Methods and compositions for use of therapeutic t cells in combination with kinase inhibitors

Abstract

The present disclosure relates to methods, compositions and uses involving immunotherapies and inhibitors of a target protein tyrosine kinase in which the kinase is not IL-2-inducible T cell kinase (ITK) and/or is selected from Bruton's tyrosine kinase (BTK), tec protein tyrosine kinase (TEC), BMX non-receptor tyrosine kinase (Etk), TXK tyrosine kinase (TXK) and/or receptor tyrosine-protein kinase ErbB4 (ErbB4). The provided methods, compositions and uses include administration of one or more such inhibitor with another agent, such as an immunotherapeutic agent targeting T cells and/or genetically engineered T cells, such as CAR-expressing T cells. Also provided are methods of manufacturing engineered cells, cells, compositions, methods of administration, nucleic acids, articles of manufacture and kits. In some aspects, features of the methods and cells provide for improved activity, efficacy, persistence, expansion and/or proliferation of T cells for adoptive cell therapy or endogenous T cells recruited by immunotherapeutic agents.

1 .- 123 . (canceled) 
     
     
         124 . A method of treatment, the method comprising:
 (a) administering, to a subject having a disease or condition, T cells that specifically recognize or specifically bind to an antigen associated with, or expressed or present on cells of, the disease or condition; and   (b) administering to the subject an inhibitor of a target protein tyrosine kinase, wherein the inhibitor does not inhibit interleukin-2-inducible kinase (ITK) and/or inhibits ITK with a half-maximal inhibitory concentration (IC 50 ) of greater than or greater than about 1000 nM.   
     
     
         125 . The method of  claim 124 , wherein the target protein tyrosine kinase is a tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinase. 
     
     
         126 . The method of  claim 125 , wherein the target protein tyrosine kinase is a tyrosine kinase expressed in hepatocellular carcinoma (TEC), a resting lymphocyte kinase (RLK/TXK), a BMX non-receptor tyrosine kinase (BMX/ETK), or a receptor tyrosine-protein kinase ErbB4 (ERBB4). 
     
     
         127 . The method of  claim 124 , wherein the inhibitor is selected from the group consisting of the compound of Formula (II) 
       
         
           
           
               
               
           
         
       
       ONO/GS-4059, Compound 30 or Compound 38, GDC-0834; RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; and LFM-A13. 
     
     
         128 . The method of  claim 124 , wherein the inhibitor comprises the compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or an enantiomer, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, polymorph or prodrug thereof or a pharmaceutical composition comprising any of the foregoing. 
     
     
         129 . A method of treatment, the method comprising:
 (1) administering, to a subject having a disease or condition, T cells that specifically recognize or specifically bind to an antigen associated with the disease or condition; and   (2) administering to the subject an inhibitor of a target protein tyrosine kinase, which target protein tyrosine kinase is a tyrosine kinase expressed in hepatocellular carcinoma (TEC), a resting lymphocyte kinase (RLK/TXK), a BMX non-receptor tyrosine kinase (BMX/ETK), or a receptor tyrosine-protein kinase ErbB4 (ERBB4), wherein:
 the inhibitor is a selective inhibitor of the target protein tyrosine kinase; and/or 
 the inhibitor inhibits the target protein tyrosine kinase with a half-maximal inhibitory concentration (IC 50 ) that is at least 10 or at least 100 times lower than that of the IC 50  of the inhibitor for any protein tyrosine kinase or TEC family kinase distinct from the target protein tyrosine kinase, and/or inhibits the target protein tyrosine kinase with an IC 50  at least 2, at least 10 or at least 100 times lower than that the IC 50  value of the inhibitor for both interleukin-2-inducible kinase (ITK) and Bruton's tyrosine kinase (BTK); and/or 
 the inhibitor inhibits the target protein tyrosine kinase with a half-maximal inhibitory concentration (IC 50 ) of less than or less than about 1000 nM or less. 
   
     
     
         130 . The method of  claim 129 , wherein the inhibitor is not ibrutinib. 
     
     
         131 . The method of  claim 129 , wherein the inhibitor does not inhibit ITK and/or inhibits ITK with a half-maximal inhibitory concentration (IC 50 ) of greater than or greater than about 1000 nM. 
     
