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  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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  • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
  • C12N15/09—Recombinant DNA-technology
  • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
  • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
  • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
  • C12N15/86—Viral vectors
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  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
  • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• • C—CHEMISTRY; METALLURGY
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  • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
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  • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
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  • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

• the immunomodulatory compound is administered once daily, twice daily, three times daily, four times daily, five times daily, or six times daily. In some embodiments, the immunomodulatory compound is administered at a total daily dosage amount of at least or at least about 0.1 mg per day, 0.5 mg per day, 1.0 mg per day, 2.5 mg per day, 5 mg per day, 10 mg per day, 25 mg per day, 50 mg per day or 100 mg per day. [0052] In some embodiments of any of the methods provided herein, the immunomodulatory compound is administered in an amount greater than or greater than about 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg and less than 25 mg; or the immunomodulatory compound is
• the amount of cells administered in the T cell therapy is less than the amount in another method in which the T cell therapy is administered without administration of the immunomodulatory compound, optionally which other method results in a similar or lower degree of amelioration or reduction or prevention of the disease or condition or symptom or burden thereof, as compared to that resulting from the method.
• the amount of cells administered is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, or 10-fold less than that administered in the other method.
• immunomodulatory compound is administered in the absence of the T cell therapy, optionally at the same dose or dosing schedule.
• the instructions specify continuing administration of the immunomodulatory compound, from at least after initiation of administration of the T cells, until the number of cells of or derived from the administered T cell therapy detectable in the blood from the subject is increased compared to in the subject at a preceding time point just prior to administration of the immunomodulatory compound or compared to a preceding time point after administration of the T-cell therapy; the number of cells of or derived from the T cell therapy detectable in the blood is within 2.0-fold (greater or less) the peak or maximum number observed in the blood of the subject after initiation of administration of the T cells; the number of cells of the T cell therapy detectable in the blood from the subject is greater than or greater than about 10%, 15%, 20%, 30%, 40%, 50%, or 60% total peripheral blood mononuclear cells (PBMCs) in the blood of the subject; and/or the subject exhibits a reduction in tumor burden as compared to tumor burden at a time immediately prior to the administration of the T cell therapy or at a time immediately prior to
• PBMCs peripheral blood mononu
• the immunomodulatory compound is formulated for oral administration.
• the immunomodulatory compound is formulated in a capsule or a tablet.
• the T cell therapy contains primary cells derived from a subject.
• the subject is a human.
• FIG. 7A shows the tumor volume of mice over time after administration of a low dose of anti-BCMA CAR+ T cells in the presence and absence of lenalidomide.
• FIGs. 10A-10D show the survival of mice in the presence or absence of
• Lenalidomide was administered via Regimen A (Len A; administration of lenalidomide initiated at day -1) or Regimen B (Len B; administration of lenalidomide initiated at day 14) in combination with low (5 x 10 5 or 5e 5 ) or high (1 x 10 6 or le 6 ) doses of CAR+ T cells.
• T cells that did not express a CAR (mock) were administered in the presence and absence of lenalidomide via both Regimen A and Regimen B, and lenalidomide without T cells was also administered via both Regimen A and Regimen B.
• FIG. 24D shows results of flow cytometric analysis of surface CD25 and PD-1 expression (mean fluorescent intensity (MFI), for CD4+ or CD8+ anti-BCMA CAR T-cells after stimulation (pretreatment) with BCMA beads for 7 days, in the presence or absence of 1 ⁇ lenalidomide.
• FIG. 24E shows the flow cytometric analysis across CAR T donors for median fluorescence intensity (MFI; CD25 and Tim3) or percentage positive PD-1 and Lag3 on the surface of T-cell markers in CD4+ CAR+ and CD8+ CAR+ subsets (gated on live CD3+ cells). Values shown are percentage baseline (Veh) MFI, viability, or count.
