharmaceutical compositions may be for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, an aqueous solution may be pyrogen-free, or substantially pyrogen-free. In some embodiments, excipients may be chosen, for example, to affect delayed release of an agent or to selectively target one or more cells, tissues or organs. In some embodiments, a pharmaceutical composition may be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. In some embodiments, a composition may also be present in a transdermal delivery system, e.g., a skin patch. In some embodiments, a composition may also be present in a solution suitable for topical administration, such as an eye drop.

[0137] A pharmaceutically acceptable excipient may contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase an absorption of a composition such as a therapeutically effective amount of an anti-programmed cell death protein 1 agent and an

immunotherapeutic agent. Such physiologically acceptable agents can include, for example,

carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. In some embodiments, a choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, may depend, for example, on a route of administration of a composition. In some embodiments, a preparation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-micro emulsifying drug delivery system. In some embodiments, a pharmaceutical composition (preparation) also may be a liposome or other polymer matrix, which may have incorporated therein, for example, a therapeutically effective amount of an anti-programmed cell death protein 1 agent and an

immunotherapeutic agent. Liposomes, for example, which may comprise phospholipids or other lipids, may be nontoxic, physiologically acceptable and metabolizable carriers that may be relatively simple to make and administer.

[0138] In some embodiments, an immunotherapeutic agent or a salt thereof may be administered in a pharmaceutical composition.

[0139] In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt of any one thereof, or any combination thereof, and an immunotherapeutic agent or a salt thereof may be independently

administered in an amount from about 0.1 mg to about 10 g. In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt of any one thereof, or any combination thereof, and an immunotherapeutic agent or a salt thereof may be independently from about 0.001% to about 99% by weight of a composition. In some embodiments, an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti-programmed death ligand 2 agent, or a salt of any one thereof, or any combination thereof, and an immunotherapeutic agent or a salt thereof may be independently administered in an amount of from about 0.1 mg to about 100 mg per kg body weight.

[0140] In some embodiments, a composition may be in a form of a tablet, a capsule, a gel, or a liquid formulation.

[0141] In some embodiments, a pharmaceutical composition disclosed herein can comprise a nucleic acid coding for a protein. In some embodiments, a protein can comprise a pharmaceutical composition. In some embodiments, a nucleic acid can code for any pharmaceutical composition as disclosed herein. In some embodiments a nucleic acid can code for an antibody. In some embodiments a nucleic acid can code for multiple antibodies. In some embodiments, a nucleic acid can code for an antibody as disclosed herein. In some embodiments, a nucleic acid can code for a combination of antibodies as disclosed herein. In some embodiments, a nucleic acid can comprise part of a vector. In some embodiments, a vector can be used for delivery of a nucleic acid to a subject. In some embodiments, a vector can comprise a plasmid, a virus, a nanoparticle, a cell, a T-cell, or any combination thereof. In some embodiments, transfection of a cell with a vector can transform a cell to produce a protein. In some embodiments, a cell can produce a pharmaceutical composition as described herein. In some embodiments, a cell can produce an antibody as described herein. In some embodiments, a cell can produce a combination of antibodies as described herein.

[0142] The term“vector” as used herein can refer to a polynucleotide that is used to deliver a nucleic acid to the inside of a cell. In some embodiments, a vector can be an expression vector comprising expression control sequences (for example, a promoter) operatively linked to a nucleic acid to be expressed in a cell. Vectors known in the art include, but are not limited to, plasmids, phages, cosmids and viruses.

[0143] In some embodiments, disclosed herein, in certain embodiments, are polypeptides encoded by the nucleic acid sequence as disclosed herein. In some embodiments, also disclosed herein, can be vectors comprising the nucleic acid sequence as disclosed herein. In some embodiments, the vectors can further comprise a promoter. In some embodiments, the promoter can be functional in a mammalian cell. In some embodiments, promoters, regions of DNA that initiate transcription of a particular nucleic acid sequence, can be well known in the art.

[0144] In some embodiments, the vector can be designed for expression in mammalian cells such as T cells. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector.

[0145] In some embodiments, vectors that can be useful can comprise vectors derived from lentiviruses, Murine Stem Cell Viruses (MSCV), pox viruses, oncoretro viruses, adenoviruses, and adeno- associated viruses. Other delivery vectors that are useful comprise vectors derived from herpes simplex viruses, transposons, vaccinia viruses, human papilloma virus, Simian immunodeficiency viruses, HTLV, human foamy virus and variants thereof. Further vectors that are useful comprise vectors derived from spumaviruses, mammalian type B retroviruses, mammalian type C retroviruses, avian type C retroviruses, mammalian type D retroviruses and HTLV/BLV type retroviruses.

[0146] In some embodiments, a nucleic acid can be a recombinant, or engineered, nucleic acid. In some embodiments, a polynucleotides described herein can be modified or mutated to optimize the function of the encoded polypeptide and/or the function, activity and/or expression. In some

embodiments, the nucleic acid encodes a polypeptide described herein. In some embodiments, modifications can be made to the polynucleotide sequences including vector sequences and polypeptides sequences disclosed herein. Modifications can include substitution, insertion or deletion of nucleotides or amino acids or altering the relative positions or order of nucleotides or amino acids.

[0147] Further disclosed herein are kits. In one aspect, the present disclosure provides a method of making a kit disclosed herein. In some embodiments, a method may comprise contacting or combining an anti-programmed cell death protein 1 agent, an anti-programmed death ligand 1 agent, an anti programmed death ligand 2 agent, or a salt of any one thereof, or any combination thereof, and an immunotherapeutic agent or a salt thereof. In some embodiments, a composition may be in a form of a tablet, a capsule, a gel, or a liquid formulation.

Routes of Administration

[0148] A pharmaceutical composition may be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecal as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermal, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, as an eye drop, or any combination thereof. In some embodiments, a pharmaceutical composition may also be formulated for inhalation. A composition may be administered directly to a cancer or a tumor. Administration of a composition may be to a different location of a body than where a cancer or tumor may be detected or present.

[0149] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. In some embodiments, a excipients described herein may be examples and are in no way limiting. An effective amount or therapeutically effective amount may refer to an amount of one or more pharmaceutical compositions administered to a subject, either as a single dose or as part of a series of doses, which can be effective to produce a desired therapeutic effect.

[0150] Subjects can generally be monitored for therapeutic effectiveness using assays and diagnostic methods suitable for a condition being treated. Pharmacokinetics of a composition administered to a subject may be monitored by determining a level of a pharmaceutical composition or metabolite in a biological fluid. In some embodiments a biological fluid can comprise blood, a blood fraction, serum, urine, cell-free nucleic acids or another biological sample or biological tissue from a subject.

[0151] The dose of a therapeutically effective amount of a composition described herein for treating a cancer may depend upon a subject’s condition, that is, stage of a disease, severity of symptoms caused by a disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. A subject may have been previously diagnosed with a cancer or a tumor. A subject may have previously undergone treatment for a cancer or a tumor. A subject may be currently undergoing treatment for a cancer or a tumor. In some embodiments, a current treatment of a subject may be less than therapeutically effective. In some embodiments, a subject may have been previously treated with a checkpoint inhibitor, and a cancer or a tumor may have been at least partially refractive. In some embodiments, a cancer or tumor may be considered partially refractive if a mass or volume of a cancer or tumor continues to grow at a constant rate, or if a mass or volume of a cancer or tumor may not substantially change or decrease.

[0152] Pharmaceutical compositions may be administered in a manner appropriate to a disease to be treated as determined by persons skilled in the medical arts. In addition to factors described herein and above related to use of pharmaceutical composition for treating a cancer, suitable duration and frequency of administration of a pharmaceutical composition may also be determined or adjusted by such factors such as a condition of a subject, a type and severity of a subject’s disease, a particular form of an active ingredient, and a method of administration. Optimal doses of an agent may generally be determined using experimental models and/or clinical trials. In some embodiments, an optimal dose may depend upon a body mass, weight, or blood volume of a subject. Design and execution of pre-clinical and clinical studies for a pharmaceutical composition, including when administered for prophylactic benefit, described herein may be within the skill of a person skilled in the relevant art.

[0153] When two or more pharmaceutical compositions may be administered to treat a cancer, an optimal dose of each pharmaceutical composition may be different, such as less than when either agent may be administered alone as a single agent therapy. Two pharmaceutical compositions in combination may act synergistically, and either agent may be used in a lesser amount than if administered alone. Administration of a checkpoint inhibitor and an immunotherapeutic agent may act synergistically or more than additive ly, when compared to either agent administered alone. A composition comprising a checkpoint inhibitor and an immunotherapeutic agent may produce a more than additive effect on a tumor or a cancer. In some embodiments, a synergy of a combination of the current disclosure may be at least about: 1%, 2%, 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater than the additive effect.

[0154] In some embodiments, a composition of the disclosure comprising an anti -programmed cell death protein 1 agent and an immunotherapeutic agent may be more effective as compared to a corresponding additive effect of an anti-programmed cell death protein 1 agent and an immunotherapeutic agent. A composition of a disclosure may be at least about: 15% more effective, 20% more effective, 25% more effective, 30% more effective, 35% more effective, 40% more effective, 45% more effective, 50% more effective, 55% more effective, 60% more effective, 65% more effective, 70% more effective, 75% more effective, 80% more effective, 85% more effective, 95% more effective, or 100% more effective than an effect of a monotherapy comprising an anti-programmed cell death protein 1 agent, and/or an effect of a monotherapy comprising an immunotherapeutic agent.

[0155] A composition of a disclosure may be at least about: 1% more effective, 5% more effective, 10% more effective, 15% more effective, 20% more effective, 25% more effective, 30% more effective, 35% more effective, 40% more effective, 45% more effective, 50% more effective, 55% more effective, 60% more effective, 65% more effective, 70% more effective, 75% more effective, 80% more effective, 85% more effective, 95% more effective, or 100% more effective than a corresponding additive effect of an anti-programmed cell death protein 1 agent and an immunotherapeutic agent.

[0156] An amount of a pharmaceutical composition or active therein that may be administered per day may be, for example, from, between about 0.01 mg/kg and about 100 mg/kg, e.g., from between about 0.1 to about 1 mg/kg, from between about 1 to about 10 mg/kg, from between about lOmg/kg and about 50 mg/kg, from between about 50mg/kg to about 100 mg/kg body weight. In other embodiments, an amount of a pharmaceutical composition that may be administered per day may be from between about 0.01 mg/kg and about 1000 mg/kg, from between about lOOmg/kg and about500 mg/kg, or from between about 500 mg/kg and about 1000 mg/kg body weight. In some embodiments, an optimal dose, per day or per course of treatment, may be different for a cancer or tumor to be treated and may also vary with an administrative route and therapeutic regimen. [0157] Pharmaceutical compositions comprising a pharmaceutical composition can be formulated in a manner appropriate for a delivery method by using techniques routinely practiced in the art. In some embodiments, a composition can comprise a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In some embodiments, a pharmaceutical composition can be administered as a bolus infusion.

