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  • C12N2710/00011—Details
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  • C12N2710/24111—Orthopoxvirus, e.g. vaccinia virus, variola
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Definitions

• fowlpox One exemplary avipoxvirus species, fowlpox, has been shown to be a safe vehicle for human administrations as fowlpox virus enters mammalian cells and expresses proteins, but replicates abortively. Skinner et al. Expert Rev Vaccines. 2005 Feb;4(l):63-76. Additionally, the use of fowlpox virus as a vehicle for expression is being evaluated in numerous clinical trials of vaccines against cancer, malaria, tuberculosis, and AIDS. Id.
• the invention encompasses methods, compositions, and kits for treating human cancer patients.
• the recombinant orthopoxivirus is a recombinant vaccinia virus or a recombinant modified Vaccinia Ankara (MVA) virus.
• the recombinant orthopoxvirus is MVA-BN.
• the recombinant avipoxvirus is a recombinant fowlpox virus.
• the PD-1 antagonist and the CTLA-4 antagonist can include an anti-PD-1 antagonist antibody and an anti-CTLA-4 antibody, respectively.
• cancer treatments described herein can be directed against cancers such as, but not limited to, breast cancer, lung cancer, gastric cancer, kidney cancer, liver cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, or combinations thereof.
• cancers such as, but not limited to, breast cancer, lung cancer, gastric cancer, kidney cancer, liver cancer, melanoma, pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, or combinations thereof.
• the present disclosure encompasses a method for treating cancer in a human patient, the method comprising administering to the patient a combination of: (a) a therapeutically effective amount of a recombinant poxvirus vector, the poxvirus vector comprising at least one tumor associated antigen (TAA); and (b) a tumor associated antigen (TAA).
• TAA tumor associated antigen
• the heterologous sequences code for epitopes that induce a response by the immune system.
• the recombinant poxvirus is used to vaccinate against the proteins or agents comprising the epitope.
• the epitope is a tumor- associated antigen, preferably, HER-2.
• the HER-2 antigen comprises the sequence of SEQ ID NO:2.
• Canarypox strain termed ALVAC (U.S. Pat. No. 5,766,598) was deposited under the terms of the Budapest treaty with the American Type Culture Collection (ATCC), accession number VR- 2547.
• ALVAC American Type Culture Collection
• Another Canarypox strain is the commercial canarypox vaccine strain designated LF2 CEP 524 24 10 75, available from Institute Merieux, Inc.
• tumor-associated antigens include, but are not limited to, 5 alpha reductase, alpha- fetoprotein, AM-1 , APC, April, BAGE, beta-catenin, Bell 2, bcr-abl, CA-125, CASP-8/FLICE, Cathepsins, CD 19, CD20, CD21 , CD23, CD22, CD33 CD35, CD44, CD45, CD46, CD5, CD52, CD55, CD59, CDC27, CDK4, CEA, c-myc, Cox-2, DCC, DcR3, E6/E7, CGFR, EMBP, Dna78, farnesyl transferase, FGF8b, FGF8a, FLK-l/KDR, folic acid receptor, G250, GAGE-family, gastrin 17, gastrin-releasing hormone, GD2/GD3/GM2, GnRH, GnTV, GP1,
• EGFr family of receptors constitutes suitable targets for tumor immunotherapy.
• they are overexpressed in many types of cancers, which should direct the immune response towards the tumor.
• the tumors often express or overexpress the ligands for this family of receptors and some are hypersensitive to the proliferative effects mediated by the ligands.
• patients with tumors that overexpress growth factor receptors often have a poor prognosis.
• the overexpression has been closely linked with poor prognosis especially in breast cancer, lung cancer, and bladder cancer and can be associated with invasive/metastatic phenotypes, which are rather insensitive to conventional therapies (Eccles et al, 1994).
• modifications to one or more of the tumor-associated antigens (TAAs) presented herein such as, but not limited to, CEA, MUC-1, PAP, PSA, HER-2, survivin, tyrpl , tyrp2, or Brachyury,are made such that, after administration to a subject, polyclonal antibodies are elicited that predominantly react with the one or more of the TAAs described herein .
• TAAs tumor-associated antigens
• Such antibodies could attack and eliminate tumor cells as well as prevent metastatic cells from developing into metastases. The effector mechanism of this anti-tumor effect would be mediated via complement and antibody dependent cellular cytotoxicity.
• the induced antibodies could also inhibit cancer cell growth through inhibition of growth factor dependent oligo-dimerisation and internalization of the receptors.