• MFI mean fluorescent intensity
• FIGS. 27C and 27D show volcano plots depicting statistical significance of expression (logio of adjusted p-value) with the log 2 fold-change in g chromatin accessibility, including genes or peaks that show increased (right side) or decreased (left side) accessibility, in CAR+ T cells stimulated with BCMA-conjugated beads, for 24 hours (24 hr + stim, FIG. 27C) or 7 days (d7 + stim, FIG. 27D).
• the tables indicate the number of genes or peaks that showed statistically significant increase (up) or decrease (down) in accessibility.
• an immunotherapy or immunotherapeutic agent such as a composition including cells for adoptive cell therapy, e.g., such as a T cell therapy (e.g. CAR-expressing T cells).
• a T cell therapy e.g. CAR-expressing T cells.
• the combination therapy involves administration of an immunotherapy or immunotherapeutic agent
• the cell therapy is or comprises a tumor infiltrating lymphocytic (TIL) therapy, a transgenic TCR therapy or a recombinant-receptor expressing cell therapy (optionally T cell therapy), which optionally is a chimeric antigen receptor (CAR)-expressing cell therapy.
• TIL tumor infiltrating lymphocytic
• TCR transgenic TCR therapy
• CAR chimeric antigen receptor
• the therapy is a B cell targeted therapy.
• the therapy targets B cell maturation antigen (BCMA).
• the therapy targets CD 19.
• the cells and dosage regimens for administering the cells can include any as described in the following subsection A under "Administration of T Cell therapy.”
• the dose of cells of the T cell therapy is provided as a composition or formulation, such as a pharmaceutical composition or formulation.
• a composition or formulation such as a pharmaceutical composition or formulation.
• Such compositions can be used in accord with the provided methods, such as in the prevention or treatment of diseases, conditions, and disorders.
• the pharmaceutical composition further includes other pharmaceutically active agents or drugs, such as chemotherapeutic agents, e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.
• chemotherapeutic agents e.g., asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.
• the immunomodulatory compound is 1-oxo- and 1,3 dioxo-2- (2,6-dioxopiperldin-3-yl) isoindolines substituted with amino in the benzo ring as described in U.S. Pat. No. 5,635,517 which is incorporated herein by reference.
• R 5 is other than hydrogen if X and Y are -C(O)- and (i) each of R 1 , R 2 , R 3 , and R 4 is fluoro; or (ii) one of R 1 , R 2 , R 3 , and R 4 is amino;
• the immunomodulatory compound is a compound that belongs to a class of isoindole-immunomodulatory compounds disclosed in U.S. Patent
• the immunomodulatory compound is an inhibitor of E3 ubiquitin ligase. In some embodiments, the immunomodulatory compound is a derivative of thalidomide. In some embodiments, the immunomodulatory compound is a structural and/or functional analogue of thalidomide. In some embodiments, the immunomodulatory compound is lenalidomide, pomalidomide, avadomide, or a pharmaceutically acceptable salt thereof.
• the immunomodulatory compound is a solvate of (R)-3-(4-Amino-l-oxo-l,3-dihydro-2H- isoindol-2-yl)piperidine-2,6-dione and/or (,S)-3-(4-Amino-l-oxo-l,3-dihydro-2H-isoindol-2- yl)piperidine-2,6-dione.
• the pharmaceutical composition containing the immunomodulatory compound, e.g., lenalidomide in some aspects can employ time-released, delayed release, and sustained release delivery systems such that the delivery of the composition occurs prior to, and with sufficient time to cause, sensitization of the site to be treated.
• time-released, delayed release, and sustained release delivery systems such that the delivery of the composition occurs prior to, and with sufficient time to cause, sensitization of the site to be treated.
• Many types of release delivery systems are available and known. Such systems can avoid repeated administrations of the composition, thereby increasing convenience to the subject and the physician.
• compositions containing the immunomodulatory compound can also be lyophilized.
• the compositions can contain auxiliary substances such as wetting, dispersing, or emulsifying agents (e.g., methylcellulose), pH buffering agents, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts may in some aspects be consulted to prepare suitable preparations.