[0158] Exemplary pharmaceutically acceptable excipients may include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in a pharmaceutical composition. In addition, antioxidants and suspending agents can also be used. In some embodiments, a type of excipient selected may be based on a mode of administration, as well as a chemical composition of a pharmaceutical composition. Alternatively, compositions described herein may be formulated as a lyophibzate. A composition described herein may be lyophilized or otherwise formulated as a lyophibzed product using one or more appropriate excipient solutions for solubilizing and/or diluting a pharmaceutical composition of a composition upon administration. In other

embodiments, a pharmaceutical composition may be encapsulated within liposomes. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein.

[0159] A pharmaceutical composition, which may be combined with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition, can be administered directly to a target tissue or organ comprising tumor cells that contribute to manifestation of a disease or disorder.

[0160] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may comprise a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, physiological saline solution, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as a solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for an adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. In some embodiments, a physiological saline may be used. In some embodiments, an injectable pharmaceutical composition may be sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to an eye as eye drops. A liquid

pharmaceutical composition may be delivered orally.

[0161] In some embodiments, a composition can comprise an oral formulation. In some embodiments, an oral formulation can comprise at least one pharmaceutical composition described herein either alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. In some embodiments, a pharmaceutical composition may be formulated with a buffering agent to provide for protection of a pharmaceutical composition from low pH of a gastric environment and/or an enteric coating. A pharmaceutical composition included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and/or with an enteric coating.

[0162] A pharmaceutical composition comprising any one of the pharmaceutical compositions described herein may be formulated for sustained release, slow release, timed release, or controlled release. Such compositions may generally be prepared and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at a desired target site. Sustained-release formulations may contain a pharmaceutical composition dispersed in a carrier matrix and/or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such

formulations may be biocompatible, and may also be biodegradable. In some embodiments, an amount of pharmaceutical composition contained within a sustained release formulation can depend upon a site of implantation, a rate and expected duration of release, and a nature of a condition, disease or disorder to be treated or prevented.

[0163] The pharmaceutical compositions comprising a pharmaceutical composition may be formulated for transdermal, intradermal, or topical administration. In some embodiments, a composition may be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder/talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. In some

embodiments, an active composition may also be delivered via iontophoresis. Preservatives may be used to prevent a growth of fungi and other microorganisms. Suitable preservatives may include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, or any combination thereof.

[0164] Pharmaceutical compositions may be formulated as emulsions for topical application. In some embodiments, a pharmaceutical composition described herein may be formulated as in inhalant. Inhaled methods may deliver medication directly to an airway. In some embodiments, a pharmaceutical composition may be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape.

[0165] Controlled or sustained release transdermal or topical formulations may be achieved by an addition of time-release additives, such as polymeric structures, and matrices. For example, a composition may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. In some embodiments, a formulation may comprise a cross-linked poly carboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow a system to remain attached to target epithelial or endothelial cell surfaces for a sufficient time to allow a desired release of a pharmaceutical composition.

[0166] A polymer formulation may also be utilized to provide controlled or sustained release.

Bioadhesive polymers may be used. By way of example, a sustained-release gel and a pharmaceutical composition may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix.

Examples of a polymeric matrix may include a microparticle. In some embodiments, a microparticle may be a microsphere, and a core may be of a different material than a polymeric shell. Alternatively, a polymer may be cast as a thin slab or fdm, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. In some embodiments, a polymer may also be in a form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of a pharmaceutical composition. In some embodiments, a matrix may be formed by solvent evaporation, spray drying, or solvent extraction.

[0167] In some embodiments, disclosed herein are kits. In some embodiments, a kit can comprise unit doses of one or more agents described herein. In some embodiments a unit dose can comprise oral or injectable doses. In some embodiments, a kit can comprise a container containing a unit dose, an informational package insert describing a use and attendant benefits of a drug in treating a tumor or cancer. In some embodiments, a kit can comprise instructions for use. In some embodiments, a kit can comprise an appliance or device for delivery of a composition.

Dosing and Treatment Regimens

[0168] In some embodiments, a pharmaceutical composition described herein can be used in a preparation of medicaments for a prevention or treatment of a cancer. In addition, a method for treating a diseases or conditions described herein in a subject in need of such treatment, can involve administration of pharmaceutical compositions containing at least a therapeutically effective amount of an anti -PD 1, PD- L1 or PD-L2 agent and an immunotherapeutic agent, or a pharmaceutically acceptable salt,

pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to a subject.

[0169] In some embodiments, the present disclosure may provide a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, wherein a treatment may involve administration of pharmaceutical composition containing at least a therapeutically effective amount of an anti-programmed cell death protein 1 agent and an immunotherapeutic agent, wherein an immunotherapeutic agent may an APRIL inhibitor or a fragment or a salt thereof.

[0170] In some embodiments, compositions containing a pharmaceutical composition described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, a composition can be administered to a subject already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest a symptom of a disease or condition. Amounts effective for this use may depend on a severity and course of a disease or condition, previous therapy, a subject's health status, weight, and response to drugs, and a judgment of a treating physician.

[0171] In some embodiments, in a case wherein a subject’s condition does not improve, upon a doctor’s discretion, an administration of a pharmaceutical composition may be administered chronically, that is, for an extended period of time, including throughout a duration of a subject’s life in order to ameliorate or otherwise control or limit symptoms of a subject’s disease or condition.

[0172] In some embodiments, wherein a subject’s status does improve, upon a doctor’s discretion, an administration of a pharmaceutical composition may be given continuously; alternatively, a dose of drug being administered may be temporarily reduced or temporarily suspended for a length of time (i.e., a “drug holiday”). In some embodiments, a length of a drug holiday may vary from between about 2 days and about 1 year, including by way of example only about: 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. In some embodiments, a dose reduction during a drug holiday may be from about 10% to about 100%, including, by way of example, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% relative to a dosage administered before or after a drug holiday.

[0173] In some cases, an administration of a pharmaceutical composition may be given indefinitely.

[0174] In some embodiments, a subject may exhibit a desired response to an anti-programmed cell death protein 1 therapy. In some cases, a subject may exhibit a partial desired response to an anti programmed cell death protein 1 therapy. In some cases, a subject may have been previously treated with a monotherapy. In some cases, a subject may become resistant to a monotherapy. A subject may become resistant, or show signs of resistance, after about: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, 400 days, 500 days, 600 days, 700 days, 800 days, 900 days, or more after treatment of a monotherapy.

[0175] In some embodiments, the current disclosure provides a method of treating a patient in need thereof comprising a treatment regimen of a monotherapy for a desired amount of time, followed by treatment of a combination therapy for a desired amount of time.

[0176] In some embodiments, once improvement of a subject's conditions may have occurred, a maintenance dose may be administered if necessary. Subsequently, a dosage or a frequency of administration, or both, may be reduced, as a function of symptoms, to a level at which an improved disease, disorder or condition status can be retained. Subjects can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0177] In some embodiments, an amount of a given agent that may correspond to such an amount may vary depending upon factors. In some embodiments, factors can comprise a particular

pharmaceutical composition, disease or condition and its severity, an identity (e.g., weight) of a subject or host in need of treatment, and any combination thereof. In some embodiments, a factor can be determined in a manner recognized in the field according to a particular circumstance surrounding a case, including, e.g., a specific agent being administered, a route of administration, a condition being treated, a subject or host being treated, and any combination thereof. In some embodiments, doses employed for adult human treatment may typically be in a range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 - about 1500 mg per day. In some embodiments, a desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day. [0178] In some embodiments, a pharmaceutical composition described herein can comprise unit dosage forms suitable for single administration of precise dosages. In unit dosage form, a formulation may be divided into unit doses containing appropriate quantities of one or more pharmaceutical compositions. In some embodiments, a unit dosage may be in a form of a package containing discrete quantities of a formulation. In some embodiments, a unit dosage may comprise packaged tablets or capsules, and powders in vials or ampoules. In some embodiments, aqueous suspension compositions may be packaged in single-dose non-reclosable containers. In some embodiments, a, multiple-dose reclosable container may be used. In some embodiments a composition may comprise a preservative. In some embodiments, parenteral injection may be presented in unit dosage form. In some embodiments, a unit dosage form may comprise multi-dose containers. In some embodiments, multi -dose containers may comprise an added preservative.

[0179] In some embodiments, a single dosage appropriate for a pharmaceutical composition described herein may be from about 0.01 mg/kg to about 20 mg/kg. In one embodiment, a single dosage of a checkpoint inhibitor may be from about 0.1 mg/kg to about 10 mg/kg. In some embodiments, a single dosage of an anti-programmed cell death protein 1 agent, an anti-programed death ligand 1 agent, an anti programmed death ligand 2 agent, a salt of any one thereof, or any combination thereof, may be from about 0.1 mg/kg to about 10 mg/kg. In some embodiments, an indicated single dosage in a larger mammal, including, but not limited to, humans, may be in a range from about 0.5 mg to about 1000 mg, conveniently administered in a single dose or in divided doses, including, but not limited to, up to four times a day or in extended release form. Suitable unit dosage forms for administration may include from about 1 to about 500 mg active ingredient. In one embodiment, a unit dosage may be about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. In some embodiments, an anti-programmed cell death protein 1 agent, an anti programed death ligand 1 agent, an anti-programmed death ligand 2 agent, a salt of any one thereof, or any combination thereof, may be 0.001% to 99% by weight of a pharmaceutical composition.

[0180] In some embodiments, a foregoing range may be merely suggestive, as a number of variables in regard to an individual treatment regime may be large, and considerable excursions from these recommended values may be not uncommon. Such dosages may be altered depending on a number of variables, not limited to an activity of a pharmaceutical composition used, a disease or condition to be treated, a mode of administration, the requirements of an individual subject, a severity of a disease or condition being treated, and a judgment of a practitioner.

[0181] Toxicity and therapeutic efficacy of such therapeutic regimens may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, a determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose

therapeutically effective in 50% of the population). In some embodiments, a dose ratio between a toxic and therapeutic effect may be a therapeutic index and it may be expressed as a ratio between LD50 and ED50. In some embodiments, data obtained from cell culture assays and animal studies may be used in formulating a range of dosage for use in human. In some embodiments, a dosage may vary within this range depending upon a dosage form employed and a route of administration utilized.

[0182] In some embodiments, a method used for cancer therapy with a pharmaceutical composition described herein can comprise one or more of a decreased single dose, decreased cumulative dose over a single therapeutic cycle, or decreased cumulative dose of the pharmaceutical composition over multiple therapeutic cycles compared with the amount required for cancer therapy.

[0183] In some embodiments, a treatment regimen of the methods for cancer therapy comprises administering a pharmaceutical composition for a time sufficient and in an amount sufficient that kills tumor cells. In some embodiments, a pharmaceutical composition may be administered within a treatment cycle, which treatment cycle may comprise a treatment course followed by a non-treatment interval. In some embodiments, a treatment course of administration refers herein to a finite time frame over which one or more doses of the pharmaceutical composition on one or more days may be administered. In some embodiments, a finite time frame may be also called herein a treatment window.