• such modified TAAs could induce CTL responses directed against known and/or predicted TAA epitopes displayed by the tumor cells.
• the intracellular (Kinase) domain extends from amino acids 655-1235 and contains the tyrosine kinase domain, which extends from amino acids 655-1010 (core TK domain extends from 725-992); and the C-terminal domain, which extends from amino acids 101 1-1235.
• Regions predicted (by their hydrophobic properties) to be interior in the molecule preferably should be conserved as these could be involved in the folding. In contrast, solvent exposed regions could serve as candidate positions for insertion of the model T H epitopes P2 and P30. [0120] Finally, the domain organization of the protein should be taken into consideration because of its relevance for protein structure and function.
• mHER2 modified HER-2 polypeptide antigen
• mHER2 comprises the extracellular domains and nine amino acids of the transmembrane domain; the P2 epitope inserted in Domain II between amino acid residues 273 to 287 of the modified HER-2 polypeptide; and the P30 epitope inserted in Domain IV between amino acid residues 655 to 675 of the modified HER-2 polypeptide.
• the plasmid pBN146 contains sequences which are also present in MVA-BN (the 14L and 15L open reading frames).
• the mHER2 sequence is inserted between the MVA-BN sequences to allow for recombination into the MVA-BN viral genome.
• the plasmid also contains a selection cassette comprising one or more selection genes to allow for selection of recombinant constructs in CEF cells.
• the recombinant MVA encodes a polypeptide comprising SEQ ID NO:2.
• the invention encompasses the use of immune checkpoint antagonists.
• immune checkpoint antagonists include antagonists of immune checkpoint molecules such as Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4),
• PD-1 Programmed Cell Death Protein 1
• PDL-1 Programmed Death-Ligand 1
• LAG-3 Lymphocyte- activation gene 3
• TIM-3 T-cell immunoglobulin and mucin domain 3
• An antagonist of CTLA-4, PD-1 , PDL-1 , LAG-3, or TIM-3 interferes with CTLA-4, PD-1 , PDL-1, LAG-3, or TIM-3 function, respectively.
• Such antagonists of CTLA-4, PD-1, PDL-1 , LAG-3, and TIM-3 can include antibodies which specifically bind to CTLA-4, PD-1 , PDL-1 , LAG-3, and TIM-3, respectively and inhibit and/or block biological activity and function.
• Candidate antagonists of CTLA-4, PD-1, PDL-1, LAG-3, and TIM-3 can be screened for function by a variety of techniques known in the art and/or disclosed within the instant application, such as ability to interfere with CTLA-4, PD-1 , PDL-1 , LAG-3, and TIM- 3function in an in vitro or mouse model.
• the invention further encompasses agonists of ICOS.
• An agonist of ICOS activates ICOS.
• ICOS is a positive co-stimulatory molecule expressed on activated T cells and binding to its' ligand promotes their proliferation (Dong, Nature 2001 ; 409:97-101).
• the agonist is ICOS-L, an ICOS natural ligand.
• the agonist can be a mutated form of ICOS-L that retains binding and activation properties. Mutated forms of ICOS-L can be screened for activity in stimulating ICOS in vitro.
• the antagonist of CTLA-4, PD-1 , PDL-1, LAG-3, TIM-3, and the agonist of ICOS is an antibody.
• Antibodies can be synthetic, monoclonal, or polyclonal and can be made by techniques well known in the art. Such antibodies specifically bind to CTLA-4, PD-1 , PDL-1 , LAG-3, TIM-3, or ICOS via the antigen-binding sites of the antibody (as opposed to non-specific binding).
• CTLA-4, PD-1, PDL-1, LAG-3, TIM-3, or ICOS polypeptides, fragments, variants, fusion proteins, etc. can be employed as immunogens in producing antibodies immunoreactive therewith. More specifically, the polypeptides, fragment, variants, fusion proteins, etc. contain antigenic determinants or epitopes that elicit the formation of antibodies.
• These antigenic determinants or epitopes can be either linear or conformational (discontinuous).
• Linear epitopes are composed of a single section of amino acids of the polypeptide, while conformational or discontinuous epitopes are composed of amino acids sections from different regions of the polypeptide chain that are brought into close proximity upon protein folding (C. A. Janeway, Jr. and P. Travers, Immuno Biology 3:9 (Garland
• Epitopes can be identified by any of the methods known in the art.