• the immunomodulatory compound, e.g., lenalidomide is administered daily for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, is administered twice a day for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, is administered three times a day for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days. In some embodiments, the immunomodulatory compound, e.g., lenalidomide, is administered every other day for 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 days.
• Tyrosinase related protein 1 (TRPl, also known as TYRPl or gp75), Tyrosinase related protein 2 (TRP2, also known as dopachrome tautom erase, dopachrome delta-isomerase or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms Tumor 1 (WT-1), a pathogen-specific or pathogen-expressed antigen, or an antigen associated with a universal tag, and/or biotinylated molecules, and/or molecules expressed by HIV, HCV, HBV or other pathogens.
• TRPl Tyrosinase related protein 1
• TRP2 also known as dopachrome tautom erase, dopachrome delta-isomerase or DCT
• VEGFR vascular endothelial growth factor receptor
• VEGFR2 vascular endothelial growth factor receptor 2
• WT-1 Wilms Tumor 1
• the CAR is an anti-CD 19 CAR that is specific for CD 19, e.g. human CD 19.
• the antigen-binding domain includes a V H and/or V L derived from FMC63, which, in some aspects, can be an scFv.
• the scFv and/or V H domains is derived from FMC63.
• FMC63 generally refers to a mouse monoclonal IgGl antibody raised against Nairn- 1 and -16 cells expressing CD19 of human origin (Ling, N. R., et al. (1987). Leucocyte typing III. 302).
• the svFv comprises a variable light chain containing the CDRLl sequence of SEQ ID NO:48, a CDRL2 sequence of SEQ ID NO:49, and a CDRL3 sequence of SEQ ID NO:51 and/or a variable heavy chain containing a CDRHl sequence of SEQ ID NO:44, a CDRH2 sequence of SEQ ID NO:45, and a CDRH3 sequence of SEQ ID NO:46.
• the scFv comprises a variable heavy chain region of FMC63 set forth in SEQ ID NO:53 and a variable light chain region of FMC63 set forth in SEQ ID NO:54.
• the variable heavy and variable light chains are connected by a linker.
• the linker is set forth in SEQ ID NO: 70, 72, 73, 74 or 189.
• the scFv comprises, in order, a V H , a linker, and a V L . In some embodiments, the scFv comprises, in order, a V L , a linker, and a V H . In some embodiments, the svFv is encoded by a sequence of nucleotides set forth in SEQ ID NO:69 or a sequence that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:69.
• the antibody is an antigen-binding fragment, such as an scFv, that includes one or more linkers joining two antibody domains or regions, such as a heavy chain variable (V H ) region and a light chain variable (V L ) region.
• the antibodies include single-chain antibody fragments, such as scFvs and diabodies, particularly human single-chain antibody fragments, typically comprising linker(s) joining two antibody domains or regions, such V H and V L regions.
• the linker typically is a peptide linker, e.g., a flexible and/or soluble peptide linker, such as one rich in glycine and serine.
• the spacer includes a sequence of an immunoglobulin hinge region, a C H 2 and C H 3 region.
• one of more of the hinge, C H 2 and C H 3 is derived all or in part from IgG4 or IgG2. In some cases, the hinge, C H 2 and C H 3 is derived from IgG4.
• the spacer has the sequence set forth in any of SEQ ID NOs: 117-119, In some embodiments, the spacer has the sequence set forth in SEQ ID NO: 120. In some embodiments, the spacer has the sequence set forth in SEQ ID NO: 122. In some embodiments, the spacer has the sequence set forth in SEQ ID NO: 124.
• the intracellular signaling component(s) of the recombinant receptor contains an intracellular costimulatory signaling domain of human CD28 or a functional variant or portion thereof, such as a domain with an LL to GG substitution at positions 186-187 of a native CD28 protein.