[0184] In some embodiments, ingredients of a pharmaceutical composition described herein may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially. An immunotherapeutic agent and a checkpoint inhibitor may be administered concurrently. In some embodiments, an immunotherapeutic agent and a checkpoint inhibitor may be administered sequentially. In some embodiments, an immunotherapeutic agent and a checkpoint inhibitor may be administered within the same formulation. In some embodiments, an immunotherapeutic agent and a checkpoint inhibitor may be administered in different formulations within a single treatment schedule, or the immunotherapeutic agent and a checkpoint inhibitor may be administered on different treatment schedules.

[0185] In some embodiments, a composition of the current disclosure may be made by contacting combining, mixing, adding, or any combination thereof, an anti-PD-1, an anti-PD-Ll, an anti-PD-L2, or a salt of any one thereof, or any combination thereof, and an immunotherapeutic agent or a salt thereof. A kit of the current disclosure may be made by contacting combining, mixing, adding, or any combination thereof, an anti-PD-1, an anti-PD-Ll, an anti-PD-L2, or a salt of any one thereof, or any combination thereof, and an immunotherapeutic agent or a salt thereof.

[0186] A method of the current disclosure may comprise administering the pharmaceutical composition in at least two treatment cycles. In a specific embodiment, the non-treatment interval may be at least about 2 weeks or between from at least about 0.5 to about 12 months, such as at least about one month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, or at least about 12 months (i.e., 1 year). The non-treatment interval may be between about 1 years to about 2 years or between about 1 years to about 3 years, or longer. Each treatment course may be no longer than about 1 month, no longer than about 2 months, or no longer than about 3 months; or may be no longer than about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, or 31 days.

[0187] In some embodiments, a treatment window (i.e., treatment course) may be only one day. In some embodiments, a single treatment course may occur over no longer than about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, or 31 days. During such treatment windows, the pharmaceutical composition may be administered at least on about two days (i.e., two days or more) with a variable number of days on which the agent may be not administered between the at least two days of administration. In some embodiments, , when the pharmaceutical composition may be administered on two or more days within a treatment course, there may be one or more intervals of one or more days when the pharmaceutical composition, may not be administered. In some embodiments, when the pharmaceutical composition may be administered on 2 or more days during a treatment course not to exceed 21 days, the agent may be administered on any total number of days between from about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29, 30, or 31 days. In some embodiments, a pharmaceutical composition may be administered to a subject during a treatment course of 3 days or more, and the agent may be administered every 2^nd day (i.e., every other day). In some embodiments, a pharmaceutical composition may be administered to a subject for a treatment window of about 4 days or more, the pharmaceutical composition may be administered every about 3^rd day. In one embodiment, the pharmaceutical composition may be administered on at least about two days during a treatment course that can comprise at least about 2 days and no more than about 21 days (i.e., from about 2 days to about 21 days); at least about 2 days and no longer than about 14 days (i.e., from about 2 days to about 14 days); at least about 2 days and no longer than about 10 days (i.e., from about 2 days to about 10 days); or at least about 2 days and no longer than about 9 days (i.e., from about 2 days to about 9 days); or at least about 2 days and no longer than about 8 days (i.e., from about 2 days to about 8 days). In other specific embodiments, the pharmaceutical composition may be administered on at least about two days (i.e., about 2 days or more) during a treatment window may be at least about 2 days and no longer than about 7 days (i.e., from about 2 days to about 7 days); at least about 2 days and no longer than about 6 days (i.e., from about 2 days to about 6 days) or at least about 2 days and no more than about 5 days (i.e., from about 2 days to about 5 days) or at least about 2 days and no longer than about 4 days (i.e., from about 2 days to about 4 days). In yet another embodiment, the treatment window can comprise at least about 2 days and no longer than about 3 days (i.e., from about 2 days to about 3 days), or about 2 days. The treatment course may be no longer than about 3 days. The treatment course may be no longer than about 5 days. The treatment course may be no longer than about: 7 days, 10 days, or 14 days or 21 days. The pharmaceutical composition may be administered on at least about two days (i.e., about 2 or more days) during a treatment window that may be at least about 2 days and no longer than about 11 days (i.e., from about 2 days to about 11 days); or the pharmaceutical composition may be administered on at least about two days (i.e., about 2 or more days) during a treatment window that can comprise at least about 2 days and no longer than about 12 days (i.e., from about 2 days to about 12 days); or the pharmaceutical composition may be administered on at least about two days (i.e., about 2 or more days) during a treatment window that may be at least about 2 days and no more than about 13 days (i.e.. from about 2 days to about 13 days); or the pharmaceutical composition may be administered on at least about two days (i.e.. about 2 or more days) during a treatment course that may be at least about 2 days and no more than about 15 days (i.e.. from about 2 days to about 15 days); or the pharmaceutical composition may be administered on at least about two days (i. e.. about 2 or more days) during a treatment course that may be at least about 2 days and no longer than about: 16 days, 17 days, 18 days, 19 days, or 20 days (i.e., 2-16, 2-17, 2-18, 2-19, 2-20 days,

respectively). In other embodiments, the pharmaceutical composition may be administered on at least 3 days over a treatment course of at least about 3 days and no longer than any number of days between about 3 days and about 21 days; or may be administered on at least about 4 days over a treatment course of at least about 4 days and no longer than any number of days between about 4 days and about 21 days; or may be administered on at least about 5 days over a treatment course of at least about 5 days and no longer than any number of days between about 5 days and about 21 days; or may be administered on at least about 6 days over a treatment course of at least about 6 days and no longer than any number of days between about 6 and about 21 days; or may be administered at least about 7 days over a treatment course of at least about 7 days and no longer than any number of days between about 7 days and about 21 days; or may be administered at least about 8 days or about 9 days over a treatment course of at least about 8 days or about 9 days, respectively, and no longer than any number of days between about 8 days or about 9 days, respectively, and about 21 days; or may be administered at least about 10 days over a treatment course of at least about 10 days and no longer than any number of days between about 10 days and about 21 days; or can be administered at least about 14 days over a treatment course of at least about 14 days and no longer than any number of days between about 14 days and about 21 days; or may be administered at least about 11 days or about 12 days over a treatment course of at least about 11 days or about 12 days, respectively, and no longer than any number of days between about 11 days or about 12 days, respectively, and about 21 days; or may be administered at least about 15 days or about 16 days over a treatment course of at least about 15 days or about 16 days, respectively, and no longer than any number of days between about 15 days or about 16 days, respectively, and about 21 days. By way of additional example, when the treatment course may be no longer than about 14 days, a pharmaceutical composition may be administered on at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 days over a treatment of window of at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 days, respectively, and no longer than about 14 days. When the treatment course may be no longer than about 10 days, a pharmaceutical composition may be administered on at least about: 2, 3, 4, 5, 6, 7, 8, 9, or 10 days over a treatment of window of at least about: 2, 3, 4, 5, 6, 7, 8, 9, or 10 days, respectively, and no longer than about 10 days. Similarly, when the treatment course may be no longer than about 7 days, a pharmaceutical composition may be administered on at least about 2, 3, 4, 5, 6, or 7 days over a treatment window of at least about 2, 3, 4, 5, 6, or 7 days, respectively, and no longer than about 7 days. When the treatment course may be no longer than about 5 days, a pharmaceutical composition may be administered on at least about 2, 3, 4, or 5 days over a treatment of window of at least about 2, 3, 4, or 5 days, respectively, and no longer than about 5 days.

[0188] In some embodiments, wherein a treatment course comprises about three or more days, doses of a pharmaceutical composition may be administered for a lesser number of days than the total number of days within a particular treatment window. By way of non-limiting example, when a course of treatment may have a treatment course of no more than about: 7, 10, 14, or 21 days, the number of days on which a pharmaceutical composition may be administered may be any number of days between from about 2 days and about: 7, 10, 14, or 21 days, respectively, and at any interval appropriate for the particular disease being treated, the pharmaceutical composition being administered, the health status of the subject and other relevant factors, which are discussed in greater detail herein. In some embodiments, a person may appreciate that when the pharmaceutical composition may be administered on about two or more days over a treatment window, the agent may be delivered on the minimum number days of the window, the maximum number of days of the window, or on any number of days between the minimum and the maximum.

[0189] In some embodiments, a treatment course may be one day or the treatment course may be of a length not to exceed about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, which may be examples of a course wherein the pharmaceutical composition may be administered on two or more days over a treatment course not to exceed (i.e., no longer than) about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days, respectively. In some embodiments, a treatment course may be about 2 weeks (about 14 days or 0.5 months), about 3 weeks (about 21 days), about 4 weeks (about one month), about 5 weeks, about 6 weeks (about 1.5 months), about 2 months (or about 60 days), or about 3 months (or about 90 days). In some embodiments, a treatment course may be a single daily dosing of the pharmaceutical composition. In other embodiments, with respect to any treatment course a daily dose of the pharmaceutical composition may be as a single administration or the dose may be divided into 2, 3, 4, or 5 separate administrations to provide the total daily dose of the agent.

[0190] In some embodiments, wherein a treatment window when the pharmaceutical composition may be administered comprises two or more days, a treatment course may have one or more intervals of one or more days when a pharmaceutical composition, may be not administered. Solely as a non-limiting example, when a treatment window may be between two and seven days, a first dose may be administered on a first day of a treatment window and a second dose may be administered on a third day of a course, and a third dose may be administered on a seventh day of a treatment window. A person may appreciate that varying dosing schedules may be used during a particular treatment window. In other specific embodiments, a pharmaceutical composition may be administered daily on each consecutive day for a duration of a treatment course. A daily dose may be administered as a single dose or a daily dose may be divided into 2, 3, or 4, or 5 separate administrations to provide a total daily dose of a pharmaceutical composition. [0191] In some embodiments, a treatment course comprises a length of time during which a pharmaceutical composition may be administered daily. In some embodiments, a pharmaceutical composition may be administered daily for 2 days. In some embodiments, a pharmaceutical composition may be administered daily for 3 days. In some embodiments, a pharmaceutical composition may be administered daily for 4 days. In some embodiments, a pharmaceutical composition may be administered daily for 5 days. In some embodiments, a pharmaceutical composition may be administered daily for 6 days. In some embodiments, a pharmaceutical composition may be administered daily for 7 days. In some embodiments, a pharmaceutical composition may be administered daily for 8 days. In some

embodiments, a pharmaceutical composition may be administered daily for 9 days. In some

embodiments, a pharmaceutical composition may be administered daily for 10 days. In some

embodiments, a pharmaceutical composition may be administered daily for 11 days. In some

embodiments, a pharmaceutical composition may be administered daily for 12 days. In some

embodiments, a pharmaceutical composition may be administered daily for 13 days. In some

embodiments, a pharmaceutical composition may be administered daily for 14 days. In some

embodiments, a treatment window (i. e. , course) for each of the above examples may be no longer than about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, respectively.

[0192] In some embodiments, a pharmaceutical composition may be administered every 2^nd day (i.e., every other day) for 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. The pharmaceutical composition may be administered every 3^nd day (i.e., one day receiving the agent followed by two days without receiving the agent) for 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. The pharmaceutical composition may be administered on every 2^nd - 3^rd day during a treatment window of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. The pharmaceutical composition may be administered every 4^th day during a treatment course of 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days; or every 5^th day during a treatment course of 6, 7, 8, 9, 10, 11, 12, 13, or 14 days. A person may appreciate the minimum numbers of days in a treatment window when the pharmaceutical composition may be administered every 6^th, 7^th, etc. day over a treatment window of a finite number of days as described herein.

