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 - 299 . (canceled) 
     
     
         300 . A unit dose comprising therapeutically effective amounts of at least 4 different modified cancer cell lines, wherein the unit dose comprises a first composition of at least 2 modified cancer cell lines and a second composition of at least 2 modified cancer cell lines,
 wherein each cell line is modified to (a) express or increase expression of at least 1 immunostimulatory factor and (b) inhibit or decrease expression of at least 1 immunosuppressive factor,   wherein the combination of cell lines comprises cells that express at least 5 tumor associated antigens (TAAs) associated with non-small cell lung cancer (NSCLC), and wherein said unit dose is capable of eliciting an immune response specific to the at least 5 TAAs.   
     
     
         301 . The unit dose of  claim 300 , wherein the unit dose comprises 6 different modified cancer cell lines, wherein the first composition comprises 3 modified cancer cell lines and the second composition comprises 3 modified cancer cell lines. 
     
     
         302 . The unit dose of  claim 300 , wherein the modified cancer cell lines are selected from the group consisting of NCI-H460, NCI-H520, A549, DMS 53, LK-2, and NCI-H23. 
     
     
         303 . The unit dose of  claim 300 , wherein the at least 1 immunostimulatory factor is selected from the group consisting of GM-CSF, membrane bound CD40L, GITR, IL-15, IL-23, and IL-12. 
     
     
         304 . The unit dose of  claim 300 , wherein the at least 1 immunosuppressive factor is selected from the group consisting of CD276, CD47, CTLA4, HLA-E, HLA-G, IDO1, IL-10, TGFβ1, TGFβ2, and TGFβ3. 
     
     
         305 . The unit dose of  claim 300 , wherein each cell line is modified to express or increase expression of at least 2 immunostimulatory factors, and each cell line is modified to inhibit or decrease expression of at least 2 immunosuppressive factors. 
     
     
         306 . The unit dose of  claim 305 , wherein the at least 2 immunostimulatory factors are selected from the group consisting of GM-CSF, membrane bound CD40L, GITR, IL-15, IL-23, and IL-12, and wherein the at least 2 immunosuppressive factors are selected from the group consisting of CD276, CD47, CTLA4, HLA-E, HLA-G, IDO1, IL-10, TGFβ1, TGFβ2, and TGFβ3. 
     
     
         307 . The unit dose of  claim 300 , wherein at least 1 of the modified cancer cell lines is modified to increase expression of at least one tumor associated antigen (TAA) that is either not expressed or minimally expressed by the at least one cell line. 
     
     
         308 . The unit dose of  claim 307 , wherein the at least 1 tumor associated antigen (TAA) is selected from the group consisting of CT83, MSLN, BORIS, TBXT, and WT1, or mutated versions thereof. 
     
     
         309 . The unit dose of  claim 305 , wherein the unit dose is capable of stimulating a 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 unit dose comprising unmodified cancer cell lines. 
     
     
         310 . The unit dose of  claim 300 , wherein the therapeutically effective amount comprises approximately 1.0×10 6 -6.0×10 7  cells of each cell line. 
     
     
         311 . The unit dose of  claim 300 , wherein the first composition comprises therapeutically effective amounts of cancer cell lines NCI-H460, NCI-H520 and A549, and the second composition comprises therapeutically effective amounts of cancer cell lines DMS 53, LK-2 and NCI-H23. 
     
     
         312 . The unit dose of  claim 311 , wherein:
 (a) NCI-H460 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (b) NCI-H520 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (c) A549 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (d) DMS 53 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ2 and CD276;   (e) LK-2 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express MSLN and CT83; and   (f) NCI-H23 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276.   
     
     
         313 . The unit dose of  claim 311 , wherein:
 (a) NCI-H460 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express modBORIS;   (b) NCI-H520 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (c) A549 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express modTBXT and modWT1;   (d) DMS 53 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2 and CD276;   (e) LK-2 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, (ii) decrease expression of TGFβ1, TGFβ2, and CD276; and   (f) NCI-H23 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express modMSLN.   
     
