Engineered safety in cell therapy
The present disclosure relates to compositions and methods for treating cancer. For example, a modified cell may include a polynucleotide comprising an NFAT promoter, a nucleotide sequence encoding therapeutic agent, and a nucleotide sequence encoding a VHL-interaction domain of HIF1α, wherein the therapeutic agent comprises, for example, IL-12, IL-6, and/or IFNγ.
1. A modified cell comprising a polynucleotide comprising a nucleotide sequence comprising a nuclear factor of activated T-cells (NFAT) promoter and comprising SEQ ID NO: 481, a nucleotide sequence encoding a therapeutic agent, and a nucleotide sequence encoding a VHL-interaction domain of hypoxia-inducible factor 1-alpha (HIF1α) and comprising SEQ ID NO: 511, wherein the nucleotide sequence encoding the therapeutic agent is flanked by the NFAT promoter and the nucleotide sequence encoding the VHL-interaction domain of HIF1α.
2. The modified cell of claim 1 , wherein the modified cell comprises SEQ ID NO: 505 or 506.
3. The modified cell of claim 1 , wherein the polynucleotide comprises SEQ ID NO: 527 that is flanked by SEQ ID NOS: 481 and 511.
4. The modified cell of claim 1 , wherein the polynucleotide comprises a nucleotide sequence encoding SEQ ID NO: 486 that is flanked by SEQ ID NOS: 481 and 511.
5. The modified cell of claim 1 , wherein the polynucleotide comprises a nucleotide sequence encoding SEQ ID NO: 482 that is flanked by SEQ ID NOS: 481 and 511.
6. The modified cell of claim 1 , wherein the polynucleotide comprises SEQ ID NO: 509 that is flanked by SEQ ID NOS: 481 and 511.
7. The modified cell of claim 1 , wherein the polynucleotide comprises SEQ ID NO: 510 that is flanked by SEQ ID NOS: 481 and 511.
8. The modified cell of claim 1 , wherein the polynucleotide comprises a nucleotide sequence encoding SEQ ID NO: 525 that is flanked by SEQ ID NOS: 481 and 511.
9. The modified cell of claim 1 , wherein the therapeutic agent comprises at least one of IL-12, IL-6, IL-7, IL-15, IL-23, IL-2, GCSF, CCL19, or GM-CSF.
10. The modified cell of claim 1 , wherein the modified cell comprises a chimeric antigen receptor (CAR) or a modified TCR.
11. The modified cell of claim 10 , wherein the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain.
12. The modified cell of claim 11 , wherein the antigen-binding domain binds one or more of the following tumor antigens: GUCY2C (GCC), 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, Lewis Y, 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, 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, telomerase, PCTA-1 (Galectin 8), MelanA (MART1), Ras mutant, 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 (hTERT), RU1, RU2, intestinal carboxyl esterase, mut hsp70-2, CD79a, CD79b, CD72, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, or IGLL1.
13. The modified cell of claim 11 , wherein the intracellular signaling domain comprises a co-stimulatory signaling domain comprising a functional signaling domain of at least one of CD27, CD28, 4-1BB (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.
14. The modified cell of claim 1 , wherein the modified cell is an immune cell.
15. The modified cell of claim 1 , wherein the modified cell is a T or NK cell.
16. The modified cell of claim 1 , wherein the modified cell has a reduced expression of endogenous TRAC gene.
17. The modified cell of claim 1 , wherein the modified cell is prepared from cells derived from a healthy donor or a subject having cancer.
18. A pharmaceutical composition comprising a population of the modified cells of claim 1 .
19. A method of eliciting or enhancing T cell response in a subject having prostate cancer, treating a subject having prostate cancer, or enhancing cancer treatment of a subject having prostate cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 18 to the subject having prostate cancer, wherein the therapeutic agent comprises IL-12 comprising SEQ ID NO: 486, IL-6 comprising SEQ ID NO: 482, or IFN-γ comprising SEQ ID NO: 484.
20. The modified cell of claim 1 , wherein the polynucleotide comprises a nucleotide sequence encoding SEQ ID NO: 484 that is flanked by SEQ ID NOS: 481 and 511.