[0193] In some embodiments, a pharmaceutical composition may be administered daily for a longer duration than 14 days and may be administered at least about: 15, 16, 17, 18, 19, 20, or at least 21 days. The pharmaceutical composition may be administered daily on each of the about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be administered every second day during a treatment window of about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be

administered every third day during a treatment window of about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be administered on every 2^nd - 3^rd day during a treatment window of about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be administered every 4^th day during a treatment course of about: 15, 16, 17, 18, 19, 20, or 21 days; or every 5^th day during a treatment course of about: 15, 16, 17, 18, 19, 20, or 21 days. A person may readily appreciate the minimum numbers of days in a treatment window when the pharmaceutical composition may be administered every 6^th, 7^th, etc. day over a treatment window of a finite number of days as described herein.

[0194] In some embodiments, a pharmaceutical composition may be administered daily for a longer duration than 14 days and may be administered at least about: 15, 16, 17, 18, 19, 20, or at least 21 days. The pharmaceutical composition may be administered daily on each of the about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be administered every second day during a treatment window of about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be administered every third day during a treatment window of about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be administered on every 2^nd - 3^rd day during a treatment window of about: 15, 16, 17, 18, 19, 20, or 21 days. The pharmaceutical composition may be administered every 4^th day during a treatment course of about: 15, 16, 17, 18, 19, 20, or 21 days; or every 5^th day during a treatment course of about: 15, 16, 17, 18, 19, 20, or 21 days. A person may readily appreciate the minimum numbers of days in a treatment window when the pharmaceutical composition can be administered every 6^th, 7^th, etc. day over a treatment window of a finite number of days as described herein.

[0195] In some embodiments, a pharmaceutical composition may be administered in a treatment course daily for a longer duration than about 14 days or about 21 days and may be administered in a treatment course of about one month, about two months, or about three months. The pharmaceutical composition may be administered daily on each of a one month, two month, or three month treatment course. The pharmaceutical composition may be administered every second day during a treatment course of about one month, about two months, or about three months. The pharmaceutical composition may be administered every third day during a treatment course of about one month, about two months, or about three months. The pharmaceutical composition may be administered on every 2^nd - 3^rd day during a treatment course of about one month, about two months, or about three months. The pharmaceutical composition may be administered every 4^th day during a treatment course of about one month, about two months, or about three months; or every 5^th day during a treatment course of about one month, about two months, or about three months s. A person may readily appreciate the minimum numbers of days in a treatment course when the pharmaceutical composition can be administered every 6^th, 7^th, etc. day over a treatment window of a finite number of days as described herein.

[0196] In some embodiments, a, a longer treatment window with a decreased dose per day may be a treatment option for a subject. By way of example, the stage or severity of the cancer or tumor may indicate that a longer term course may provide clinical benefit. The pharmaceutical composition may be administered daily, or optionally, every other day (every 2^nd day) or every 3 ^rd day, or greater interval (i.e., every 4^th day, 5^th day, 6^th day) during a treatment course of about 1-2 weeks (e.g., about 5-14 days), about 1-3 weeks (e.g., about 5-21 days), about 1-4 weeks (e.g., about 5-28 days, about 5-36 days, or about 5-42 days, 7-14 days, 7-21 days, 7-28 days, 7-36 days, or 7-42 days; or 9-14 days, 9-21 days, 9-28 days, 9-36 days, or 9-42 days. The treatment course may be between about 1-3 months. The pharmaceutical composition may be administered daily for at least five days. The pharmaceutical composition may be administered daily for 5-14 days. The pharmaceutical composition may be administered for at least seven days, for example, for 7-14, 7-21, 7-28 days, 7-36 days, or 7-42 days. The pharmaceutical composition may be administered for at least nine days, for example, for 9-14 days, 9-21 days, 9-28 days, 9-36 days, or 9-42 days.

[0197] In some embodiments, a, a treatment course comprising administering a pharmaceutical composition can provide clinical benefit. In some embodiments a treatment course may be repeated with a time interval between each treatment course when a pharmaceutical composition may not be administered (i.e., non-treatment interval, off-drug treatment). A treatment cycle as described herein and in the art may comprise a treatment course followed by a non-treatment interval. A treatment cycle may be repeated as often as needed. For example, a treatment cycle may be repeated at least once, at least twice, at least three times, at least four times, at least five times, or more often as needed. A treatment cycle may be repeated once (i.e., administration of the pharmaceutical composition comprises 2 treatment cycles). The treatment cycle may be repeated twice or repeated 3 or more times. Accordingly, one, two, three, four, five, six, seven, eight, nine, ten, or more treatment cycles of treatment with a pharmaceutical composition may be performed. A treatment course or a treatment cycle may be repeated, such as when the cancer or tumor recurs, or when symptoms or sequelae of the disease or disorder that were significantly diminished by one treatment course as described above may have increased or may be detectable, or when the symptoms or sequelae of the disease or disorder may be exacerbated, a treatment course may be repeated. In other embodiments when the pharmaceutical composition can be administered to a subject to prevent (i.e., reduce likelihood of occurrence or development) or to delay onset, progression, or severity of the cancer or tumor, a subject may receive the pharmaceutical composition over two or more treatment cycles. Accordingly, one cycle of treatment may be followed by a subsequent cycle of treatment. Each treatment course of a treatment cycle or each treatment course of two or more treatment cycles may be typically the same in duration and dosing of the pharmaceutical composition. In other embodiments, the duration and dosing of the pharmaceutical composition during each treatment course of a treatment cycle may be adjusted as determined by a person skilled in the medical art depending, for example, on the particular disease or disorder being treated, the pharmaceutical composition being administered, the health status of the subject and other relevant factors, which are discussed in greater detail herein. Accordingly, a treatment course of a second or any subsequent treatment cycle may be shortened or lengthened as deemed medically necessary or prudent. In other words, as may be appreciated by a person, each treatment course of two or more treatment cycles may be independent and the same or different; and each non-treatment interval of each treatment cycle may be independent and the same or different.

[0198] In some embodiments, a, each course of treatment in a treatment cycle may be separated by a time interval of days, weeks, or months without treatment with a pharmaceutical composition (i.e., non treatment time interval or off-drug interval; called non-treatment interval herein). In some embodiments, a non-treatment interval (such as days, weeks, months) between one treatment course and a subsequent treatment course may be typically greater than the longest time interval (i.e., number of days) between any two days of administration in the treatment course. By way of example, if a treatment course may be no longer than 14 days and the agent may be administered every other day during this treatment course, the non-treatment interval between two treatment courses may be greater than 2 days, such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days or about 3 weeks, about 4 weeks, about 6 weeks, or about 2 months or longer as described herein. The non-treatment interval between two treatment courses may be about 5 days, about 1 week, about 2 weeks, about 3 weeks, about 1 month, about 6 weeks, about 2 months (8 weeks), about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months (about 1 year), about 18 months (about 1.5 years), or longer. The non-treatment interval may be about 2 years or about 3 years. The non-treatment time interval may be at least about 14 days, at least about 21 days, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or at least about 1 year. A course of treatment (whether daily, every other day, every 3^rd day, or other interval between administrations within the treatment course as described above ( e.g ., 1-14 days, 2-14 days, 2-21 days, or 1-21 days)) may be administered about every 14 days (i.e., about every 2 weeks) (i.e., 14 days without pharmaceutical composition treatment), about every 21 days (i.e., about every 3 weeks), about every 28 days (i.e., about every 4 weeks), about every one month, about every 36 days, about every 42 days, about every 54 days, about every 60 days, or about every month (about every 30 days), about every two months (about every 60 days), about every quarter (about every 90 days), or about semi-annually (about every 180 days). A course of treatments (e.g., by way of non limiting example, administration on at least one day or on at least two days during a course for about 2-21 days, about 2-14, days, about 5-14 days, about 7-14 days, about 9-14 days, about 5-21 days, about 7-21 days, about 9-21 days) may be administered every 28 days, every 36 days, every 42 days, every 54 days, every 60 days, or every month (about every 30 days), every two months (about every 60 days), every quarter (about every 90 days), or semi-annually (about every 180 days), or about every year (about 12 months). In other embodiments, a course of treatment (such as by way of non-limiting examples, e.g., for about 5-28 days, about 7-28 days, or about 9-28 days whether daily, every other day, every 3^rd day, or other interval between administrations within the treatment course) may be administered every 36 days,

42 days, 54 days, 60 days, or every month (about every 30 days), every two months (about every 60 days), every quarter (about every 90 days), or semi-annually (about every 180 days). A course of treatment (e.g., for about 5-36 days, 7-36 days, or 9-36 days whether daily, every other day, every 3^rd day, or other interval between administrations within the treatment course) may be administered every 42 days, 54 days, 60 days, or every month (about every 30 days), every two months (about every 60 days), every quarter (about every 90 days), or semi-annually (about every 180 days), or about every year (about 12 months). [0199] In some embodiments, a treatment course may be one day and the non-treatment interval may be at least about 14 days, about 21 days, about 1 month, about 2 months (8 weeks), about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months (about 1 year), about 18 months (about 1.5 years), or longer. The treatment course may be at least two days or may be at least 3 days and no longer than 10 days, and the non-treatment interval may be at least about 14 days, about 21 days, about 1 month, about 2 months (8 weeks), about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months (about 1 year), about 18 months (about 1.5 years), or longer. The treatment course may be at least three days and no longer than 10 days, no longer than 14 days, or no longer than 21 days, and the non-treatment interval may be at least about 14 days, about 21 days, about 1 month, about 2 months (8 weeks), about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months (about 1 year), about 18 months (about 1.5 years), or longer. A treatment course ( e.g ., for about 5-42, 7-42, or 9-42 days whether daily, every other day, every 3^rd day, or other interval between administrations within the treatment course) may be administered every 42 days,

60 days, or every month (about every 30 days), every two months (about every 60 days), every quarter (about every 90 days), or semi-annually (about every 180 days), or about every year (about 12 months). The pharmaceutical composition may be administered daily for 5-14 days every 14 days (about every 2 weeks), or every 21-42 days. The pharmaceutical composition may be administered daily for 5-14 days quarterly. The pharmaceutical composition may be administered daily for 7-14 days every 21-42 days. The pharmaceutical composition may be administered daily for 7-14 days quarterly. The pharmaceutical composition may be administered daily for 9-14 days every 21-42 days or every 9-14 days quarterly. The non-treatment interval may vary between treatment courses. By way of non-limiting example, the non treatment interval may be 14 days after the first course of treatment and may be 21 days or longer after the second, third, or fourth (or more) course of treatment. The pharmaceutical composition may be administered to the subject in need thereof once every 0.5-12 months. The pharmaceutical composition may be administered to the subject in need once every 4-12 months.

[0200] In some embodiments, a pharmaceutical composition may be administered to a subject to reduce the likelihood or the risk that the subject may develop a cancer. The pharmaceutical composition may be administered for one or more days (e.g., any number of consecutives days between and including 2-3, -4, -5, -6, -7, -8, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19, -20, and 2-21 days) every 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. The pharmaceutical composition may be administered for one or more days (e.g., any number of consecutives days between and including 1-9 days) every 5 or 6 months.