     
         132 . The method of  claim 129 , wherein the inhibitor comprises is a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or an enantiomer, a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, polymorph or prodrug thereof or a pharmaceutical composition comprising any of the foregoing. 
     
     
         133 . The method of  claim 124 , wherein the disease or condition (i) is not a B cell-derived disease or condition (ii) is not associated with expression of CD19, CD22, or CD20; (iii) does not express the target protein tyrosine kinase, (iv) does not contain a form of the target protein tyrosine kinase that is sensitive to the inhibitor, (v) does not contain a kinase sensitive to the inhibitor and/or (vi) is not sensitive to inhibition by the inhibitor and/or wherein the subject or disease or condition is resistant or refractory to the inhibitor and/or to an inhibitor of BTK and/or the target kinase is not ordinarily expressed or is not suspected of being expressed in cells from which the disease or condition is derived. 
     
     
         134 . The method of  claim 124 , wherein:
 (i) the subject and/or the disease or condition (a) is resistant to inhibition of Bruton's tyrosine kinase (BTK) and/or (b) comprises a population of cells that are resistant to inhibition by the inhibitor;   (ii) the subject and/or the disease or condition comprises a mutation or disruption in a nucleic acid encoding BTK, capable of reducing or preventing inhibition of the BTK by the inhibitor and/or by ibrutinib; and/or   (iii) at the time of the administration in (1) and at the time of the administration in (2) the subject has relapsed following remission after treatment with, or been deemed refractory to treatment with the inhibitor and/or with a BTK inhibitor therapy.   
     
     
         135 . The method of  claim 134 , wherein the mutation in the nucleic acid encoding BTK comprises a C481S or C481R substitution, and/or a T474I or T474M substitution. 
     
     
         136 . The method of  claim 124 , wherein:
 the target protein tyrosine kinase is not expressed by cells of the disease or condition, is not ordinarily expressed or is not suspected of being expressed in cells from which the disease or condition is derived, and/or   the disease or condition is not sensitive to the inhibitor; and/or   at least a plurality of the T cells express the target protein tyrosine kinase; and/or   the target protein tyrosine kinase is expressed in T cells.   
     
     
         137 . The method of  claim 124 , wherein the disease or condition is a cancer. 
     
     
         138 . The method of  claim 137 , wherein the disease or condition is a cancer selected from the group consisting of sarcomas, carcinomas, lymphomas, non-Hodgkin lymphomas (NHLs), diffuse large B cell lymphoma (DLBCL), leukemia, CLL, ALL, AML and myeloma. 
     
     
         139 . The method of  claim 124 , wherein the T cells recognize or target an antigen selected from ROR1, B cell maturation antigen (BCMA), tEGFR, Her2, L1-CAM, CD19, CD20, CD22, mesothelin, CEA, and hepatitis B surface antigen, anti-folate receptor, CD23, CD24, CD30, CD33, CD38, CD44, EGFR, EGP-2, EGP-4, EPHa2, ErbB2, 3, or 4, erbB dimers, EGFR vIII, FBP, FCRLS, FCRHS, fetal acethycholine e receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kdr, kappa light chain, Lewis Y, L1-cell adhesion molecule, (L1-CAM), Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Preferentially expressed antigen of melanoma (PRAIVIE), survivin, EGP2, EGP40, TAG72, B7-H6, IL-13 receptor a2 (IL-13Ra2), CA9, GD3, HMW-MAA, CD171, G250/CAIX, HLA-AI MAGE A1, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7/8, avb6 integrin, 8H9, NCAM, VEGF receptors, 5T4, Fetal AchR, NKG2D ligands, CD44v6, dual antigen, and an antigen associated with a universal tag, a cancer-testes antigen, mesothelin, MUC1, MUC16, PSCA, NKG2D Ligands, NY-ESO-1, MART-1, gp100, oncofetal antigen, ROR1, TAG72, VEGF-R2, carcinoembryonic antigen (CEA), prostate specific antigen, PSMA, Her2/neu, estrogen receptor, progesterone receptor, ephrinB2, CD123, c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms Tumor 1 (WT-1), a cyclin, cyclin A2, CCL-1, CD138, and a pathogen-specific antigen. 
     
     
         140 . The method of  claim 124 , wherein the T cells comprise tumor infiltrating lymphocytes (TILs) or comprises genetically engineered T cells expressing a recombinant receptor that specifically binds to an antigen. 
     
