CHIMERIC TIM4 RECEPTORS AND USES THEREOF

1 . A chimeric T-cell immunoglobulin and mucin 4 (Tim4) receptor comprising a single chain chimeric protein, the single chain chimeric protein comprising:

(a) an extracellular domain comprising a Tim4 binding domain comprising the amino acid sequence of SEQ ID NO:6:

(b) an intracellular signaling domain, wherein the intracellular signaling domain comprises:

(i) a primary CD28 intracellular signaling domain comprising the amino acid sequence of SEQ ID NO:12, a secondary CD3ζ intracellular signaling domain comprising the amino acid sequence of SEQ ID NO:14, and a tertiary TLR2 TIR intracellular signaling domain comprising the amino acid sequence of SEQ ID NO:17; and

(c) a CD28 transmembrane domain comprising the amino acid sequence of SEQ ID NO: 11 positioned between and connecting the extracellular domain and the CD28 intracellular signaling domain.

2 . The chimeric Tim4 receptor of claim 1 , wherein the chimeric Tim4 receptor further comprises a signal peptide at the N-terminus, optionally wherein the signal peptide is a Tim4 signal peptide, further optionally wherein the Tim4 signal peptide comprises the amino acid sequence of SEQ ID NO:7.

3 . (canceled)

4 . The chimeric Tim4 receptor of claim 1 , wherein the chimeric Tim4 receptor comprises the amino acid sequence of SEQ ID NO:19 or SEQ ID NO:19 absent amino acids 1-24.

5 . A polynucleotide encoding the chimeric Tim4 receptor of claim 1 .

6 . An expression vector comprising the polynucleotide of claim 5 .

7 . (canceled)

8 . An engineered T cell comprising the expression vector of claim 6 .

9 . (canceled)

10 . (canceled)

11 . The engineered cell of claim 8 , wherein the T cell is a CD4+ T cell, a CD8+ T cell, or a CD4+/CD8+ T cell.

12 . The engineered T cell of claim 8 , wherein the T cell is a human T cell.

13 . A pharmaceutical composition comprising the engineered T cell of claim 8 and a pharmaceutically acceptable excipient.

14 . (canceled)

15 . A method of treating cancer in a subject comprising administering the engineered T cell of claim 8 to the subject.

16 . (canceled)

17 . The method of claim 15 , wherein the cancer is breast cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, or lung cancer; adenocarcinoma of the breast, prostate, and colon; all forms of bronchogenic carcinoma of the lung; myeloid leukemia; melanoma; hepatoma; neuroblastoma; papilloma; apudoma; choristoma; branchioma; malignant carcinoid syndrome; carcinoid heart disease; and carcinoma (e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal, Ehrlich tumor, Krebs 2, Merkel cell, mucinous, non-small cell lung, oat cell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell, and transitional cell); histiocytic disorders; malignant histiocytosis; leukemia; Hodgkin's disease; immunoproliferative small; non-Hodgkin's lymphoma; plasmacytoma; multiple myeloma; chronic myeloid leukemia (CML); plasmacytoma; reticuloendotheliosis; melanoma; chondroblastoma; chondroma; chondrosarcoma; fibroma; fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma; mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; chordoma; craniopharyngioma; dysgerminoma; hamartoma; mesenchymoma; mesonephroma; myosarcoma, ameloblastoma; cementoma; odontoma; teratoma; thymoma; trophoblastic tumor, adenoma; cholangioma; cholesteatoma; cyclindroma; cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma; hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma; sertoli cell tumor; theca cell tumor; leimyoma; leiomyosarcoma; myoblastoma; myomma; myosarcoma; rhabdomyoma; rhabdomyosarcoma; ependymoma; ganglioneuroma; glioma; medulloblastoma; meningioma; neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neuroma; paraganglioma; paraganglioma nonchromaffin; angiokeratoma; angiolymphoid hyperplasia with eosinophilia; angioma sclerosing; angiomatosis; glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma; hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma; pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes; fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukosarcoma; liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovarian carcinoma; rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; cervical dysplasia, and peritoneal cancer; B-cell cancers, including B-cell lymphomas (such as various forms of Hodgkin's disease, non-Hodgkin's lymphoma (NHL) or central nervous system lymphomas), leukemias (such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hairy cell leukemia, B cell blast transformation of chronic myeloid leukemia) and myelomas (such as multiple myeloma); small lymphocytic lymphoma, small lymphocytic leukemia, Waldenström macroglobulinemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, B-cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorder.