[0201] In some embodiments, a total daily dose of a pharmaceutical composition may be delivered as a single dose or as multiple doses on each day of administration. When multiple cycles of the pharmaceutical composition may be administered, the dose of a pharmaceutical composition administered on a single day may be less than the daily dose administered if only a single treatment course may be intended to be administered.

Combination Therapies

[0202] In some embodiments, a composition comprising a therapeutically effective amount of an anti -PD 1, anti-PD-Ll or anti-PD-L2 agent and an immunotherapeutic agent (for example an APRIL inhibitor), may also be used in combination with other therapeutic agents that may be selected for their therapeutic value for the condition to be treated. In general, the compositions described herein and, in embodiments where combinational therapy may be employed, other agents do not have to be

administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, may be within the knowledge of the clinician. The initial administration may be made according to established protocols recognized in the field, and then, based upon the observed effects, the dosage, modes of administration and times of administration may be modified by the clinician.

[0203] In some embodiments, it may be appropriate to administer at least one pharmaceutical composition described herein in combination with another therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the pharmaceutical compositions described herein may be enhanced by administration of an adjuvant, i.e., by itself the adjuvant may have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the subject may be enhanced. Or, by way of example only, the benefit experienced by a subject may be increased by administering one of the pharmaceutical compositions described herein with another therapeutic agent, which also includes a therapeutic regimen that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the subject may simply be additive of the two agents or the subject may experience a synergistic benefit.

[0204] In some embodiments, a particular choice of pharmaceutical compositions used may depend upon the diagnosis of the attending physicians and their judgment of the condition of the subject and the appropriate treatment protocol. The pharmaceutical compositions may be administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially, depending upon the nature of the disease, disorder, or condition, the condition of the subject, and the actual choice of pharmaceutical compositions used. The determination of the order of administration, and the number of repetitions of administration of each therapeutic agent during a treatment protocol, may be well within the knowledge of the physician after evaluation of the disease being treated and the condition of the subject.

[0205] In some embodiments, therapeutically-effective dosages may vary when the drugs may be used in treatment combinations. Methods for experimentally determining therapeutically-effective dosages of drugs and other agents for use in combination treatment regimens may be described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects, has been described extensively in the literature. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the subject.

[0206] In some embodiments, for combination therapies described herein, dosages of the co administered pharmaceutical compositions may vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth. In addition, when co administered with one or more biologically active agents, the pharmaceutical composition provided herein may be administered either simultaneously with the pharmaceutical composition, or sequentially. If administered sequentially, the attending physician may decide on the appropriate sequence of administering the pharmaceutical composition in combination with a biologically active agent(s).

[0207] In some embodiments, a composition comprising a therapeutically effective amount of an anti -PD 1, anti-PD-Ll or anti-PD-L2 agent and an immunotherapeutic agent may be administered in any order or approximately simultaneously. In one embodiment, a composition comprising a therapeutically effective amount of an anti-PDl, anti-PD-Ll or anti-PD-L2 agent and an immunotherapeutic agent may be administered in any order or approximately simultaneously, wherein an immunotherapeutic agent may be an APRIL inhibitor or a fragment or a salt thereof. In some embodiments, if administered

approximately simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms, by way of example only, either as a single pill or as two separate pills. One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not approximately simultaneous, the timing between the multiple doses may vary from more than zero weeks to less than four weeks. Disclosed herein in some embodiments are combination methods. Disclosed herein in some embodiments, are compositions and formulations that can comprise one or more agents, two or more agents, three or more agents, or a multiple number of agents.

[0208] In some embodiments disclosed herein, a dosage regimen to treat, prevent, or ameliorate a condition(s) for which relief is sought, may be modified in accordance with a variety of factors. These factors include the disorder or condition from which the subject suffers, as well as the age, weight, sex, diet, and medical condition of the subject. Thus, the dosage regimen actually employed may vary widely and therefore may deviate from the dosage regimens set forth herein.

[0209] In some embodiments, pharmaceutical compositions which make up the combination therapy disclosed herein may be a combined dosage form or in separate dosage forms intended for substantially simultaneous administration. The pharmaceutical compositions that make up the combination therapy may also be administered sequentially, with either pharmaceutical composition being administered by a regimen calling for two-step administration. The two-step administration regimen may call for sequential administration of the active agents or spaced-apart administration of the separate active agents. The time period between the multiple administration steps may range from, a few minutes to several hours, depending upon the properties of each pharmaceutical composition, such as potency, solubility, bioavailability, plasma half-life and kinetic profile of the pharmaceutical composition. Circadian variation of the target molecule concentration may also determine the optimal dose interval.

[0210] In some embodiments,, the pharmaceutical compositions described herein also may be used in combination with procedures that may provide additional or synergistic benefit to the subject. By way of example only, subjects may be expected to find therapeutic and/or prophylactic benefit in the methods described herein, wherein pharmaceutical composition of a pharmaceutical composition disclosed herein and /or combinations with other therapeutics may be combined with genetic testing to determine whether that individual may be a carrier of a mutant gene that may be known to be correlated with a disease or condition.

[0211] In some embodiments, pharmaceutical compositions described herein and combination therapies may be administered before, during or after the occurrence of a disease or condition, and the timing of administering the composition containing a pharmaceutical composition may vary. Thus, for example, the pharmaceutical composition may be used as a prophylactic and may be administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. The pharmaceutical compositions and compositions may be administered to a subject during or as soon as possible after the onset of the symptoms. The

administration of the pharmaceutical compositions may be initiated within the first 48 hours of the onset of the symptoms, such as within the first 48 hours of the onset of the symptoms, such as within the first 6 hours of the onset of the symptoms, such as within 3 hours of the onset of the symptoms. The initial administration may be via any route practical, such as, for example, an intravenous injection, a bolus injection, infusion over about 5 minutes to about 5 hours, a pill, a capsule, transdermal patch, buccal delivery, and the like, or combination thereof. A pharmaceutical composition may be administered as soon as may be practicable after the onset of a disease or condition may be detected or suspected, and for a length of time necessary for the treatment of the disease, such as, for example, from 1 day to about 3 months. The length of treatment may vary for each subject, and the length may be determined using the known criteria. For example, the pharmaceutical composition or a formulation containing the

pharmaceutical composition may be administered for at least 2 weeks, such as about 1 month to about 5 years.

[0212] In some embodiments, a pharmaceutical composition described herein may reduce the likelihood of a cancer in a subject in need thereof. The pharmaceutical composition described herein may be administered one or more days within a window of treatment. In some embodiments, the treatment window may be about: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days. In some embodiments, a pharmaceutical composition described herein may be administered on two or more days within a treatment window of no longer than 7 days or 14 days; on 3 or more days within a treatment window of no longer than 7 days or 14 days; on 4 or more days within a treatment window of no longer than 7 days or 14 days; on 5 or more days within a treatment window of no longer than 7 days or 14 days; or on 6, 7, 8, 9, 10, 11, 12, 13, or 14 days within treatment window of no longer than 7 days or 14 days. [0213] In some embodiments, chemotherapy and radiotherapy treatment regimens may comprise a finite number of cycles of on-drug therapy followed by off-drug therapy, or comprise a finite timeframe in which the chemotherapy or radiotherapy may be administered. The protocols may be determined by clinical trials, drug labels, and clinical staff in conjunction with the subject to be treated. The number of cycles of a chemotherapy or radiotherapy or the total length of time of a chemotherapy or radiotherapy regimen may vary depending on the subject’s response to the cancer therapy. A pharmaceutical composition described herein may be administered after the treatment regimen of chemotherapy or radiotherapy has been completed.

Indications

[0214] In some embodiments, a method of the current disclosure may be used to treat a cancer or a tumor. The cancer or tumor may be malignant. The cancer or tumor may be present in an organ. The cancer or tumor may be present in the head or neck region, the abdominal region, an upper limb, a lower limb, the skin, blood, the digestive tract, a germ cell, or the nervous system of a subject. The cancer or tumor may be present in at least one of: the blood, the lymph, or the cerebral spinal fluid.

[0215] In some embodiments, the tumor may be a solid tumor. The tumor may be a liquid tumor. Cancers that are liquid tumors may be those that occur, for example, in blood, bone marrow, and lymph nodes, and may include, for example, leukemia, myeloid leukemia, lymphocytic leukemia, lymphoma, Hodgkin’s lymphoma, melanoma, and multiple myeloma. Leukemias include, for example, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), and hairy cell leukemia. Cancers that may be solid tumors include, for example, prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, ovarian cancer, Kaposi’s sarcoma, skin cancer, squamous cell skin cancer, renal cancer, head and neck cancers, throat cancer, squamous carcinomas that form on the moist mucosal linings of the nose, mouth, throat, bladder cancer, osteosarcoma, cervical cancer, endometrial cancer, esophageal cancer, liver cancer, and kidney cancer. In some embodiments, the condition treated by the methods described herein may be metastasis of melanoma cells, prostate cancer cells, testicular cancer cells, breast cancer cells, brain cancer cells, pancreatic cancer cells, colon cancer cells, thyroid cancer cells, stomach cancer cells, lung cancer cells, ovarian cancer cells, Kaposi’s sarcoma cells, skin cancer cells, renal cancer cells, head or neck cancer cells, throat cancer cells, squamous carcinoma cells, bladder cancer cells, osteosarcoma cells, cervical cancer cells, endometrial cancer cells, esophageal cancer cells, liver cancer cells, or kidney cancer cells.

[0216] In some embodiments, a method of the current disclosure may be used to treat cancer, wherein the cancer may be prostate cancer, testicular cancer, breast cancer, brain cancer, pancreatic cancer, colon cancer, thyroid cancer, stomach cancer, lung cancer, melanoma, multiple myeloma, Hodgkin’s lymphoma, or ovarian cancer.

