Tumor cell vaccines

Abstract

The present disclosure provides an allogeneic whole cell cancer vaccine platform that includes compositions and methods for treating and preventing cancer. Provided herein are compositions containing a therapeutically effective amount of cells from one or more cancer cell lines, some or all of which are modified to (i) inhibit or reduce expression of one or more immunosuppressive factors by the cells, and/or (ii) express or increase expression of one or more immunostimulatory factors by the cells, and/or (iii) express or increase expression of one or more tumor-associated antigens (TAAs), including TAAs that have been mutated, and which comprise cancer cell lines that natively express a heterogeneity of tumor associated antigens and/or neoantigens. Also provided herein are methods of making the vaccine compositions, methods of preparing, and methods of use thereof.

1 . A composition comprising a therapeutically effective amount of at least 1 cancer cell line, wherein the cell line or a combination of the cell lines comprises cells that express at least 5 tumor associated antigens (TAAs) associated with a cancer of a subject intended to receive said composition, and wherein said composition is capable of eliciting an immune response specific to the at least 5 TAAs. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . A composition comprising a therapeutically effective amount of at least 2 cancer cell lines, wherein each cell line or a combination of the cell lines comprises cells that express at least 5 tumor associated antigens (TAAs) associated with a cancer of a subject intended to receive said composition, and wherein each cell line or the combination of the cell lines are modified to express or increase expression of at least 1 immunostimulatory factor. 
     
     
         5 . (canceled) 
     
     
         6 . The composition of  claim 1 , wherein said composition is capable of stimulating a 1, 1.1 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25-fold or higher increase in IFNγ production compared to a composition comprising unmodified cancer cell lines. 
     
     
         7 . A composition comprising a therapeutically effective amount of at least 2 cancer cell lines, wherein each cell line or a combination of the cell lines comprises cells that express at least 5 tumor associated antigens (TAAs) associated with a cancer of a subject intended to receive said composition, and wherein each cell line or the combination of the cell lines are modified to inhibit or decrease expression of at least 1 immunosuppressive factor. 
     
     
         8 . A composition comprising a therapeutically effective amount of at least 2 cancer cell lines, wherein each cell line or a combination of the cell lines comprises cells that express at least 5 tumor associated antigens (TAAs) associated with a cancer of a subject intended to receive said composition, and wherein each cell line or the combination of the cell lines are modified to (i) express or increase expression of at least 1 immunostimulatory factor, and (ii) inhibit or decrease expression of at least 1 immunosuppressive factor. 
     
     
         9 . (canceled) 
     
     
         10 . The composition of  claim 1 , wherein the composition comprises 2, 3, 4, 5, or 6 cancer cell lines. 
     
     
         11 . The composition of  claim 10 , wherein each cell line or a combination of the cell lines are modified to (i) express or increase expression of 2, 3, 4, 5, 6, 7, or 8 immunostimulatory factors, and (ii) inhibit or decrease expression of 1, 2 or 3 immunosuppressive factors. 
     
     
         12 .- 20 . (canceled) 
     
     
         21 . An immunogenic composition comprising a therapeutically effective amount of at least 1 cancer cell line, wherein the cell line or a combination of the cell lines comprises cells that are modified to (i) express or increase expression of at least 1 immunostimulatory factor, and (ii) increase expression of at least 1 tumor associated antigen (TAA) that is either not expressed or minimally expressed by 1 cell line or the combination of the cell lines. 
     
     
         22 .- 25 . (canceled) 
     
     
         26 . An immunogenic composition comprising a therapeutically effective amount of at least 1 cancer cell line, wherein the cell line or a combination of the cell lines comprises cells that are modified to (i) express or increase expression of at least 1 immunostimulatory factor, (ii) inhibit or decrease expression of at least 1 immunosuppressive factor, and (iii) increase expression of at least 1 tumor associated antigen (TAA) that is either not expressed or minimally expressed by 1 cell line or the combination of the cell lines. 
     
     
         27 .- 39 . (canceled) 
     
     
         40 . A composition comprising a therapeutically effective amount of a cancer stem cell line, wherein said cancer stem cell line is modified to (i) express or increase expression of at least 1 immunostimulatory factor, (ii) inhibit or decrease expression of at least 1 immunosuppressive factor, and (iii) increase expression of at least 1 tumor associated antigen (TAA) that is either not expressed or minimally expressed by the cancer stem cell line. 
     