• the intracellular signaling domain can comprise the sequence of amino acids set forth in SEQ ID NO: 10 or 11 or a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%), 98%), 99% or more sequence identity to SEQ ID NO: 10 or 11.
• variable region of the ⁇ -chain can contain a further hypervariable region (CDR4 or HVR4), which generally is involved in superantigen binding and not antigen recognition (Kotb (1995) Clinical Microbiology Reviews, 8:411-426).
• CDR4 or HVR4 hypervariable region
• phage display is used to isolate TCRs against a target antigen (see, e.g., Varela- Rohena et al. (2008) Nat Med. 14: 1390-1395 and Li (2005) Nat Biotechnol. 23 :349-354.
• HLA-A0201 -binding motifs and the cleavage sites for proteasomes and immune- proteasomes using computer prediction models are known.
• such models include, but are not limited to, ProPredl (described in more detail in Singh and Raghava, ProPred: prediction of HLA-DR binding sites. BIOINFORMATICS 17(12): 1236- 1237 2001), and SYFPEITHI (see Schuler et al, SYFPEITHI, Database for Searching and T- Cell Epitope Prediction, in Immunoinformatics Methods in Molecular Biology, vol 409(1): 75-93 2007)
• nucleic acid or nucleic acids encoding a TCR can be amplified by PCR, cloning or other suitable means and cloned into a suitable expression vector or vectors.
• the expression vector can be any suitable recombinant expression vector, and can be used to transform or transfect any suitable host. Suitable vectors include those designed for propagation and expansion or for expression or both, such as plasmids and viruses.
• the first and/or second genetically engineered antigen receptor ⁇ e.g. CAR or TCR is capable of inducing an activating signal to the cell.
• the receptor includes an intracellular signaling component containing ITAM or ITAM-like motifs.
• the activation induced by the first receptor involves a signal transduction or change in protein expression in the cell resulting in initiation of an immune response, such as ITAM phosphorylation and/or initiation of ITAM-mediated signal
• the cells include one or more subsets of T cells or other cell types, such as whole T cell populations, CD4 + cells, CD8 + cells, and subpopulations thereof, such as those defined by function, activation state, maturity, potential for differentiation, expansion, recirculation, localization, and/or persistence capacities, antigen-specificity, type of antigen receptor, presence in a particular organ or compartment, marker or cytokine secretion profile, and/or degree of differentiation.
• the cells may be allogeneic and/or autologous.
• the methods include off-the-shelf methods.
• isolation of the cells includes one or more preparation and/or non-affinity based cell separation steps.
• cells are washed, centrifuged, and/or incubated in the presence of one or more reagents, for example, to remove unwanted
• the methods include density-based cell separation methods, such as the preparation of white blood cells from peripheral blood by lysing the red blood cells and centrifugation through a Percoll or Ficoll gradient.
• T cells such as cells positive or expressing high levels of one or more surface markers, e.g., CD28 + , CD62L + , CCR7 + , CD27 + , CD127 + , CD4 + , CD8 + , CD45RA + , and/or CD45RO + T cells, are isolated by positive or negative selection techniques.
• surface markers e.g., CD28 + , CD62L + , CCR7 + , CD27 + , CD127 + , CD4 + , CD8 + , CD45RA + , and/or CD45RO + T cells.
• isolation of a CD8 + population enriched for TCM cells is carried out by depletion of cells expressing CD4, CD14, CD45RA, and positive selection or enrichment for cells expressing CD62L.
• enrichment for central memory T (TCM) cells is carried out starting with a negative fraction of cells selected based on CD4 expression, which is subjected to a negative selection based on expression of CD 14 and
• the incubation generally is carried out under conditions whereby the antibodies or binding partners, or molecules, such as secondary antibodies or other reagents, which specifically bind to such antibodies or binding partners, which are attached to the magnetic particle or bead, specifically bind to cell surface molecules if present on cells within the sample.