[0217] In some embodiments, methods described herein may also be used for inhibiting progression of metastatic cancer tumors. Non-limiting examples of cancers include adrenocortical carcinoma, childhood adrenocortical carcinoma, aids-related cancers, anal cancer, appendix cancer, basal cell carcinoma, childhood basal cell carcinoma, bladder cancer, childhood bladder cancer, bone cancer, brain tumor, childhood astrocytomas, childhood brain stem glioma, childhood central nervous system atypical teratoid/rhabdoid tumor, childhood central nervous system embryonal tumors, childhood central nervous system germ cell tumors, childhood craniopharyngioma brain tumor, childhood ependymoma brain tumor, breast cancer, childhood bronchial tumors, carcinoid tumor, childhood carcinoid tumor, gastrointestinal carcinoid tumor, carcinoma of unknown primary, childhood carcinoma of unknown primary, childhood cardiac tumors, cervical cancer, childhood cervical cancer, childhood chordoma , chronic myeloproliferative disorders, colon cancer, colorectal cancer, childhood colorectal cancer, extrahepatic bile duct cancer , ductal carcinoma in situ (DCIS), endometrial cancer, esophageal cancer, childhood esophageal cancer, childhood esthesioneuroblastoma, eye cancer, malignant fibrous histiocytoma of bone, gallbladder cancer, gastric (stomach) cancer, childhood gastric cancer,

gastrointestinal stromal tumors (GIST), childhood gastrointestinal stromal tumors (GIST), childhood extracranial germ cell tumor, extragonadal germ cell tumor, gestational trophoblastic tumor, glioma, head and neck cancer, childhood head and neck cancer, hepatocellular cancer, hypopharyngeal cancer, kidney cancer, renal cell kidney cancer, Wilms tumor, childhood kidney tumors, Langerhans cell histiocytosis, laryngeal cancer, childhood laryngeal cancer, leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (cml), hairy cell leukemia, lip cancer, liver cancer (primary), childhood liver cancer (primary), lobular carcinoma in situ (LCIS), lung cancer, non-small cell lung cancer, small cell lung cancer, lymphoma, aids-related lymphoma, burkitt lymphoma, cutaneous t-cell lymphoma, Hodgkin lymphoma, non- Hodgkin lymphoma, primary central nervous system lymphoma (CNS), melanoma, childhood melanoma, intraocular melanoma, Merkel cell carcinoma, malignant mesothelioma, childhood malignant mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, childhood multiple endocrine neoplasia syndromes, mycosis fungoides, myelodysplastic syndromes, myelodysplastic neoplasms, myeloproliferative neoplasms, multiple myeloma, nasal cavity cancer, nasopharyngeal cancer, childhood nasopharyngeal cancer, neuroblastoma, oral cancer, childhood oral cancer, oropharyngeal cancer, ovarian cancer, childhood ovarian cancer, epithelial ovarian cancer, low malignant potential tumor ovarian cancer, pancreatic cancer, childhood pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors) , childhood papillomatosis , paraganglioma, paranasal sinus cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm , childhood pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis transitional cell cancer, retinoblastoma, salivary gland cancer, childhood salivary gland cancer, Ewing sarcoma family of tumors, Kaposi Sarcoma, osteosarcoma, rhabdomyosarcoma, childhood rhabdomyosarcoma, soft tissue sarcoma, uterine sarcoma, Sezary syndrome, childhood skin cancer, nonmelanoma skin cancer, small intestine cancer, squamous cell carcinoma, childhood squamous cell carcinoma, testicular cancer, childhood testicular cancer, throat cancer, thymoma and thymic carcinoma, childhood thymoma and thymic carcinoma, thyroid cancer, childhood thyroid cancer, ureter transitional cell cancer, urethral cancer, endometrial uterine cancer, vaginal cancer, vulvar cancer, and Waldenstrom macroglobulinemia.

[0218] In some embodiments, the cancer or tumor may be squamous non-small cell lung cancer, adeno non-small cell lung cancer, colorectal cancer, head and neck squamous cell carcinoma, breast cancer, or melanoma.

[0219] In some embodiments, the cancer or tumor contacts a blood vessel. In some embodiments, the cancer or the tumor may be in the interior of a blood vessel.

[0220] In some embodiments, at least one of the anti-programmed cell death protein 1 agent, the anti-programmed death ligand 1 agent, the anti-programmed death ligand 2 agent, or a salt of any one thereof, or any combination thereof; and the immunotherapeutic agent or salt thereof may be isolated and purified.

[0221] In some embodiments, the administration may be oral. In some embodiments, the administration may be topical, intravenous, intramuscular, or spinal. In some embodiments, the administration may be administered directly to the cancer or the tumor. In some embodiments, the administration may be an administration at a location different from the cancer or the tumor. In some embodiments, the subject has been previously diagnosed with the cancer or the tumor. In some embodiments, the cancer or the tumor may be a solid tumor or a solid cancer. In some embodiments, the cancer or the tumor may be a liquid cancer or a liquid tumor. In some embodiments, the cancer or the tumor may be malignant. In some embodiments, the cancer or the tumor may be present in an organ. In some embodiments, the tumor or the cancer may be present in at least one of: blood, lymph, cerebral spinal fluid. In some embodiments, the cancer or the tumor may be located in a head or neck region, abdominal region, a upper limb, a lower limb, skin, blood, digestive tract, germ cell, or nervous system. Computer Control Systems

[0222] In some embodiments, the present disclosure provides computer control systems that are programmed to implement methods of the disclosure . FIG. 4 shows a computer control system 401. The computer control system 401 may be implemented on an electronic device of a user or a computer system that can be remotely located with respect to the electronic device. The electronic device may be a mobile electronic device.

[0223] In some embodiments, a computer system 401 includes a central processing unit (CPU, also “processor” and“computer processor” herein) 405, which may be a single core or multi core processor, or a plurality of processors for parallel processing. The computer control system 401 also includes memory or memory location 410 (e.g., random -access memory, read-only memory, flash memory), electronic storage unit 415 (e.g., hard disk), communication interface 420 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 425, such as cache, other memory, data storage and/or electronic display adapters. The memory 410, storage unit 415, interface 420 and peripheral devices 425 are in communication with the CPU 405 through a communication bus (solid lines), such as a motherboard. The storage unit 415 may be a data storage unit (or data repository) for storing data. The computer control system 401 may be operatively coupled to a computer network (“network”) 430 with the aid of the communication interface 420. The network 430 may be the Internet, an internet and/or extranet, or an intranet and/or extranet that can be in communication with the Internet. The network 430 in some cases can comprise a telecommunication and/or data network. The network 430 may include one or more computer servers, which may enable distributed computing, such as cloud computing. The network 430, in some cases with the aid of the computer system 401, may implement a peer-to-peer network, which may enable devices coupled to the computer system 401 to behave as a client or a server.

[0224] In some embodiments, a CPU 405 may execute a sequence of machine-readable instructions, which may be embodied in a program or software. The instructions may be stored in a memory location, such as the memory 410. The instructions may be directed to the CPU 405, which may subsequently program or otherwise configure the CPU 405 to implement methods of the present disclosure. Examples of operations performed by the CPU 405 may include fetch, decode, execute, and writeback.

[0225] In some embodiments, a CPU 405 may be part of a circuit, such as an integrated circuit. One or more other components of the system 401 may be included in the circuit. In some cases, a circuit can comprise an application specific integrated circuit (ASIC).

[0226] In some embodiments, a storage unit 415 may store files, such as drivers, libraries and saved programs. The storage unit 415 may store user data, e.g., user preferences and user programs. The computer system 401 in some cases may include one or more additional data storage units that are external to the computer system 401, such as located on a remote server that can be in communication with the computer system 401 through an intranet or the Internet.

[0227] In some embodiments, a computer system 401 may communicate with one or more remote computer systems through the network 430. For instance, the computer system 401 may communicate with a remote computer system of a user. Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user may access the computer system 401 via the network 430.

[0228] In some embodiments, methods as described herein may be implemented by way of machine (e.g., computer processor) executable code stored on an electronic storage location of the computer system 401, such as, for example, on the memory 410 or electronic storage unit 415. The machine executable or machine readable code may be provided in the form of software. During use, the code may be executed by the processor 405. In some cases, the code may be retrieved from the storage unit 415 and stored on the memory 410 for ready access by the processor 405. In some situations, the electronic storage unit 415 may be precluded, and machine-executable instructions are stored on memory 410.

[0229] In some embodiments, a code may be pre-compiled and configured for use with a machine having a processer adapted to execute the code, or may be compiled during runtime. The code may be supplied in a programming language that may be selected to enable the code to execute in a pre-compiled or as-compiled fashion.

[0230] In some embodiments, systems and methods provided herein, such as the computer system 401, may be embodied in programming. Various aspects of the technology may be thought of as “products” or“articles of manufacture” typically in the form of machine (or processor) executable code and/or associated data that can be carried on or embodied in a type of machine readable medium.

Machine -executable code may be stored on an electronic storage unit, such as memory (e.g., read-only memory, random-access memory, flash memory) or a hard disk.“Storage” type media may include any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which may provide non- transitory storage at any time for the software programming. All or portions of the software may at times be communicated through the Internet or various other telecommunication networks. Such

communications, for example, may enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server. Thus, another type of media that may bear the software elements includes optical, electrical and electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various air-links. The physical elements that carry such waves, such as wired or wireless links, optical links or the like, also may be considered as media bearing the software. As used herein, unless restricted to non-transitory, tangible“storage” media, terms such as computer or machine“readable medium” refer to any medium that participates in providing instructions to a processor for execution.

[0231] In some embodiments,, a machine readable medium, such as computer-executable code, may take many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium. Non-volatile storage media include, for example, optical or magnetic disks, such as any of the storage devices in any computer(s) or the like, such as may be used to implement the databases, etc. shown in the drawings. Volatile storage media include dynamic memory, such as main memory of such a computer platform. Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system. Carrier-wave transmission media may take the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications. Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which a computer may read programming code and/or data. Many of these forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution.

[0232] In some embodiments, a computer system 401 may include or be in communication with an electronic display 435 that comprises a user interface (UI) 440.

[0233] In some embodiments, methods and systems of the present disclosure may be implemented by way of one or more algorithms. An algorithm may be implemented by way of software upon execution by the central processing unit 405.

EXAMPLES

Example 1 : Multiplexed Fluorescence IHC

[0234] Formaldehyde-fixed, paraffin-embedded tumor tissue slides were baked for 30 min at 65°C. The slides were placed in a Tissue-Tek 24-slide holder (Fisher Scientific) and transferred to a Tissue-Tek staining dish (Fisher Scientific) containing 250 mL Borg Decloaker (BioCare Medical) for de- paraffinization/rehydration/antigen retrieval. The slide holder containing the slides was then placed into a Decloaking Chamber NxGen pressure cooker (BioCare Medical). A Tissue-Tek staining dish containing 250 mL Hot Rinse (BioCare Medical) was also placed into the pressure cooker. The pressure cooker was set for 110°C, and run for 15 min. After antigen retrieval was completed, both staining dishes were removed from the pressure cooker. The slides were rinsed with the Hot Rinse and transferred to DI water according to manufacturer’s protocol. For blocking endogenous peroxidases, slides were transferred to a Tissue-Tek staining dish containing 250 mL 0.3% hydrogen peroxide (Sigma) and incubated for 10 min. Slides were then washed in TBS for 5 min, and transferred to TBS containing 0.1% Tween-20 (TBS-T) (Cell Signaling Technologies) before staining.

[0235] The slides were transferred to a Stain Tray (Electron Microscopy Sciences). Two hundred pL primary antibody solution (diluted in antibody diluent (Dako)) was pipetted over the tissue and incubated for 30 min at room temperature. Excess antibody solution was aspirated, and the slides were then washed 4 times in TBS-T, 3 minutes each. Following washing, 150 pL of Opal Polymer HRP anti-Mouse/Rabbit secondary detection reagent (Perkin Elmer) was added to the slides and incubated for 10 min at room temperature. Excess secondary detection reagent was aspirated, and the slides were then washed 3 times in TBS-T, 3 minutes each. Following washing, 150 pL of the diluted (1: 100 in amplification buffer (Perkin Elmer)) fluorochrome-conjugated TSA reagent (Perkin Elmer) was added to the slides and incubated for 10 min at room temperature. Excess TSA reagent was aspirated, and the slides were then washed 3 times in TBS-T, 3 minutes each. Following washing, the slides were placed into a Tissue-Tek staining dish containing lx AR6 Buffer (Perkin Elmer) and microwaved on 100% power for 2 min followed by 20 minutes at 20% power. After microwaving, the staining dish containing the slides was transferred to the sink and a total of 500 mL DI water was gradually added to rinse and cool the slides, and finally transferred to TBS-T. These steps were repeated for each subsequent stain. [0236] After the final stain, the slides were stained with 200 pL DAPI solution (Perkin Elmer) for 5 min, and washed in TBS-T, followed by TBS, 5 min each. The slides were transferred to DI water and mounted with Prolong Diamond Antifade Mountant (ThermoFisher Scientific). A coverslip was placed, and allowed to cure overnight before imaging.