18 . The method of claim 17 , wherein the cancer is a B cell cancer, optionally wherein the B cell cancer is a B cell lymphoma, further optionally wherein the B cell lymphoma is mantle cell lymphoma.

19 . The method of claim 15 , further comprising administration of an additional therapeutic agent.

20 . The method of claim 19 , wherein the additional therapeutic agent comprises radiation, cellular immunotherapy, antibody, immune checkpoint molecule inhibitor, chemotherapy, hormone therapy, peptide, antibiotic, anti-viral agent, anti-fungal agent, anti-inflammatory agent, UV light therapy, electric pulse therapy, high intensity focused ultrasound therapy, oncolytic virus therapy, a small molecule therapy, or any combination thereof.

21 . (canceled)

22 . The method of claim 19 , wherein the additional therapeutic agent comprises an angiogenesis inhibitor (e.g., a VEGF pathway inhibitor), tyrosine kinase inhibitor (e.g., an EGF pathway inhibitor), receptor tyrosine kinase inhibitor, growth factor inhibitor, GTPase inhibitor, serine/threonine kinase inhibitor, transcription factor inhibitor, B-Raf inhibitor, RAF inhibitor, MEK inhibitor, mTOR inhibitor, EGFR inhibitor, ALK inhibitor, PARP inhibitor, ROS1 inhibitor, BCL-2 inhibitor, PI3K inhibitor, VEGFR inhibitor, BCR-ABL inhibitor, MET inhibitor, MYC inhibitor, ABL inhibitor, HER2 inhibitor, BTK inhibitor, H-RAS inhibitor, K-RAS inhibitor, PDGFR inhibitor, TRK inhibitor, c-KIT inhibitor, c-MET inhibitor, CDK4/6 inhibitor, FAK inhibitor, FGFR inhibitor, FLT3 inhibitor, IDH1 inhibitor, IDH2 inhibitor, PDGFRA inhibitor, or RET inhibitor.

23 . The method of claim 22 , wherein the inhibitor is a BTK inhibitor.

24 . The method of claim 23 , wherein the BTK inhibitor is ibrutinib, pirtobrutinib (Loxo-305), tirabrutinib, tolebrutinib, evobrutinib, fenebrutinib (GDC-0853), acalabrutinib, ONO-4059, spebrutinib, zanubrutinib (BGB-3111), HM71224, or M7583.

25 . The method of claim 23 , wherein the cancer is mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, small lymphocytic leukemia, Waldenström macroglobulinemia, and marginal zone lymphoma.

26 . The method of claim 22 , wherein the inhibitor is an EGFR inhibitor.

27 . The method of claim 26 , wherein the EGFR inhibitor is osimertinib, erlotinib, gefitnib, afatinib, or dacomitinib.

28 . The method of claim 26 , wherein the cancer is non-small cell lung cancer.

29 . The method of claim 22 , wherein the inhibitor is a Poly ADP-ribose polymerase (PARP) inhibitor.

30 . The method of claim 29 , wherein the PARP inhibitor is talazoparib, niraparib, rucaparib, olaparib, veliparib, CEP 9722, E7016, AG014699, MK4827, BMN-673, or pamiparib.

31 . The method of claim 29 , wherein the cancer is breast cancer, ovarian cancer, colorectal cancer, fallopian cancer, peritoneal cancer, prostate cancer, lung cancer, or melanoma.

32 .- 45 . (canceled)

46 . The method of claim 15 , wherein the additional therapeutic agent is administered at a subtherapeutic dose.

47 . The method of claim 15 , wherein the additional therapeutic agent is administered to the subject sequentially or concurrently with the chimeric Tim4 receptor.

48 . A method of enhancing an effector response or anti-tumor efficacy in a subject having cancer comprising administering the engineered T cell of claim 8 to the subject.

49 . A method for enhancing CCR7+ expressing T cells in a subject having cancer, the method comprising administering to the subject the engineered T cell of claim 8 ; and

optionally, a Poly ADP-ribose polymerase (PARP) inhibitor.

50 - 62 . (canceled)

63 . A method for enhancing CD4/CD8 T cell ratio in a subject having cancer, comprising administering to the subject the engineered T cell of claim 8 ; and

optionally, a Poly ADP-ribose polymerase (PARP) inhibitor.

64 .- 76 . (canceled)