Methods and compositions for cellular immunotherapy

1. A method of treating a hyperproliferative disease, comprising administering to a subject having the hyperproliferative disease an effective amount of a MNK-specific inhibitor and a modified T cell comprising a transgene encoding an engineered antigen specific receptor, wherein the MNK-specific inhibitor is a compound according to the following formula:

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

W 1 and W 2 are independently O, S or N—OR′, where R′ is lower alkyl;

Y is N(R 5 ), —O—, —S—, —C(O)—, —S═O, —S(O) 2 —, or —CHR 9 —;

R 1 is hydrogen, lower alkyl, cycloalkyl or heterocyclyl wherein any lower alkyl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;

n is 1, 2 or 3;

R 2 and R 3 are each independently hydrogen, alkyl, alkenyl, alkynyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, wherein any alkyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, is optionally substituted with 1, 2 or 3 J groups;

or R 2 and R 3 taken together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;

R 4a and R 4b are each independently hydrogen, halogen, hydroxyl, thiol, hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heterocyclyl;

R 5 is hydrogen, cyano, or lower alkyl;

or R 5 and R 8 taken together with the atoms to which they are attached form a fused heterocyclyl optionally substituted with 1, 2 or 3 J groups;

R 6 , R 7 and R 8 are each independently hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl is optionally substituted with 1, 2 or 3 J groups;

or R 7 and R 8 taken together with the atoms to which they are attached form a fused heterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 J groups;

J is —SH, —SR 9 , —S(O)R 9 , —S(O) 2 R 9 , —S(O)NH 2 , —S(O)NR 9 R 9 , —NH 2 , —NR 9 R 9 , —COOH, —C(O)OR 9 , —C(O)R 9 , —C(O)—NH 2 , —C(O)—NR 9 R 9 , hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH 2 —C(O)-alkylene, NR 9 R 9 —C(O)-alkylene, —CHR 9 —C(O)-lower alkyl, —C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl, —CHR 9 —C(O)-cycloalkyl, —C(O)— cycloalkyl, —CHR 9 —C(O)-aryl, —CHR 9 -aryl, —C(O)-aryl, —CHR 9 —C(O)-heterocycloalkyl, —C(O)— heterocycloalkyl, heterocyclylaminyl, or heterocyclyl; or any two J groups bound to the same carbon or hetero atom may be taken together to form oxo; and

R 9 is hydrogen, lower alkyl or —OH;

wherein the modified T cell is a CD4+ or CD8+ T cell made from a CD45RO Hi CD62L Hi central memory T cell-enriched CD4+ or CD8+ population, respectively; and

wherein the engineered antigen specific receptor is a chimeric antigen receptor (CAR), a T cell receptor (TCR), a TCR-CAR, or any combination thereof.

2. The method of claim 1 , wherein the MNK-specific inhibitor is

a compound according to the following formula:

3. The method of claim 1 , further comprising administering to the subject an inhibitor of an immunosuppression component.

4. The method of claim 3 , wherein the inhibitor of the immunosuppression component is:

an siRNA specific for PD-1, PD-L1, PD-L2, CTLA-4, B7-H3, B7-H4, HVEM, adenosine, GAL9, VISTA, CEACAM-1, CEACAM-3, CEACAM-5, PVRL2, BTLA, KIR, LAG3, TIM-3, A2AR, CD244/2B4, CD160, TIGIT, LAIR-1, PVRIG/CD112R, arginase, indoleamine 2,3-dioxygenase (IDO), IL-10, IL-4, IL-1RA, IL-35, or any combination thereof; or

an antibody specific for PD-1, PD-L1, PD-L2, CTLA-4, B7-H3, B7-H4, HVEM, adenosine, GAL9, VISTA, CEACAM-1, CEACAM-3, CEACAM-5, PVRL2, BTLA, KIR, LAG3, TIM-3, A2AR, CD244/2B4, CD160, TIGIT, LAIR-1, PVRIG/CD112R, arginase, indoleamine 2,3-dioxygenase (IDO), IL-10, IL-4, IL-1RA, IL-35, or any combination thereof.

5. The method of claim 4 , wherein:

the antibody specific for PD-1 is pidilizumab, nivolumab, pembrolizumab, or any combination thereof;

the antibody specific for PD-L1 is avelumab, atezolizumab, durvalumab, MDX-1105 (BMS-936559), or any combination thereof; or

the antibody specific for CTLA4 is tremelimumab, ipilimumab, or both.