• Antibodies including scFV fragments, which bind specifically to CTLA-4, PD-1, PDL-1, LAG-3, TIM-3, or ICOS and either block its function (“antagonist antibodies”) or enhance/ activate its function (“agonist antibodies”), are encompassed by the invention.
• Such antibodies can be generated by conventional means.
• the invention further encompasses antibodies that bind to epitopes within close proximity to a CTLA-4, PD-1 , PDL-1, LAG-3, TIM-3, or an ICOS ligand binding site.
• the invention encompasses antibodies that interfere with intermolecular interactions (e.g. protein-protein interactions), as well as antibodies that perturb intramolecular interactions (e.g. conformational changes within a molecule).
• Antibodies can be screened for the ability to block or enhance/activate the biological activity of CTLA-4, PD-1, PDL-1, LAG-3, TIM-3, or ICOS, or the binding of CTLA-4, PD-1 , PDL-1 , LAG-3, TIM-3, or ICOS to a ligand, and/or for other properties.
• CTLA-4, PD-1, PDL-1, LAG-3, TIM-3, and ICOS and peptides based on the amino acid sequence of CTLA-4, PD-1, PDL-1 , LAG-3, TIM-3, and ICOS can be utilized to prepare antibodies that specifically bind to CTLA-4, PD-1 , PDL-1 , LAG-3, TIM-3, or ICOS.
• the term "antibodies” is meant to include polyclonal antibodies, monoclonal antibodies, fragments thereof, such as F(ab')2 and Fab fragments, single-chain variable fragments (scFvs), single-domain antibody fragments (VHHs or Nanobodies), bivalent antibody fragments
• Antibodies are defined to be specifically binding if they bind CTLA-4, PD-1, PDL-1 3 LAG-3, TIM-3, and ICOS polypeptide with a Ka of greater than or equal to about 10 7 M " . Affinities of binding partners or antibodies can be readily determined using conventional techniques, for example those described by Scatchard et al., Ann. N.Y. Acad. Sci., 51 :660 (1949).
• Polyclonal antibodies can be readily generated from a variety of sources, for example, horses, cows, goats, sheep, dogs, chickens, rabbits, mice, or rats, using procedures that are well known in the art.
• purified CTLA-4, PD-1, PDL-1 , LAG-3, TIM-3, and ICOS or a peptide based on the amino acid sequence of CTLA-4, PD-1 , PDL-1 , LAG-3, TIM-3, and ICOS that is appropriately conjugated is administered to the host animal typically through parenteral injection.
• CTLA-4, PD-1, PDL-1 3 LAG-3, TIM-3, and ICOS can be enhanced through the use of an adjuvant, for example, Freund's complete or incomplete adjuvant.
• an adjuvant for example, Freund's complete or incomplete adjuvant.
• small samples of serum are collected and tested for reactivity to CTLA-4, PD-1, PDL-1, LAG-3, TIM-3, and ICOS polypeptide.
• Examples of various assays useful for such determination include those described in Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press, 1988; as well as procedures, such as countercurrent immuno-electrophoresis (CIEP), radioimmunoassay, radio- immunoprecipitation, enzyme-linked immunosorbent assays (ELISA), dot blot assays, and sandwich assays. See U.S. Pat. Nos. 4,376,110 and 4,486,530.
• mice are given an intravenous boost of CTLA-
• Fusion is plated out into plates containing media that allows for the selective growth of the fused cells.
• the fused cells can then be allowed to grow for approximately eight days.
• Supernatants from resultant hybridomas are collected and added to a plate that is first coated with goat anti-mouse Ig. Following washes, a label, such as a labeled CTLA-4, PD-1 , PDL-1 , LAG-3, TIM-3, and ICOS polypeptide, is added to each well followed by incubation. Positive wells can be subsequently detected. Positive clones can be grown in bulk culture and supernatants are subsequently purified over a Protein A column (Pharmacia).
• Antibodies produced by genetic engineering methods such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, can be used.
• Such chimeric and humanized monoclonal antibodies can be produced by genetic engineering using standard DNA techniques known in the art, for example using methods described in Robinson et al.
• Human monoclonal antibodies against CTLA-4, PD-1 , PDL-1 , LAG-3, TIM-3, and ICOS polypeptides can also be prepared by constructing a combinatorial immunoglobulin library, such as a Fab phage display library or a scFv phage display library, using
• the antagonists and agonists can include those known in the art.
• Ipilimumab® and tremelimumab are known CTLA-4 antibodies.
• AMP-224 Amplimmune-224
• immune checkpoint antagonists or agonists can be embodied in small molecules, peptides, soluble receptor proteins, and other types of fusion proteins.