     
         141 . The method of  claim 140 , wherein the recombinant receptor is a transgenic T cell receptor (TCR) or a chimeric antigen receptor (CAR). 
     
     
         142 . The method of  claim 141 , wherein the chimeric antigen receptor (CAR) comprises an extracellular antigen-recognition domain that specifically binds to the antigen and an intracellular signaling domain comprising an ITAM. 
     
     
         143 . The method of  claim 142 , wherein the intracellular signaling domain comprises an intracellular domain of a CD3-zeta (CD3) chain. 
     
     
         144 . The method of  claim 142 , wherein the chimeric antigen receptor (CAR) further comprises a costimulatory signaling region. 
     
     
         145 . The method of  claim 144 , wherein the costimulatory signaling region comprises a signaling domain of CD28 or 4-1BB. 
     
     
         146 . The method of  claim 124 , wherein the inhibitor irreversibly reduces or eliminates the activation of the target protein tyrosine kinase, specifically binds to a binding site in the active site of the target protein tyrosine kinase comprising an amino acid residue corresponding to residue C481 in the sequence set forth in SEQ ID NO:18, and/or reduces or eliminates autophosphorylation activity of the target protein tyrosine kinase. 
     
     
         147 . The method of  claim 124 , wherein the inhibitor is administered concurrently with or subsequently to initiation of administration of the T cells. 
     
     
         148 . The method of  claim 124 , wherein the inhibitor is administered subsequently to initiation of administration of the T cells. 
     
     
         149 . The method of  claim 148 , wherein the inhibitor is administered within, or within about, 1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours or 1 week of the initiation of the administration of the T cells. 
     
     
         150 . The method of  claim 148 , wherein the inhibitor is administered at a time in which:
 the number of administered T cells detectable in the blood from the subject is decreased compared to in the subject at a preceding time point after initiation of the administration of the T cells;   the number of administered T cells detectable in the blood is less than or less than about 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 50-fold or 100-fold or less the peak or maximum number of the cells of the T cell therapy detectable in the blood of the subject after initiation of administration of the administration of the T cells; and/or   at a time after a peak or maximum level of the administered T cells are detectable in the blood of the subject, the number of cells of or derived from the T cells detectable in the blood from the subject is less than less than 10%, less than 5%, less than 1% or less than 0.1% of total peripheral blood mononuclear cells (PBMCs) in the blood of the subject.   
     
     
         151 . The method of  claim 124 , wherein the administration of the inhibitor is continued, from at least after initiation of administration of the T cells, until:
 the number of cells of or derived from the T cells administered 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 inhibitor or compared to a preceding time point after administration of the T-cell therapy;   the number of cells of or derived from the T cells detectable in the blood is within 2.0-fold (greater than or less than) 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 cells 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 cells or at a time immediately prior to the administration of the inhibitor; and/or   the subject exhibits complete or clinical remission.   
     
     
         152 . The method of  claim 124 , wherein the inhibitor is administered orally. 
     
     
         153 . The method of  claim 124 , wherein the inhibitor is administered at a total daily dosage amount of at least or at least about 50 mg/day. 
     
     
         154 . The method of  claim 124 , wherein the inhibitor is administered in an amount that is at or about or less than or at or about 200 mg/day. 
     
     
         155 . The method of  claim 124 , wherein the administered T cells comprise CD4+ T cells and/or CD8+ T cells. 
     
     
         156 . The method of  claim 124 , wherein the administered T cells comprise administration of a dose comprising a number of cells between at or about 5×10 5  cells/kg body weight of the subject and at or about 1×10 7  cells/kg body weight of the subject. 
     
     
         157 . The method of  claim 124 , wherein the administered T cells comprise administration of a dose comprising a number of cells between at or about 1×10 7  and at or about 2×10 8  total T cells comprising the recombinant receptor. 
     
     
         158 . The method of  claim 124 , wherein the method further comprises administering a lymphodepleting chemotherapy prior to administration of the T cells and/or wherein the subject has received a lymphodepleting chemotherapy prior to administration of the T cells. 
     
     
         159 . The method of  claim 124 , wherein the method further comprises administering an immune modulatory agent to the subject, wherein the administration of the cells and the administration of the immune modulatory agent are carried out simultaneously, separately or in a single composition, or sequentially, in either order. 
     