• the antibodies or binding partners, or molecules such as secondary antibodies or other reagents, which specifically bind to such antibodies or binding partners, which are attached to the magnetic particle or bead, specifically bind to cell surface molecules if present on cells within the sample.
• the affinity-based selection is via magnetic-activated cell sorting (MACS) (Miltenyi Biotec, Auburn, CA). Magnetic Activated Cell Sorting (MACS) systems are capable of high-purity selection of cells having magnetized particles attached thereto.
• MACS operates in a mode wherein the non-target and target species are sequentially eluted after the application of the external magnetic field. That is, the cells attached to magnetized particles are held in place while the unattached species are eluted. Then, after this first elution step is completed, the species that were trapped in the magnetic field and were prevented from being eluted are freed in some manner such that they can be eluted and recovered.
• the non-target cells are labelled and depleted from the heterogeneous population of cells.
• the separation and/or other steps is carried out using CliniMACS system (Miltenyi Biotec), for example, for automated separation of cells on a clinical-scale level in a closed and sterile system.
• Components can include an integrated microcomputer, magnetic separation unit, peristaltic pump, and various pinch valves.
• the integrated computer in some aspects controls all components of the instrument and directs the system to perform repeated procedures in a standardized sequence.
• the magnetic separation unit in some aspects includes a movable permanent magnet and a holder for the selection column.
• the peristaltic pump controls the flow rate throughout the tubing set and, together with the pinch valves, ensures the controlled flow of buffer through the system and continual suspension of cells.
• the CliniMACS Prodigy system can also include an onboard camera and image recognition software that determines the optimal cell fractionation endpoint by discerning the macroscopic layers of the source cell product. For example, peripheral blood is automatically separated into erythrocytes, white blood cells and plasma layers.
• the CliniMACS Prodigy system can also include an integrated cell cultivation chamber which accomplishes cell culture protocols such as, e.g., cell differentiation and expansion, antigen loading, and long-term cell culture. Input ports can allow for the sterile removal and replenishment of media and cells can be monitored using an integrated microscope. See, e.g., Klebanoff et al, J Immunother. 35(9): 651-660 (2012), Terakura et al, BloodA :12-%2 (2012), and Wang et al, J Immunother.
• tEGFR may contain an epitope recognized by the antibody cetuximab (Erbitux®) or other therapeutic anti-EGFR antibody or binding molecule, which can be used to identify or select cells that have been engineered with the tEGFR construct and an encoded exogenous protein, and/or to eliminate or separate cells expressing the encoded exogenous protein.
• cetuximab Erbitux®
• the marker e.g.
• the marker is a selection marker.
• the selection marker is or comprises a polypeptide that confers resistance to exogenous agents or drugs.
• the selection marker is an antibiotic resistance gene.
• the selection marker is an antibiotic resistance gene confers antibiotic resistance to a mammalian cell.
• the selection marker is or comprises a Puromycin resistance gene, a Hygromycin resistance gene, a Blasticidin resistance gene, a Neomycin resistance gene, a Geneticin resistance gene or a Zeocin resistance gene or a modified form thereof.
• 2A sequences that can be used in the methods and nucleic acids disclosed herein, without limitation, 2A sequences from the foot-and-mouth disease virus (F2A, e.g., SEQ ID NO: 27), equine rhinitis A virus (E2A, e.g., SEQ ID NO: 26), Thosea asigna virus (T2A, e.g., SEQ ID NO: 6 or 23), and porcine teschovirus-1 (P2A, e.g., SEQ ID NO: 24 or 25) as described in U.S. Patent Publication No. 20070116690.
• F2A foot-and-mouth disease virus
• E2A equine rhinitis A virus
• T2A e.g., SEQ ID NO: 6 or 23
• P2A porcine teschovirus-1
• the marker is a molecule, e.g., cell surface protein, not naturally found on T cells or not naturally found on the surface of T cells, or a portion thereof.
• the molecule is a non-self molecule, e.g., non-self protein, i.e., one that is not recognized as "self by the immune system of the host into which the cells will be adoptively transferred.