• the recombinant poxvirus is for administration on the same day or within 1 , 2, 3, 4, 5, 6, or 7, days of immune checkpoint agonist and/or antagonist administration.
• the recombinant poxvirus can be administered before or after the immune checkpoint agonist and/or antagonist.
• the recombinant poxvirus according to the present invention may also be used in heterologous prime-boost regimens in which one or more of the initial prime vaccinations are done with a poxvirus as defined herein and in which one or more subsequent boosting vaccinations is done with a different vaccine, e.g., another virus vaccine, a protein or a nucleic acid vaccine.
• a different vaccine e.g., another virus vaccine, a protein or a nucleic acid vaccine.
• the one or more subsequent boosting vaccinations of a heterologous prime-boost regimen are selected from poxviruses of a different genus than the initial prime vaccinations.
• the first or initial pox virus vaccine includes vaccinia
• the second and subsequent poxvirus vaccines are selected from the poxviruses from a different genus such as suipox, avipox, capripox or an orthopox
• a heterologous prime-boost may be employed wherein a poxvirus, such as vaccinia, expressing one or more TAAs is administered in a first dose in combination with one or more immune checkpoint antagonists or agonists. This first dose is followed by one or more administrations of different poxvirus, such as fowlpox, expressing one or more TAAs.
• the one or more TAAs in the fowlpox virus are the same or similar TAAs to those included in the vaccinia virus of the first administration.
• the one or more TAAs in the heterologous prime- boost regimen include prostate specific antigen (PSA) and/or prostatic acid phosphatase (PAP) antigen.
• PSA antigen can include those PSA antigens found in US Patents 7,247,615 and 7,598,225 both of which are incorporated by reference herein.
• the heterologous prime-boost including PSA is
• the one or more TAAs in the heterologous prime -boost regimen include A mucin 1, cell surface associated (MUC1) antigen and a carcinoembryonic antigen (CEA).
• MUC1 and CEA antigens can include those found in US Patents 7,1 18,738; 7,723,096; and PCT application No. PCT/US2013/020058, all of which are incorporated by reference herein.
• the heterologous prime -boost regimen including a MUC-1 antigen and CEA is CV301.
• the one or more boosting vaccinations are administered at any combination of intervals after administration of the initial the priming vaccination)(e.g., 1 , 2, 3, 4, 5, 6, 7 or more days, 1, 2, 3, 4, 5, 6, 7, 8 or more weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or more months).
• compositions of the invention can be administered in a variety of unit dosage forms depending on the method of administration.
• unit dosage forms suitable for oral administration include solid dosage forms such as powder, tablets, pills, capsules, and dragees, and liquid dosage forms, such as elixirs, syrups, and suspensions.
• the active ingredients can also be administered parenterally in sterile liquid dosage forms.
• Gelatin capsules contain the active ingredient and as inactive ingredients powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like.
• compositions of the invention in the pharmaceutical formulations can vary widely, i.e., from less than about 0.1%, usually at or at least about 2% to as much as 20% to 50% or more by weight, and will be selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected.
• the recombinant poxviruses of the present invention can be embodied in one or more pharmaceutical compositions.
• pharmaceutical compositions may comprise one or more pharmaceutically acceptable and/or approved carriers, additives, antibiotics, preservatives, adjuvants, diluents and/or stabilizers.
• additives include, for example, but not limited to, water, saline, glycerol, ethanol, wetting or emulsifying agents, and pH buffering substances.
• Exemplary carriers are typically large, slowly metabolized molecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, lipid aggregates, or the like.
• the present disclosure includes administering to the patient a subsequent (relative to the dosage in the previous paragraph) or a second dosage of a therapeutic cancer vaccine, such as but not limited to, a recombinant poxvirus comprising at least one tumor-associated antigen (TAA); and (b) administering to the patient a subsequent (relative to the dosage in the previous paragraph) or a second dosage of at least one immune checkpoint antagonist or agonist; wherein the subsequent dosage of the at least one immune checkpoint antagonist or agonist is administered after the subsequent dosage of the therapeutic cancer vaccine.
• a therapeutic cancer vaccine such as but not limited to, a recombinant poxvirus comprising at least one tumor-associated antigen (TAA)
• TAA tumor-associated antigen
• the sub-therapeutically effective dosages are configured to maximize therapeutic benefits while minimizing adverse side effects that have been seen in the immune checkpoint treatments in the prior art.