     
         160 . The method of  claim 124 , wherein the administered T cells exhibit increased or prolonged expansion and/or persistence in the subject as compared to a method in which the administered T cells are administered to the subject in the absence of the inhibitor. 
     
     
         161 . The method of  claim 124 , wherein the method reduces tumor burden to a greater degree and/or for a greater period of time as compared to the reduction that would be observed with a comparable method in which the administered T cells are administered to the subject in the absence of the inhibitor. 
     
     
         162 . A combination, comprising:
 T cells expressing a recombinant receptor that binds to an antigen associated with a disease or condition, and   an inhibitor of a target protein tyrosine kinase, wherein the inhibitor does not inhibit interleukin-2-inducible kinase (ITK) and/or inhibits ITK with a half-maximal inhibitory concentration (IC 50 ) of greater than or greater than about 1000 nM and/or the target protein tyrosine kinase is a tyrosine kinase expressed in hepatocellular carcinoma (TEC), a resting lymphocyte kinase (RLK/TXK), a BMX non-receptor tyrosine kinase (BMX/ETK), or a receptor tyrosine-protein kinase ErbB4 (ERBB4).   
     
     
         163 . A combination, comprising:
 T cells comprising a recombinant antigen receptor that specifically binds to an antigen associated with a disease or condition; and   a kinase inhibitor or a pharmaceutical composition comprising the inhibitor, wherein the inhibitor comprises the compound of Formula (II):   
       
         
           
           
               
               
           
         
       
       or an enantiomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, polymorph or prodrug thereof. 
     
     
         164 . A kit, comprising the combination of  claim 162  and instructions for administering, to a subject for treating a disease or condition, the genetically engineered cells and the inhibitor. 
     
     
         165 . A kit, comprising the combination of  claim 163  and instructions for administering, to a subject for treating a disease or condition, the genetically engineered cells and the inhibitor. 
     
     
         166 . A method of engineering immune cells expressing a recombinant receptor, comprising:
 contacting a population of cells comprising T cells with an inhibitor of a target protein tyrosine kinase, wherein the inhibitor does not inhibit interleukin-2-inducible kinase (ITK) and/or inhibits ITK with a half-maximal inhibitory concentration (IC 50 ) of greater than or greater than about 1000 nM and/or the target protein tyrosine kinase is a tyrosine kinase expressed in hepatocellular carcinoma (TEC), a resting lymphocyte kinase (RLK/TXK), a BMX non-receptor tyrosine kinase (BMX/ETK), or a receptor tyrosine-protein kinase ErbB4 (ERBB4); and   introducing a nucleic acid encoding a recombinant receptor into the population of T cells under conditions such that the recombinant receptor is expressed.   
     
     
         167 . The method of  claim 166 , wherein the population of cells is or comprises T cells. 
     
     
         168 . The method of  claim 167 , wherein the population of cells comprises CD4+ T cells and/or CD8+ T cells. 
     
     
         169 . The method of  claim 166 , wherein the inhibitor comprises the compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or an enantiomer, pharmaceutically acceptable salt, solvate, hydrate, co-crystal, polymorph or prodrug thereof or a pharmaceutical composition comprising any of the foregoing. 
     
     
         170 . A method of producing genetically engineered T cells, comprising introducing a nucleic acid molecule encoding a recombinant receptor into a primary T cell, wherein the T cells is from a subject having been administered an inhibitor of a target protein tyrosine kinase, wherein the inhibitor does not inhibit interleukin-2-inducible kinase (ITK) and/or inhibits ITK with a half-maximal inhibitory concentration (IC 50 ) of greater than or greater than about 1000 nM and/or the target protein tyrosine kinase is a tyrosine kinase expressed in hepatocellular carcinoma (TEC), a resting lymphocyte kinase (RLK/TXK), a BMX non-receptor tyrosine kinase (BMX/ETK), or a receptor tyrosine-protein kinase ErbB4 (ERBB4). 
     
     
         171 . The method of  claim 170 , wherein the inhibitor comprises the compound of Formula (II) 
       
         
           
           
               
               
           
         
       
       or an enantiomer, pharmaceutically-acceptable salt, solvate, hydrate, co-crystal, polymorph or prodrug thereof or a pharmaceutical composition comprising any of the foregoing. 
     
     
         172 . The method of  claim 170 , wherein the T cells comprise CD4+ T cells and/or CD8+ T cells.