Modified Cell Expressing Therapeutic Agent and Uses thereof
Compositions and methods for enhancing T cell response which increases the efficacy of CAR T cell therapy for treating cancer are described. Embodiments include a modified cell comprising an isolated nucleic acid comprising a first nucleic acid and a second nucleic acid, the first nucleic acid encoding a chimeric antigen receptor (CAR), the second nucleic acid encoding a therapeutic agent comprising at least one of IFN- y , IL-2, IL-6, IL-7, IL-15, IL-17, and IL-23. The modified cell expresses and secretes the therapeutic agent.
1 - 19 . (canceled)
20 . A pharmaceutical composition comprising modified T cells, wherein the modified T cells comprise chimeric antigen receptor (CAR) and an exogenous polynucleotide encoding one or more proteins, the one or more proteins comprising IFNγ.
21 . The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises SEQ ID NO: 469 and a polynucleotide encoding SEQ ID NO: 328.
22 . The pharmaceutical composition of claim 20 , wherein the modified T cells express and secrete the one or more proteins in response to activation of the modified T cells, hypoxia, or a combination thereof.
23 . The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide is present in the modified T cell in a recombinant DNA construct, in an mRNA, or in a viral vector.
24 . The pharmaceutical composition of claim 20 , wherein the one or more proteins further comprise IL-6.
25 . The pharmaceutical composition of claim 24 , wherein the exogenous polynucleotide comprises a polynucleotide encoding SEQ ID NOS: 287 and a polynucleotide encoding SEQ ID NO: 328.
26 . The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises a promoter comprising a binding site for a transcription modulator that modulates the expression and/or secretion of the one or more proteins in the modified T cells.
27 . The pharmaceutical composition of claim 26 , wherein the transcription modulator comprises Hif1a, NFAT, FOXP3, or NFkB.
28 . The pharmaceutical composition of claim 20 , wherein the exogenous polynucleotide comprises SEQ ID NO: 469.
29 . The pharmaceutical composition of claim 20 , wherein the pharmaceutical composition further comprises modified T cells engineered to express IL-12.
30 . The pharmaceutical composition of claim 29 , wherein the modified T cells engineered to express IL-12 express and secrete IL-12 in response to activation of the modified T cells, hypoxia, or a combination thereof.
31 . The pharmaceutical composition of claim 20 , wherein the CAR comprises an extracellular domain, a transmembrane domain, and an intracellular domain.
32 . The pharmaceutical composition of claim 31 , wherein the CAR binds TSHR, CD19, CD123, CD22, CD30, CD171, CS-1, CLL-1, CD33, EGFRvIII, GD2, GD3, BCMA, Tn Ag, PSMA, ROR1, FLT3, FAP, TAG72, CD38, CD44v6, CEA, EPCAM, B7H3, KIT, IL-13Ra2, Mesothelin, IL-11Ra, PSCA, PRSS21, VEGFR2, LewisY, CD24, PDGFR-beta, SSEA-4, CD20, Folate receptor alpha, ERBB2 (Her2/neu), MUC1, EGFR, NCAM, Prostase, PAP, ELF2M, Ephrin B2, IGF-I receptor, CAIX, LMP2, gp100, bcr-abl, tyrosinase, EphA2, Fucosyl GM1, sLe, GM3, TGS5, HMWMAA, o-acetyl-GD2, Folate receptor beta, TEM1/CD248, TEM7R, CLDN6, GPRC5D, CXORF61, CD97, CD179a, ALK, Polysialic acid, PLAC1, GloboH, NY-BR-1, UPK2, HAVCR1, ADRB3, PANX3, GPR20, LY6K, OR51E2, TARP, WT1, NY-ESO-1, LAGE-1a, MAGE-A1, legumain, HPV E6, E7, MAGE A1, ETV6-AML, sperm protein 17, XAGE1, Tie 2, MAD-CT-1, MAD-CT-2, Fos-related antigen 1, p53, p53 mutant, prostein, survivin and telomerase, PCTA-1/Galectin 8, MelanA/MART1, Ras mutant, hTERT, sarcoma translocation breakpoints, ML-IAP, ERG (TMPRSS2 ETS fusion gene), NA17, PAX3, Androgen receptor, Cyclin B1, MYCN, RhoC, TRP-2, CYP1B1, BORIS, SART3, PAX5, OY-TES1, LCK, AKAP-4, SSX2, RAGE-1, human telomerase reverse transcriptase, RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, or IGLL1.
33 . The pharmaceutical composition of claim 31 , wherein the intracellular domain comprises a co-stimulatory domain comprising an intracellular domain of a co-stimulatory molecule selected from the group consisting of CD27, CD28, 4-1 BB (CD137), OX40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46, and NKG2D.
34 . A method of inducing T cell response in a subject in need thereof, the method comprising administering an effective amount of the pharmaceutical composition of claim 20 to the subject.