     
         314 . A composition comprising therapeutically effective amounts of cancer cell lines NCI-H460, NCI-H520 and A549, wherein:
 (a) NCI-H460 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (b) NCI-H520 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276; and   (c) A549 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276.   
     
     
         315 . The composition of  claim 314 , wherein cancer cell line NCI-H460 is further modified to express modBORIS and cancer cell line A549 is further modified to express modTBXT and modWT1. 
     
     
         316 . The composition of  claim 314 , wherein the therapeutically effective amount is approximately 1.0×10 7  cells for each cell line. 
     
     
         317 . The composition of  claim 315 , wherein the therapeutically effective amount is approximately 1.0×10 7  cells for each cell line. 
     
     
         318 . The composition of  claim 314 , wherein said composition is capable of eliciting an immune response specific to at least 5 tumor associated antigens (TAAs) associated with non-small cell lung cancer (NSCLC). 
     
     
         319 . The composition of  claim 315 , wherein said composition is capable of eliciting an immune response specific to at least 5 tumor associated antigens (TAAs) associated with non-small cell lung cancer (NSCLC). 
     
     
         320 . A composition comprising therapeutically effective amounts of cancer cell lines DMS 53, LK-2 and NCI-H23, wherein:
 (a) DMS 53 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ2 and CD276;   (b) LK-2 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and optionally (iii) express MSLN and CT83; and   (c) NCI-H23 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276.   
     
     
         321 . The composition of  claim 320 , wherein cancer cell line DMS 53 is further modified to increase expression of IL-12 and to decrease expression of TGFβ1, cancer cell line LK-2 is not modified to express MSLN and CT83, and cancer cell line NCI-H23 is further modified to express modMSLN. 
     
     
         322 . The composition of  claim 320 , wherein the therapeutically effective amount is approximately 1.0×10 7  cells for each cell line. 
     
     
         323 . The composition of  claim 321 , wherein the therapeutically effective amount is approximately 1.0×10 7  cells for each cell line. 
     
     
         324 . The composition of  claim 320 , wherein said composition is capable of eliciting an immune response specific to at least 5 tumor associated antigens (TAAs) associated with non-small cell lung cancer (NSCLC). 
     
     
         325 . The composition of  claim 321 , wherein said composition is capable of eliciting an immune response specific to at least 5 tumor associated antigens (TAAs) associated with non-small cell lung cancer (NSCLC). 
     
     
         326 . A method of stimulating an immune response in a subject comprising administering to the subject the unit dose of  claim 300 , wherein said immune response is specific to at least 5 tumor associated antigens (TAAs) associated with non-small cell lung cancer (NSCLC), and wherein the first composition and the second composition each comprise 3 different cell lines. 
     
     
         327 . The method of  claim 320 , wherein the first composition comprises therapeutically effective amounts of cancer cell lines NCI-H460, NCI-H520 and A549, and the second composition comprises therapeutically effective amounts of cancer cell lines DMS 53, LK-2 and NCI-H23. 
     
     
         328 . The method of  claim 327 , wherein:
 (a) NCI-H460 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (b) NCI-H520 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (c) A549 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (d) DMS 53 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ2 and CD276;   (e) LK-2 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express MSLN and CT83; and   (f) NCI-H23 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   and optionally further comprising administering to the subject a therapeutically effective amount of a checkpoint inhibitor.   
     
     
         329 . The method of  claim 327 , wherein:
 (a) NCI-H460 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express mod BORIS;   (b) NCI-H520 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276;   (c) A549 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express modTBXT and modWT1;   (d) DMS 53 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2 and CD276;   (e) LK-2 is modified to (i) increase expression of GM-CSF and membrane bound CD40L, (ii) decrease expression of TGFβ1, TGFβ2, and CD276; and   (f) NCI-H23 is modified to (i) increase expression of GM-CSF, IL-12, and membrane bound CD40L, and (ii) decrease expression of TGFβ1, TGFβ2, and CD276, and (iii) express modMSLN;   and optionally further comprising administering to the subject a therapeutically effective amount of a checkpoint inhibitor.