• the present disclosure can include a combination or medicament for use in increasing overall survival rate in a human cancer patient, the
• combination or medicament comprising: (a) a poxvirus including at least one tumor associated antigen (TAA); and (b) a therapeutically effective amount of at least one immune checkpoint antagonist or agonist; wherein the therapeutically effective amount of the at least one immune checkpoint antagonist or agonist combined with the poxvirus vector has an increased therapeutic effect as compared to an administration of either a poxvirus vector comprising at least one TAA alone or at least one immune checkpoint antagonist or agonist alone or in combination with other immune checkpoint antagonists or agonists.
• TAA tumor associated antigen
• mice were implanted with 5x 10 4 CT26-HER-2 cells, and treated with MVA-BN-HER2 and anti-CTLA-4, as described in Example 2. On day 25, tumor/lungs or spleens were pooled (4 mice/group) and re-stimulated overnight to measure virus and tumor antigen specific responses as described in Example 2.
• Results are shown in Figure 2, A) Pie charts are area weighted to reflect the number of IFNy+ cells per million CD8+ T-cells. B) IFNy MFI increases with tumor antigen specific (HER2 p63) poly functional T-cells with combination therapy.
• HER2 p63 tumor antigen specific
• mice were implanted i.v. with 5 l0 4 CT26-HER-2 cells and treated with MVA- BN-HER2 as described in Example 2. Mice were treated with anti-CTLA-4 on days 4 and 18 at 200 ⁇ g (A, 10 mg/kg), 66 ⁇ g (B, 3 mg/kg), or 22 ⁇ g (C, 1 mg/kg) i.p. in 100 ⁇ . PBS. **** pO.0001 , Log-Rank Test.
• MVA-BN-HER2 in Combination with anti-PD-1 and anti-LAG-3 reduces tumor burden at lower dosages
• MVA-BN-HER2 in Combination with anti-CTLA-4 reduces tumor burden with an increased second dosage
• mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• Mice are treated with anti-ICOS on day 1 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) and day 15 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) i.p. in 100 ⁇ L PBS.
• MVA-BN-HER2 in Combination with anti-CTLA-4 and anti-PD-1 reduces tumor burden with an increased second dosage
• mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• Mice are treated with anti-PD-1 and anti-LAG-3 on day 1 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) for each antibody and day 15 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) for each antibody i.p. in 100 ⁇ , PBS.
• mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• Mice are treated with anti-CTLA-4 and anti-ICOS on day 1 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) for each antibody and day 15 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) for each antibody i.p. in 100 ⁇ , PBS.
• mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• Mice are treated with anti-CTLA-4 on day 3 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) and day 18 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) i.p. in 100 ⁇ , PBS.
• Mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• mice are treated with anti-CTLA-4 on day 7 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) and day 21 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) i.p. in 100 ⁇ , PBS. **** pO.0001 , *** p ⁇ 0.001 , ** p ⁇ 0.01 , * p ⁇ 0.05, Two way ANOVA.
• MVA-BN-HER2 in Combination with anti-PD-1 reduces tumor burden with poxvirus prior to anti-PD-1
• mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• Mice are treated with anti-PD-1 on day 7 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) and day 21 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) i.p. in 100 ⁇ L PBS.
• MVA-BN-HER2 in Combination with anti-ICOS reduces tumor burden with poxvirus prior to anti-ICOS
• MVA-BN-HER2 in Combination with anti-CTLA-4 and anti-PD-1 reduces tumor burden with poxvirus prior to anti-CTLA-4 and anti-PD-1
• mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• Mice are treated with anti-CTLA-4 and anti-PD-1 on day 7 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) for each antibody and day 21 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) for each antibody i.p. in 100 ⁇ , PBS.
• MVA-BN-HER2 in Combination with anti-PD-1 and anti-LAG-3 reduces tumor burden with poxvirus prior to anti-PD-1 and anti-LAG-3
• mice are implanted with CT26-HER-2 cells and treated with MVA-BN-HER2 as described in Example 7.
• Mice are treated with anti-PD-1 and anti-LAG-3 on day 3 at 66 ⁇ g (3 mg/kg), 22 ⁇ g (1 mg/kg), or 2.2 ⁇ g (0.1 mg/kg) for each antibody and day 18 at 200 ⁇ g (10 mg/kg) or 66 ⁇ g (3mg/kg) for each antibody i.p. in 100 ⁇ . PBS.
• mice were treated with MVA-BN-HER2 (1E7 Inf.U., t.s.) on day 1 and 15.