• the cells prior to or during gene transfer, are incubated or cultured in the presence of an immunomodulatory compound, e.g., lenalidomide, including any as described herein.
• an immunomodulatory compound e.g., lenalidomide, including any as described herein.
• the immunomodulatory compound e.g., lenalidomide, including any as described herein.
• recombinant nucleic acids are transferred into T cells via electroporation ⁇ see, e.g., Chicaybam et al, (2013) PLoS ONE 8(3): e60298 and Van Tedeloo et al. (2000) Gene Therapy 7(16): 1431-1437).
• recombinant nucleic acids are transferred into T cells via transposition (see, e.g., Manuri et al. (2010) Hum Gene Ther 21(4): 427-437; Sharma et al. (2013) Molec Ther Nucl Acids 2, e74; and Huang et al. (2009) Methods Mol Biol 506: 115-126).
• the cells further are engineered to promote expression of cytokines or other factors.
• genes for introduction are those to improve the efficacy of therapy, such as by promoting viability and/or function of transferred cells; genes to provide a genetic marker for selection and/or evaluation of the cells, such as to assess in vivo survival or localization; genes to improve safety, for example, by making the cell susceptible to negative selection in vivo as described by Lupton S. D. et al., Mol.
• the administration of the immunomodulatory compound results in improved clinical outcomes, e.g., objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), compared to a method in which the dose of cells expressing the recombinant receptor is administered to the subject in the absence of the immunomodulatory compound.
• ORR objective response rate
• PFS progression-free survival
• OS overall survival
• the area under the curve (AUC) for concentration of receptor- (e.g, CAR-) expressing cells in a fluid, plasma, serum, blood, tissue, organ and/or disease site, e.g. tumor site, of the subject over time following the administration of the T cells, e.g., CAR- expressing T cells and/or immunomodulatory compound, e.g., lenalidomide, is greater as compared to that achieved via an alternative dosing regimen where the subject is administered the T cells, e.g., CAR-expressing T cells, in the absence of administering the
• the provided methods result in a decreased tumor burden in treated subjects compared to alternative methods in which the immunotherapy, such as a T cell therapy (e.g. CAR-expressing T cells) is given without administration of the immunomodulatory compound, e.g., lenalidomide.
• a T cell therapy e.g. CAR-expressing T cells
• the immunomodulatory compound e.g., lenalidomide.
• the tumor burden is not necessary that the tumor burden actually be reduced in all subjects receiving the combination therapy, but that tumor burden is reduced on average in subjects treated, such as based on clinical data, in which a majority of subjects treated with such a combination therapy exhibit a reduced tumor burden, such as at least 50%, 60%, 70%, 80%, 90%), 95% or more of subjects treated with the combination therapy, exhibit a reduced tumor burden.
• exemplary parameters to assess the extent of disease burden include such parameters as cellular morphology (e.g., centroblastic, immunoblastic, and anaplastic cells), gene expression, miRNA expression and protein expression (e.g., expression of BCL2, BCL6, MUM1, LM02, MYC, and p21).
• cellular morphology e.g., centroblastic, immunoblastic, and anaplastic cells
• miRNA expression and protein expression e.g., expression of BCL2, BCL6, MUM1, LM02, MYC, and p21.
• the subjects treated according to the method achieve a more durable response.
• a measure of duration of response includes the time from documentation of tumor response to disease progression.
• the parameter for assessing response can include durable response, e.g., response that persists after a period of time from initiation of therapy.
• durable response is indicated by the response rate at approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18 or 24 months after initiation of therapy.
• the response is durable for greater than 3 months, greater than 6 months, or great than 12 months.
• the subjects treated according to the method achieve a more durable response after the subject previously relapsed following remission in response to the administration of the genetically engineered cells.
• the probability of relapse is reduced as compared to other methods.
• the probability of relapse at 6 months following the method of combination therapy is less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%), less than about 20%, or less than about 10%.

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