     
         41 .- 42 . (canceled) 
     
     
         43 . A composition comprising a therapeutically effective amount of small cell lung cancer cell line DMS 53, wherein said cell line DMS 53 is modified to (i) knockdown TGFβ2, (ii) knockout CD276, and (iii) upregulate expression of GM-CSF and membrane bound CD40L. 
     
     
         44 . A composition comprising a therapeutically effective amount of small cell lung cancer cell line DMS 53, wherein said cell line DMS 53 is modified to (i) knockdown TGFβ1 and TGFβ2, (ii) knockout CD276, and (iii) upregulate expression of GM-CSF, IL-12 and membrane bound CD40L. 
     
     
         45 .- 55 . (canceled) 
     
     
         56 . The composition of  claim 26 , wherein the amino acid sequence of one or more of the TAAs has been modified to include a mutation and/or a neoepitope. 
     
     
         57 - 58 . (canceled) 
     
     
         59 . The composition of  claim 1 , wherein said immune response comprises an adaptive immune response and wherein the adaptive immune response comprises the production of antigen specific cells selected from the group consisting of CD4 30   T cells and CD8 +  T cells. 
     
     
         60 . (canceled) 
     
     
         61 . The composition of  claim 59 , wherein the antigen specific CD8 +  T cells comprise memory cells and cytotoxic T lymphocytes. 
     
     
         62 .- 69 . (canceled) 
     
     
         70 . The composition according to  claim 1 , wherein the cell lines are from parental cell lines of solid tumors originating from the lung, prostate, testis, breast, colon, bladder, gastrointestinal system, brain, spinal cord, urinary tract, colon, rectum, stomach, head and neck, liver, kidney, central nervous system, endocrine system, mesothelium, ovaries, endometrium, pancreas, esophagus, neuroendocrine system, uterus, or skin. 
     
     
         71 . The composition of  claim 70 , wherein the parental cell lines comprise cells selected from the group consisting of squamous cells, carcinoma cells, adenocarcinoma cells, adenosquamous cells, large cell cells, small cell cells, sarcoma cells, clear cell carcinoma cells, carcinosarcoma cells, mixed mesodermal cells, and teratocarcinoma cells. 
     
     
         72 . (canceled) 
     
     
         73 . The composition according to  claim 1 , wherein the cell line or cell lines are non-small cell lung cancer cell lines or small cell lung cancer cell lines. 
     
     
         74 . (canceled) 
     
     
         75 . The composition according to  claim 1 , wherein the cell line or cell lines are small cell lung cancer cell lines. 
     
     
         76 . (canceled) 
     
     
         77 . The composition according to  claim 1 , wherein the cell line or cell lines are prostate cancer cell lines or testicular cancer cell lines. 
     
     
         78 . (canceled) 
     
     
         79 . The composition according to  claim 1 , wherein the cell line or cell lines are colorectal cancer cell lines. 
     
     
         80 . (canceled) 
     
     
         81 . The composition according to  claim 1 , wherein the cell line or cell lines are breast or triple negative breast cancer cell lines. 
     
     
         82 . (canceled) 
     
     
         83 . The composition according to  claim 1 , wherein the cell line or cell lines are bladder or urinary tract cancer cell lines. 
     
     
         84 . (canceled) 
     
     
         85 . The composition according to  claim 1 , wherein the cell line or cell lines are head and neck cancer cell lines. 
     
     
         86 . (canceled) 
     
     
         87 . The composition according to  claim 1 , wherein the cell line or cell lines are gastric or stomach cancer cell lines. 
     
     
         88 . (canceled) 
     
     
         89 . The composition according to  claim 1 , wherein the cell line or cell lines are liver cancer or hepatocellular cancer cell lines. 
     
     
         90 . (canceled) 
     
     
         91 . The composition according to  claim 1 , wherein the cell line or cell lines are glioblastoma cancer cell lines. 
     
     
         92 . (canceled) 
     
     
         93 . The composition according to  claim 1 , wherein the cell line or cell lines are ovarian cancer cell lines. 
     
     
         94 . (canceled) 
     
     
         95 . The composition according to  claim 1 , wherein the cell line or cell lines are esophageal cancer cell lines. 
     