6. The method of claim 1 , wherein the hyperproliferative disease is a cancer selected from a solid tumor, melanoma, non-small cell lung cancer, renal cell carcinoma, renal cancer, a hematological cancer, prostate cancer, castration-resistant prostate cancer, colon cancer, rectal cancer, gastric cancer, esophageal cancer, bladder cancer, head and neck cancer, thyroid cancer, breast cancer, triple-negative breast cancer, ovarian cancer, cervical cancer, lung cancer, urothelial cancer, pancreatic cancer, glioblastoma, hepatocellular cancer, myeloma, multiple myeloma, leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma, or any combination thereof.

7. The method of claim 1 , wherein the modified T cell is an autologous T cell or an allogeneic T cell; or the subject is human.

8. The method of claim 1 , wherein the transgene encoding the engineered antigen specific receptor is introduced into the T cell by a DNA vector, an RNA vector, a plasmid, a lentiviral vector, an adenovirus vector, or a retrovirus vector.

9. The method of claim 1 , wherein the antigen is a tumor antigen, a pathogenic microorganism antigen, a neurodegenerative disease antigen, or an autoimmune disease antigen.

10. The method of claim 9 , wherein the tumor antigen is selected from the group consisting of human immunodeficiency virus (HIV) antigens, hepatitis C virus (HCV) antigens, hepatitis B virus (HBV) antigens, cytomegalovirus (CMV) antigens, Epstein Barr virus (EBV) antigens, parasitic antigens, and tumor antigens, such as ROR1, EGFR, EGFRvIII, HPV E6, HPV E7, L1-CAM, Lewis A, Lewis Y, MUC1, MUC16, PSMA, CD19, CD20, CD22, CD56, CD23, CD24, CD30, CD33, CD37, CD38, CD44v6, CD72, CD79a, CD79b, CD97, CD123, CD171, CD179a, CA125, c-MET, FcRH5, WT1, VEGF-α, VEGFR1, VEGFR2, IL-13Rα2, IL-11Rα, MAGE, MAGE-A1, ephrin A2, ephrin B2, NKG2D ligands, NY-ESO-1, TAG-72, mesothelin, glioma-associated antigen, carcinoembryonic antigen (CEA), IL-13Rα, FAP, B7H3, Kit, CA-IX, CS-1, BCMA, bcr-abl, β-human chorionic gonadotropin, α-fetoprotein (AFP), ALK, cyclin B1, lectin-reactive AFP, Fos-related antigen 1, ADRB3, thyroglobulin, RAGE-1, SSX2, AKAP-4, LCK, OY-TES1, PAX5, SART3, CLL-1, fucosyl GM1, GloboH, MN-CA IX, EPCAM, EVT6-AML, TGS5, human telomerase reverse transcriptase, PLAC1, RU1, RU2 (AS), intestinal carboxyl esterase, sLe, LY6K, M-CSF, MYCN, RhoC, TRP-2, CYP1B1, BORIS, prostase, prostate-specific antigen (PSA), PAX3, PAP, LAGE-1a, LMP2, NCAM, p53, p53 mutant, Ras mutant, gp100, prostein, OR51E2, PANX3, PSCA, hTERT, HMWMAA, HAVCR1, survivin, telomerase, legumain, sperm protein 17, SSEA-4, tyrosinase, TARP, ML-IAP, MAD-CT-1, MAD-CT-2, MelanA/MART1, XAGE1, ELF2M, ERG (TMPRSS2 ETS fusion gene), NA17, neutrophil elastase, sarcoma translocation breakpoints, NY-BR-1, androgen receptor, insulin growth factor (IGF)-I, IGF-II, IGF-I receptor, GD2, o-acetyl-GD2, GD3, GM3, GPRC5D, GPR20, CXORF61, folate receptor alpha (FRα), folate receptor beta, Tie 2, TSHR, UPK2, Tn Ag, FLT3, PRSS21, PDGFR-beta, ERBB2 (Her2/neu), CAIX, TEM1/CD248, TEM7R, CLDN6, polysialic acid, PCTA-1/Galectin 8, mut hsp70-2, LAIR1, FCAR, LILRA2, CD300LF, CLEC12A, BST2, EMR2, LY75, GPC3, FCRL5, IGLL1, and psor.