[0237] Slides were imaged with a Vectra Automated Quantitative Pathology Imaging System (Perkin Elmer). Images were spectrally unmixed and exported using inForm Software (Perkin Elmer).

[0238] Response to therapy was defined as either complete response (CR), partial response (PR) stable disease (SD), or progressive disease (PD). APRIL expression correlates with disease progression (FIG. 1A - FIG. IQ, FIG. 2A - FIG. 2E, and FIG. 3). Patients that initially showed a partial response to treatment developed an acquired resistance as APRIL expression increased (see Patients 1 and 2). The presence of APRIL in patients’ tumors at baseline would suggest a mechanism for resistance resulting in no response to anti -PD 1 treatment and disease progression (see Patient 3).

Example 2: Baseline BAFF and APRIL expression according to treatment outcome

[0239] Baseline FFPE Melanoma samples from anti -PD- 1 -treated patients were stained by multiplex fluorescence immunohistochemistry using the methods described in Example 1. Samples were stained for APRIL, BAFF, BAFFR, BCMA, CD 138, and IgA. FIG. 5A - FIG. 5T show expression of APRIL (FIG. 5A, FIG. 5B, FIG. 5C, FIG. 5D, FIG. 5E), BAFF (FIG. 5F, FIG. 5G, FIG. 5H, FIG. 51, FIG. 5J), BCMA (FIG. 5K, FIG. 5L, FIG. 5M, FIG. 5N, FIG. 50), and BCMA/BAFF-R/CD138 (FIG. 5P, FIG. 5Q, FIG. 5R, FIG. 5S, FIG. 5T) expression in sample (T cell inflamed tumor) from a patient with type II resistance pretreatment and post treatment with anti -PD 1 and did not respond to treatment. FIG. 6A - FIG. 6B show expression of APRIL+ cells innervated by CD 138+ cell at baseline (FIG. 6A) and BAFF-R+ tertiary follicle structures present 150 days into treatment with anti-PDl and did not respond to treatment (FIG. 6B) in sample (T cell inflamed tumor) from a patient with type II resistance. FIG. 7 shows baseline BAFF and APRIL expression according to treatment outcome. The density of BAFF+ (FIG. 7A) or APRIL+ (FIG. 7B) expression was determined as the number of positively stained cells per area of tissue analyzed. The densities were plotted according to treatment outcome (Responders (N=13) or Progressors (N=28) (Type-I (N=13) or Type-II (N=15))).

Examnle 3: BAFF and APRIL covariate in metastatic melanoma

[0240] FFPE Melanoma samples (N=75) from anti-PD-1 treated patients were stained by multiplex fluorescence immunohistochemistry for APRIL, BAFF, BAFFR, BCMA, CD 138, and IgA. The density of BAFF+ or APRIL+ expression was determined as the number of positively stained cells per area of tissue analyzed. FIG. 8 shows BAFF and APRIL covariate in metastatic melanoma. FIG. 8A shows APRIL and BAFF densities plotted together on an XY Plot. A Spearman nonparametric correlation was determined using GraphPad Prism Software. FIG. 8B and FIG. 8E show representative staining of APRIL on metastatic melanoma tissue (DAPI staining of cell nuclei). FIG. 8C and FIG. 8F show representative staining of BAFF on tissue samples, and FIG. 8D and FIG. 8G show a combination image of APRIL and BAFF .

Example 4: BAFF system signaling is associated with Type II Resistance

[0241] FFPE Melanoma samples (N=75) from anti-PD-1 -treated patients were stained by multiplex fluorescence immunohistochemistry for BAFF, IgA, and APRIL (shown in FIG. 9A), and BCMA, CD138, and BAFFR (shown in FIG. 9B). The density of cell (sub)population was determined as the number of positively stained cells per area of tissue analyzed. A heat map was generated to determine the relative abundance of each (sub)population according to treatment outcome.

Example 5: Relationship between APRIL expression and CD138+BCMA+ cell density

[0242] FFPE Melanoma samples (N=75) from anti-PD-1 -treated patients were stained by multiplex fluorescence immunohistochemistry for APRIL, BAFF, BAFFR, BCMA, CD 138, and IgA. The density of APRIL+ or CD138+BCMA+ expression was determined as the number of positively stained cells per area of tissue analyzed. APRIL and CD138+BCMA+ densities were plotted together on an XY Plot. A Spearman nonparametric correlation was determined using GraphPad Prism Software. FIG. 10 shows the relationship between APRIL expression and CD138+BCMA+ cell density.

Example 6: Gene expression of APRIL and correlation with immune activation signature

[0243] Correlation heatmaps

[0244] 11,574 HTSeq - FPKM files representing an equivalent number of cancer samples were acquired from TCGA data release v9.0. Files were annotated with disease type based on the associated project annotations also acquired from TCGA release v.9.0. Triple negative breast cancer samples were separated from other breast cancer samples using the clinical file associated with each sample record in TCGA. Samples that were false for all the following fields were counted as triple negative:

“breast_carcinoma_progesterone_receptor_status”,“breast_carcinoma_estrogen_receptor_status”, and “lab_proc_her2_neu_immunohistochemistry_receptor_status”. Information for genes were extracted as the“immune activation signature”. The selected genes are shown in Table 5.

[0245] Table 5: Genes that were extracted as the“immune activation signature”.

[0246] Information for the following genes were extracted as the“housekeeping genes” or “reference genes”. This gene set was taken from the 195 genes identified by Protein Atlas as housekeeping/reference, i.e. genes which are expressed ubiquitously. For the 144 ribosomal genes, 18 were selected representing each functional class. For the 25 RNA polymerase genes, 4 were selected representing each functional class. For the 26 citric acid cycle genes, 14 were chosen representing each functional class. That set of housekeeping genes is shown in Table 6.

[0247] Table 6: Genes that were extracted as the housekeeping/reference genes

[0248] Information on BAFF expression was extracted using the identifier ENSG00000102524.10. Information on APRIL· expression was extracted using the identifier ENSG00000161955.15.

[0249] A correlation matrix was calculated for all the above genes versus both BAFF and APRIL by filtering the dataset to only those samples representing each of the 36 disease types in the TCGA RNA- Seq dataset and calculating a Spearman’s rank order correlation coefficient of the FPKM expression values for each gene pair paired by sample filtered by the disease type using the SciPy 0.19.1 statistical package.

Correlation significance

[0250] The correlation heatmap for the target correlation significance analysis was calculated as above. Diseases with fewer than 100 samples were excluded.

[0251] A single value“immune activation score” for the genes for each disease in the immune activation was created by first normalizing each gene vector and then reducing to a single dimension using PCA. Both mathematical functions were performed using Scikit-leam v 0.19.1.

[0252] Significance for each Spearman’s Rho was calculated as follows. A model of random sample gene correlation was constructed for each disease by calculating Spearman’s Rho for a set of randomly selected 10,000 pairs of genes. Genes with no measured expression in any sample were excluded from this random model. A mean and standard deviation of this background model was calculated for each disease and used to determine the required Z-score and corresponding significant Spearman’s Rho values for a two-sided P-value test < 0.05 corrected for multiple testing using the Bonferroni method.

Spearman’s rho values corresponding to those that are significant were displayed on the heatmap and those below significance were not displayed.

Results

[0253] The relationship between APRIL expression and a housekeeping gene signature (39 genes) was examined by analyzing TCGA RNA-seq gene expression data in 11,574 cancer samples using Spearman’s Rho correlation. Numerical values are shown on a heatmap of Spearman’s Rank Correlation with p < 0.05. FIG. 11 shows the differences in gene signature between APRIL and a housekeeping gene.

[0254] The relationship between APRIL expression and a T-cell inflamed gene signature (39 genes) was examined by analyzing TCGA RNA-seq gene expression data in 11,574 cancer samples using Spearman’s Rho correlation. Numerical values are shown on a heatmap of Spearman’s Rank Correlation with p < 0.05. FIG. 12 shows the differences in gene signature between APRIL and a T-cell inflamed gene signature. [0255] The results showed an overall correlation in the APRIL (TNFS13) FPKM gene expression and an immune activation gene signature for a majority of different cancer types when compared to equivalent data correlating APRIL (TNFS13) FPKM gene expression and housekeeping/reference genes. In particular a strong correlation was observed for lung squamous cell carcinoma, sarcoma,

neuroblastoma, glioblastoma multiforme, head and neck squamous cell carcinoma, cutaneous melanoma, and brain lower grade glioma.

[0256] While preferred embodiments of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising:

a. an APRIL inhibitor or a salt thereof; and

b. a B-cell activating factor receptor (BAFF-R) inhibitor or a salt thereof.

2. The pharmaceutical composition of claim 1, wherein said BAFF-R inhibitor or said salt thereof comprises an antibody, single chain antibody molecule, or an active fragment thereof.

3. The pharmaceutical composition of claim 2, wherein said BAFF-R inhibitor or said salt thereof comprises said antibody or said active fragment thereof.

4. The pharmaceutical composition of any one of claims 2-3, wherein said antibody or said active fragment thereof comprises a monoclonal antibody or an active fragment thereof or a polyclonal antibody or an active fragment thereof.

5. The pharmaceutical composition of any one of claims 2-4, wherein said antibody or said active fragment thereof is humanized.

6. The pharmaceutical composition of any one of claims 2-5, wherein said antibody or said active fragment thereof comprises an IgG, IgE, IgM, IgD, IgA or IgY.

7. The pharmaceutical composition of any one of claims 2-6, wherein said antibody or said active fragment thereof is a recombinant protein.

8. The pharmaceutical composition of any one of claims 2-7, wherein said BAFF-R inhibitor or said salt thereof comprises a heavy chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NO: 29.

9. The pharmaceutical composition of any one of claims 2-8, wherein said BAFF-R inhibitor or said salt thereof comprises a light chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NO: 30.

10. The pharmaceutical composition of any one of claims 2-9, wherein said BAFF-R inhibitor or said salt thereof comprises a light chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 24-27; 84 or 85.

11. The pharmaceutical composition of any one of claims 2-10, wherein said BAFF-R inhibitor or said salt thereof comprises a heavy chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 21-23 or 28.

12. A pharmaceutical composition comprising:

a. an APRIL inhibitor or a salt thereof; and

b. a checkpoint inhibitor or a salt thereof.

13. The pharmaceutical composition of claim 12, wherein said checkpoint inhibitor or said salt thereof comprises a PD-1 inhibitor, PD-L1 inhibitor or PD-L2 inhibitor.