     
         96 . (canceled) 
     
     
         97 . The composition according to  claim 1 , wherein the cell line or cell lines are kidney or renal cell carcinoma cancer cell lines. 
     
     
         98 . (canceled) 
     
     
         99 . The composition according to  claim 1 , wherein the cell line or cell lines are pancreatic cancer cell lines. 
     
     
         100 . (canceled) 
     
     
         101 . The composition according to  claim 1 , wherein the cell line or cell lines are endometrial cancer cell lines. 
     
     
         102 . (canceled) 
     
     
         103 . The composition according to  claim 1 , wherein the cell line or cell lines are skin or melanoma cancer cell lines. 
     
     
         104 . (canceled) 
     
     
         105 . The composition according to  claim 1 , wherein the cell line or cell lines are mesothelioma cancer cell lines. 
     
     
         106 .- 112 . (canceled) 
     
     
         113 . The composition according to  claim 4 , wherein the modification to increase expression of the at least 1 immunostimulatory factor comprises use of a lentiviral vector or vectors encoding the at least 1 immunostimulatory factor. 
     
     
         114 .- 120 . (canceled) 
     
     
         121 . The composition according to  claim 7 , wherein the modification to inhibit or decrease expression of the at least 1 immunosuppressive factor comprises a knockout or a knockdown of said at least 1 immunosuppressive factor. 
     
     
         122 .- 132 . (canceled) 
     
     
         133 . The composition according to  claim 1 , wherein the composition comprises cell lines that express a heterogeneity of HLA supertypes, and wherein at least 2 different HLA-A and at least 2 HLA-B supertypes are represented. 
     
     
         134 .- 138 . (canceled) 
     
     
         139 . A method of stimulating an immune response in a subject comprising administering to the subject a therapeutically effective amount of a composition according to  claim 1 . 
     
     
         140 . A method of stimulating an immune response specific to at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 or more tumor associated antigens (TAAs) in a subject comprising administering to the subject a therapeutically effective amount of a composition according to  claim 1 . 
     
     
         141 . A method of stimulating an immune response in a subject comprising administering to the subject a therapeutically effective amount of 2 or more compositions according to  claim 1 . 
     
     
         142 . (canceled) 
     
     
         143 . A method of stimulating an immune response in a subject comprising administering to the subject a therapeutically effective amount of 2 compositions according to  claim 1 , wherein the compositions each comprise 3 different cell lines. 
     
     
         144 .- 152 . (canceled) 
     
     
         153 . A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of 2 compositions according to  claim 1 , wherein the compositions each comprise 3 different cell lines. 
     
     
         154 .- 181 . (canceled) 
     
     
         182 . A method of treating a cancer in a subject comprising administering to the subject a therapeutically effective amount of two compositions, wherein each composition comprises at least 2 cancer cell lines modified to (i) express or increase expression of at least 1 immunostimulatory factor, (ii) inhibit or decrease expression of at least 1 immunosuppressive factor, and (iii) increase expression of at least 1 tumor associated antigen (TAA) that is either not expressed or minimally expressed by 1 cell line or the combination of the cell lines, wherein one composition is administered to the upper body of the subject, and the other composition is administered to the lower body of the subject. 
     
     
         183 .- 224 . (canceled) 
     
     
         225 . A kit comprising a first vaccine composition in a first vial and a second vaccine composition in a second vial, wherein said first and second vaccine compositions each comprise at least 2 cancer cell lines that are modified to express or increase expression of at least 2 immunostimulatory factors. 
     
     
         226 . A kit comprising 6 vials, wherein the vials each contain a composition comprising a cancer cell line, and wherein at least 4 of the 6 vials comprise a cancer cell line that is modified to (i) express or increase expression of at least 2 immunostimulatory factors, (ii) inhibit or decrease expression of at least 2 immunosuppressive factors, and (iii) increase expression of at least 1 TAA that is either not expressed or minimally expressed by 1 cell line or the combination of the cell lines, wherein at least 4 of the vials contain different compositions. 
     
     
         227 .- 228 . (canceled) 
     
     
         229 . A unit dose of a medicament for treating cancer comprising 6 compositions of different cancer cell lines, wherein at least 4 of the compositions comprise a cell line that is modified to (i) express or increase expression of at least 2 immunostimulatory factors, and (ii) inhibit or decrease expression of at least 2 immunosuppressive factors. 
     
     
         230 .- 299 . (canceled)