Treatment using chimeric receptor t cells incorporating optimized polyfunctional t cells

Abstract

The disclosure provides methods of treating a malignancy comprising administering an effective dose of a chimeric receptor (e.g., CAR or TCR) genetically modified T cell immunotherapy. Some aspects of the disclosure relate to methods of determining an effective dose of a T cell immunotherapy comprising polyfunctional T cells prior to administration to the patient.

1 .- 65 . (canceled) 
     
     
         66 . A pharmaceutical composition comprising a plurality of T cells comprising one or more chimeric antigen receptors, wherein the composition comprises a predetermined amount of polyfunctional T cells, wherein the polyfunctional cells comprise polyfunctional CD4+ T cells that have been determined to secrete IL-17alpha, IL-8, and/or IFNgamma and/or polyfunctional CD8+ T cells that have been determined to secrete Granzyme B, IFNgamma, IL-8, and/or MIP-1alpha, when stimulated by the antigen. 
     
     
         67 . The pharmaceutical composition of  claim 66 , comprising greater than 15% polyfunctional T cells. 
     
     
         68 . The pharmaceutical composition of  claim 66 , comprising greater than 20% polyfunctional T cells. 
     
     
         69 . The pharmaceutical composition of  claim 66 , comprising greater than 25% polyfunctional T cells. 
     
     
         70 . The pharmaceutical composition of  claim 66 , wherein the polyfunctional T cells further secrete MIP-1a, IL-17A, and/or IL-5. 
     
     
         71 . The pharmaceutical composition of  claim 66 , wherein the antigen is a tumor-associated surface antigen selected from 5T4, alphafetoprotein (AFP), B7-1 (CD80), B7-2 (CD86), BCMA, B-human chorionic gonadotropin, CA-125, carcinoembryonic antigen (CEA), carcinoembryonic antigen (CEA), CD123, CD133, CD138, CD19, CD20, CD22, CD23, CD24, CD25, CD30, CD33, CD34, CD4, CD40, CD44, CD56, CD8, CLL-1, c-Met, CMV-specific antigen, CS-1, CSPG4, CTLA-4, DLL3, disialoganglioside GD2, ductal-epithelial mucine, EBV-specific antigen, EGFR variant III (EGFRvIII), ELF2M, endoglin, ephrin B2, epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), epithelial tumor antigen, ErbB2 (HER2/neu), fibroblast associated protein (fap), FLT3, folate binding protein, GD2, GD3, glioma-associated antigen, glycosphingolipids, gp36, HBV- specific antigen, HCV-specific antigen, HER1-HER2, HER2-HER3 in combination, HERV-K, high molecular weight-melanoma associated antigen (HMW-MAA), HIV-1 envelope glycoprotein gp41, HPV-specific antigen, human telomerase reverse transcriptase, IGFI receptor, IGF-II, IL-11Ralpha, IL-13R-a2, Influenza Virus-specific antigen; CD38, insulin growth factor (IGF1)-1, intestinal carboxyl esterase, kappa chain, LAGA-1a, lambda chain, Lassa Virus-specific antigen, lectin-reactive AFP, CD3, MAGE, MAGE-A1 and all other lineage-specific or tissue specific antigens, major histocompatibility complex (MHC) molecule, major histocompatibility complex (MHC) molecule presenting a tumor-specific peptide epitope, M-CSF, melanoma-associated antigen, mesothelin, mesothelin, MN-CA IX, MUC-1, mut hsp70-2, mutated p53, mutated p53, mutated ras, neutrophil elastase, NKG2D, Nkp30, NY-ESO-1, p53, PAP, prostase, prostate specific antigen (PSA), prostate-carcinoma tumor antigen-1 (PCTA-1), prostate-specific antigen protein, STEAP1, STEAP2, PSMA, RAGE-1, ROR1, RU1, RU2 (AS), surface adhesion molecule, surviving and telomerase, TAG-72, the extra domain A (EDA) and extra domain B (EDB) of fibronectin and the A1 domain of tenascin-C (TnC A1), thyroglobulin, tumor stromal antigens, vascular endothelial growth factor receptor-2 (VEGFR2), virus-specific surface antigen such as an HIV-specific antigen (such as HIV gp120), as well as any derivate or variant of these surface markers. 
     
     
         72 . The pharmaceutical composition of  claim 71 , wherein the antigen is CD19. 
     
     
         73 . The pharmaceutical composition of  claim 66 , wherein the predetermined amount of polyfunctional T cells is determined using the Polyfunctional Strength Index (PSI). 
     
     
         74 . The pharmaceutical composition of  claim 73 , wherein the PSI is calculated by multiplying the percentage of polyfunctional cells by the sum of the mean intensity of the proteins secreted by the polyfunctional cells. 
     
     
         75 . The pharmaceutical composition of  claim 74 , wherein the PSI is greater than 250, 350, 450, or 550. 
     
     
         76 . The pharmaceutical composition of  claim 66 , wherein the predetermined amount of polyfunctional T cells is at least about 10 4  polyfunctional cells, at least about 10 5  polyfunctional cells, at least about 10 6  polyfunctional cells, at least about 10 7  polyfunctional cells, at least about 10 8  polyfunctional cells, at least about 10 9  polyfunctional cells, or at least about 10 10  polyfunctional cells. 
     
     
         77 . The pharmaceutical composition of  claim 66 , wherein the predetermined amount of polyfunctional T cells comprises from approximately 2.4×10 7  to approximately 4.2×10 7  polyfunctional T cells. 
     
     
         78 . The pharmaceutical composition of  claim 66 , wherein the predetermined amount of polyfunctional T cells ranges from approximately 2.0×10 7  to 5.0×10 7 , 2.0×10 7  to 4.5×10 7 , 2.0×10 7  to 4.0×10 7 , and 1.0×10 7  to 3.5×10 7  polyfunctional T cells.