14. The pharmaceutical composition of any one of claims 12-13, wherein said checkpoint inhibitor or said salt thereof comprises a second antibody, second single chain antibody molecule, or an active fragment thereof.

15. The pharmaceutical composition of claim 14, wherein said checkpoint inhibitor or said salt thereof comprises said second antibody or said active fragment thereof.

16. The pharmaceutical composition of any one of claims 14-15, wherein said second antibody or said active fragment thereof comprises a monoclonal antibody or an active fragment thereof or a polyclonal antibody or an active fragment thereof.

17. The pharmaceutical composition of any one of claims 14-16, wherein said second antibody or said active fragment thereof is humanized.

18. The pharmaceutical composition of any one of claims 14-17, wherein said second antibody or said active fragment thereof comprises an IgG, IgE, IgM, IgD, IgA or IgY.

19. The pharmaceutical composition of any one of claims 14-18, wherein said second antibody or said active fragment thereof comprises a recombinant protein.

20. The pharmaceutical composition of any one of claims 14-19, wherein said checkpoint inhibitor or said salt thereof comprises a heavy chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 17; 19; 165; 167; 169; 171 or 173.

21. The pharmaceutical composition of any one of claims 14-20, wherein said checkpoint inhibitor or said salt thereof comprises a light chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: : 18; 20; 166; 168; 170; 172 or 174.

22. The pharmaceutical composition of any one of claims 12-21, wherein said checkpoint inhibitor inhibits PD-1,PD-L1, PD-L2, CTLA-4, A2AR, B7-H3, B7-H4, BTLA, IDO, KIR, LAG3, TIM- 3, VISTA, CD 160, TIGIT or PSGL-1.

23. The pharmaceutical composition of any one of claims 1-22, wherein said APRIL inhibitor or said salt thereof comprises a third antibody, third single chain antibody molecule, or an active fragment thereof.

24. The pharmaceutical composition of claim 23, wherein said APRIL inhibitor or said salt thereof comprises said third antibody or said active fragment thereof.

25. The pharmaceutical composition of any one of claims 23-24, wherein said third antibody or said active fragment thereof comprises a monoclonal antibody or an active fragment thereof or a polyclonal antibody or an active fragment thereof.

26. The pharmaceutical composition of any one of claims 23-25, wherein said third antibody or said active fragment thereof is humanized.

27. The pharmaceutical composition of any one of claims 23-26, wherein said third antibody or said active fragment thereof comprises an IgG, IgE, IgM, IgD, IgA or IgY.

28. The pharmaceutical composition of any one of claims 23-27, wherein said third antibody or said active fragment thereof comprises a recombinant protein.

29. The pharmaceutical composition of any one of claims 23-28, wherein said APRIL inhibitor or said salt thereof comprises a heavy chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 217-224; 227-229 or 231.

30. The pharmaceutical composition of any one of claims 23-29, wherein said APRIL inhibitor or said salt thereof comprises a light chain having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: : 225-226; 230 or 22.

31. The pharmaceutical composition of any one of claims 23-30, wherein said APRIL inhibitor or said salt thereof comprises a light chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: SEQ ID NO: 179; 181; 185-187; or 195-206.

32. The pharmaceutical composition of any one of claims 23-31, wherein said APRIL inhibitor or said salt thereof comprises a heavy chain variable region having at least 80% or 90% sequence identity with a sequence shown in SEQ ID NOS: 178; 180; 182-184; 188-194; or 207-216.

33. The pharmaceutical composition of any one of claims 1-32, wherein said APRIL inhibitor or said salt thereof is a biosimilar product to a reference product, wherein said reference product comprises atacicept or a salt of any one thereof, and any combination thereof.

34. The pharmaceutical composition of any one of claims 1-33, wherein:

a. said APRIL inhibitor or said salt thereof,

b. said checkpoint inhibitor or said or said salt thereof, or

c. said BAFF-R inhibitor or said salt thereof is a bispecific antibody.

35. The pharmaceutical composition of any one of claims 1-34, wherein said pharmaceutical

composition further comprises a pharmaceutically acceptable excipient.

36. The pharmaceutical composition of any one of claims 1-35, wherein said pharmaceutical

composition is in unit dose form.

37. The pharmaceutical composition of any one of claims 1-36, further comprising an addition agent.

38. The pharmaceutical composition of claim 37, wherein said additional agent comprises a BAFF inhibitor or a salt thereof.

39. The pharmaceutical composition of claim 38, wherein said BAFF inhibitor or said salt thereof comprises an antibody, single chain antibody molecule, or an active fragment thereof.

40. A kit comprising:

a. said APRIL inhibitor or salt thereof of any one of claims 1-39; and

b. said B-cell activating factor receptor (BAFF-R) inhibitor or a salt thereof of any one of claims 1-11; or said checkpoint inhibitor of any one of claims 12-22.

41. A bispecific antibody comprising:

a. a first domain, wherein said first domain specifically binds APRIL or a portion thereof; and b. a second domain, wherein said second domain specifically binds PD1, PDL1 or BAFF- R.

42. The bispecific antibody of claim 41, wherein said first domain comprises a heavy chain

variable region, light chain variable region, light chain or heavy chain of atacicept.

43. The bispecific antibody of claim 41, wherein said first domain comprises at least 80% or 90% sequence identity to any one of SEQ ID NOS: 178 - 232.

44. The bispecific antibody of any one of claims 41-43, wherein said second domain comprises a heavy chain variable region, light chain variable region, light chain or heavy chain of nivolumab, docetaxel, pembrolizumab, pidilizumab, BGB-A31, MEDI0680, AMP-224, MEDI0680, PDR001, Cemiplimab or a combination thereof.

45. The bispecific antibody of claim 41, wherein said second domain comprises at least 80% or 90% sequence identity to any one of SEQ ID NOS: 17-20; 165-174; 21-30; 84 or 85.

46. A method comprising administering said pharmaceutical composition of any one of claims 1-36 or said bispecific antibody of any one of claims 41-45 to a subject.

47. The method of claim 46, wherein said bispecific antibody of any one of claims 41-45 is

administered to said subject.

48. The method of claim 46, wherein said pharmaceutical composition of any one of claims 1-36 is administered to said subject.

49. The method of claim 48, wherein said APRIL inhibitor or said salt thereof and said checkpoint inhibitor or said salt thereof are administered concurrently.

50. The method of claim 49, wherein said APRIL inhibitor or said salt thereof and said checkpoint inhibitor or said salt thereof are administered together in a single composition.

51. The method of claim 48, wherein said APRIL inhibitor or said salt thereof and said checkpoint inhibitor or said salt thereof are administered sequentially.

52. The method of claim 51, wherein said APRIL inhibitor or said salt thereof is first administered and said checkpoint inhibitor or said salt thereof is administered second.

53. The method of claim 51, wherein said checkpoint inhibitor or said salt thereof is first

administered and said APRIL inhibitor or said salt thereof is administered second.

54. The method of claim 48, wherein said APRIL inhibitor or said salt thereof and said BAFF-R inhibitor or said salt thereof are administered concurrently.

55. The method of claim 54, wherein said APRIL inhibitor or said salt thereof and said BAFF-R inhibitor or said salt thereof are administered together in a single composition.

56. The method of claim 48, wherein said APRIL inhibitor or said salt thereof and said BAFF-R inhibitor or said salt thereof are administered sequentially.

57. The method of claim 56, wherein said APRIL inhibitor or said salt thereof is first administered and said BAFF-R inhibitor or said salt thereof is administered second.

58. The method of claim 56, wherein said BAFF-R inhibitor or said salt thereof is first administered and said APRIL inhibitor or said salt thereof is administered second.

59. The method of any one of claims 46-58, wherein said subject have a cancer or is suspected of having said cancer.

60. The method of claim 59, wherein said cancer comprises leukemia, melanoma, prostate cancer, bladder cancer, osteosarcoma, cervical cancer, liver cancer, multiple myeloma, testicular, renal cancer or a combination thereof.

61. The method of any one of claims 46-60, wherein said cancer was at least partially refractive to said administration.

62. The method of any one of claims 46-61, wherein said subject was previously treated with a checkpoint inhibitor or a salt thereof, and said cancer was at least partially refractive to said checkpoint inhibitor or a salt thereof.

63. The method of any one of claims 46-62, wherein said administering is intra-arterially,

intravenously, intramuscularly, orally, subcutaneously, via inhalation, or any combination thereof.

64. The method of any one claims 46-63, wherein the method comprises a method of treating a cancer.

65. The method of any one of claims 46-64, wherein prior to said administering, an expression level of APRIL is assessed.

66. The method of claim 65, wherein said expression level of APRIL is compared to a reference.

67. The method of claim 66, wherein said expression level of APRIL is above said reference.

68. The method of any one of claims 66-67, wherein said reference is derived from a non disease sample.

69. The method of any one of claims 66-67, wherein said reference is derived from a disease sample.

70. The method of claim 69, wherein said disease sample is from a subject having a disease.

71. The method of claim 69, wherein said disease sample is from a subject having a disease, wherein said disease is in remission.

72. The method of claim 69, wherein said disease sample is from a subject having a disease, wherein said disease is progressing.

73. The method of claim 69, wherein said disease sample is from a subject having a disease, wherein said disease is stable.

74. The method of any one of claims 69-73, wherein said disease sample comprises a cancer sample.

75. A method comprising:

a. administering to a subject, a single therapy or a combination therapy based on an expression of APRIL in a sample obtained from said subject.

76. The method of claim 75, wherein said single therapy is administered if said expression of APRIL is below a threshold.

77. The method of claim 76, wherein said subject is responsive to said single therapy.

78. The method of claim 76 or 77, wherein said single therapy comprises a BAFF inhibitor, BAFF- R inhibitor, checkpoint inhibiter or an APRIL inhibitor.

79. The method of claim 75, wherein said combination therapy is administered if said expression of APRIL is above a threshold.

80. The method of claim 79, wherein said subject is responsive to said combination therapy and nonresponsive to said single therapy.

81. The method of claim 79 or 80, wherein said combination therapy comprises two or more of a BAFF inhibitor, BAFF-R inhibitor, checkpoint inhibiter or an APRIL inhibitor.

82. A method comprising

a. detecting a level of APRIL in a sample obtained from a subject having cancer or

suspected of having said cancer, wherein said detecting is performed at least twice; and b. determining disease status based on said detecting.

83. The method of claim 82, wherein APRIL expression is below a reference level.

84. The method of claim 83, wherein the disease status is stable.

85. The method of claim 82, wherein APRIL expression is above a reference level.

86. The method of claim 85, wherein the disease status is progressive.

87. A method of making a pharmaceutical composition comprising:

a. contacting said APRIL inhibitor or salt thereof of any one of claims 1-39 and

i. said B-cell activating factor receptor (BAFF-R) inhibitor or a salt thereof of any one of claims 1-11; or

ii. said checkpoint inhibitor of any one of claims 12-22.

88. The pharmaceutical composition of claim 87, wherein the pharmaceutical composition is in a form of a tablet, a capsule, a gel, or a liquid formulation.