• mice were treated with MVA-BN-HER2 (1E7 Inf.U., t.s.) on day 1 and 15.
• Results The results are shown in Figure 16. Subjects were administered MVA- BN-HER-2 after which expression levels of PD-1 were measured at regular intervals. In response to the treatment, there was an initial period of very little increase in immune checkpoint expression. After approximately 1-2 days, T-cell expression of PD-1 showed a slight increase. From about day 3 to about day 12 T-cell expression of PD-1 increased dramatically. Increased expression was still seen until about day 18. With a second treatment of MVA-BN-HER2 on day 15, PD-1 expression increased starting at day 17. Even more significant, this increase in immune checkpoint expression was more profound in CD8 T-cells as compared to CD4 T-cells.
• blocking PD-1 induced by MVA-BN-HER2 may lead to LAG-3 co-expression and therapeutic benefit may be achieved with dual blockade of the PD- 1/PD-Ll and LAG-3 pathway in combination with MVA-BN-HER2.
• Results The results are shown in Figure 17. Subjects were administered MVA- BN-HER-2 after which expression levels of LAG-3 were measured at regular intervals. There was an increase in LAG-3 expression on CD4 or CD8 T cells after MVA-BN-HER2 treatment.
• mice Female C57BL/6 mice (6-8 weeks old, -20 g, Simonsen Laboratories, Gilroy CA) were implanted in day 1 with MC38-CEA cells (2x 105, i.d. in the back flank). Mice were treated on day 1 and 15 with MVA-BN-CV301 (1E7 Inf.U., s.c. above the tail base). Mice were treated i.p. with anti-PD-1 and/or anti-LAG-3 as described each of the Figures and examples and as described in in Example 2.
• PSA-specific T cells from VFF dosing were of higher avidity (Fig. 21 A and 21B), as evidenced by higher frequencies of T cells responding at the lower 0.01 ⁇ peptide concentrations in the ELISPOT.
• the number of functionally active PSA- specific CD8 CTLs resulting from the VFF heterologous prime-boost regimen was 7 to 20 fold higher than those generated by either homologous dosing regimen (Figure 21C).
• BALB/c males (5/group) were treated as described in Example 40. Spleens were harvested 14 days after the last treatment, and pooled splenocytes were restimulated overnight with PSA OPL or controls (controls not shown). The cells were stained for intracellular IFNy, TNFa, and IL-2 prior to flow cytometric analysis.
• A The pie charts are weighted in size to reflect the numbers of detected cells (total numbers of PSA-specific CD8 per million T cells are indicated below each chart).
• B Amount of IFNy production on a per cell basis as measured by mean fluorescence intensity (MFI). Graphs show representative data of two independently performed experiments.
• MVA-BN-HER2 induces tumor antigen specific T cells that produce IFNy. It is contemplated by the present disclosure that virus induced TILs (tumor infiltrating lymphocytes) that secrete IFNy may lead to increased PD-L1 on tumor cells; supporting blockade of this pathway in combination with virus treatment.
• BALB/c males (5/group) are treated every two weeks with: Buffer (Control), PROSTVAC-V prime followed by 2 PROSTVAC-F boosts (VFF) as described in example 40.
• Mice are treated i.p. with anti-CTLA-4 (60 ⁇ g) on days 1 , 15 and 29 (A), or on days 15 and 29 (B) , or on day sl6 and 30 (C) or on days 17 and 31.(D).
• PSA specific T cell responses are analyzed as described in examples 40, 41 and 42.
• administering a recombinant poxvirus comprising a TAA in combination with one or more immune checkpoint antagonists or agonists is therapeutically effective at various dosages.
• the disclosed combinations are effective at dosages that are lower than those dosages using one or more immune checkpoint antagonists or agonists or poxviral therapies by themselves.
• the present application additionally demonstrates that efficacy of the recombinant poxvirus and immune checkpoint antagonist or agonist combination is greatly enhanced dependent upon the dosing regimen used during treatment. For example, administering one or more of the immune checkpoint antagonist or agonist after a recombinant poxviral treatment greatly enhances efficacy of the combination treatment. Additionally, increasing a dosage amount of an immune checkpoint antagonist or agonist after a second or subsequent recombinant poxviral treatment greatly enhances efficacy of the combination treatments described herein.
• the present application additionally demonstrates the dosing regimens described herein are important for the greatly enhanced efficacy of the recombinant poxvirus and immune checkpoint antagonist or agonist combination therapy.

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