COMPOSITIONS AND METHODS FOR TREATING CANCER WITH CHIMERIC TIM RECEPTORS IN COMBINATION WITH INHIBITORS OF POLY (ADP-RIBOSE) POLYMERASE
The present disclosure relates to combination therapy compositions and methods comprising chimeric Tim receptors, host cells modified to include chimeric Tim receptor molecules, and PARP inhibitors.
1 . A method for treating a cancer, wherein the cancer is breast cancer, ovarian cancer, colorectal cancer, fallopian cancer, peritoneal cancer, prostate cancer, lung cancer, or melanoma, in a subject in need thereof, the method comprising administering to the subject an effective amount of an engineered T cell comprising:
a chimeric engulfment receptor comprising a single chain chimeric protein, the single chain chimeric protein comprising:
(a) an extracellular domain comprising a binding domain comprising:
(i) a Tim4 IgV domain; and
(ii) a Tim4 mucin domain;
(b) an intracellular signaling domain, wherein the intracellular signaling domain comprises a primary intracellular signaling domain, wherein the primary signaling domain comprises a CD28 signaling domain or a TLR2 signaling domain and a secondary intracellular signaling domain, wherein the secondary signaling domain comprises a CD3ζ signaling domain or a DAP12 signaling domain; and
(c) a transmembrane domain positioned between and connecting the extracellular domain and the intracellular signaling domain; and
a Poly (ADP-ribose) polymerase (PARP) inhibitor).
2 . The method of claim 1 , wherein the breast cancer is triple negative breast cancer.
3 . The method of claim 1 , wherein the ovarian cancer is advanced ovarian cancer.
4 . The method of claim 1 , wherein the prostate cancer is advanced prostate cancer.
5 . The method of claim 1 , wherein the lung cancer is non-small cell lung cancer.
6 . The method of claim 1 , wherein the cancer is a BReast CAncer gene (BRCA) mutated cancer.
7 . (canceled)
8 . The method of claim 1 , wherein the PARP inhibitor is talazoparib, niraparib, rucaparib, olaparib, veliparib, CEP 9722, E7016, AG014699, MK4827, BMIN-673, Pamiparib, or a combination thereof.
9 .- 19 . (canceled)
20 . The method of any one of claim 1 , further comprising administering an additional therapeutic agent comprising radiation, cellular immunotherapy, chimeric antigen receptor, T cell receptor, 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 a combination thereof.
21 . (canceled)
22 . (canceled)
23 . The method of claim 20 , 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, 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.
24 .- 31 . (canceled)
32 . The method of claim 1 , wherein the Tim4 IgV domain comprises the amino acid sequence set forth in SEQ ID NO:34, and/or Tim4 mucin domain comprises the amino acid sequence set forth in SEQ ID NO:35.
33 .- 35 . (canceled)
36 . The method of any claim 1 , wherein the transmembrane domain comprises a Tim4 transmembrane domain or CD28 transmembrane domain.
37 . The method of claim 36 , wherein the Tim4 transmembrane domain comprises the amino acid sequence set forth in SEQ ID NO:6 or 23, or the CD28 transmembrane domain comprises the amino acid sequence of SEQ ID NO:7.
38 . The method of claim 1 , wherein the chimeric Tim receptor further comprises an extracellular spacer domain.
39 .- 49 . (canceled)
50 . The method of claim 1 , wherein the CD28 signaling domain comprises the amino acid sequence set forth in SEQ ID NO:4 or 26, the DAP12 signaling domain comprises the amino acid sequence set forth in SEQ ID NO:9, the CD3ζ signaling domain comprises the amino acid sequence set forth in SEQ ID NO:5, or the TLR2 signaling domain comprises the amino acid sequence set forth in SEQ ID NO:222.
51 .- 64 . (canceled)
65 . The method of claim 1 , wherein the chimeric engulfment receptor comprises:
(i) the amino acid sequence of SEQ ID NO:195 or amino acids 25-473 of SEQ ID NO:195;
(ii) the amino acid sequence of SEQ ID NO:196 or amino acids 25-446 of SEQ ID NO:196;
(iii) the amino acid sequence of SEQ ID NO:197 or amino acids 25-434 of SEQ ID NO:197; or
(iv) the amino acid sequence of SEQ ID NO:198 or amino acids 25-428 of SEQ ID NO:198.
66 .- 75 . (canceled)
76 . The method of claim 1 , wherein the chimeric receptor comprises:
(a) an extracellular domain comprising a binding domain comprising: (i) a Tim4 IgV domain and a Tim4 mucin domain;
(b) an intracellular signaling domain, wherein the intracellular signaling domain comprises a primary intracellular signaling domain comprising CD3ζ signaling domain; a secondary intracellular signaling domain comprising a CD28 signaling domain; and a tertiary intracellular signaling domain comprising a TLR2 signaling domain; and
(c) a transmembrane domain positioned between and connecting the extracellular domain and the intracellular signaling domain.
77 .- 79 . (canceled)
80 . The method of claim 1 , wherein the chimeric engulfment receptor comprises the amino acid sequence of set forth in any of SEQ ID NOS: 162, 195-198, 71, 227, 228, 229, 232, 233, 238-240, 243, and 244.
81 .- 85 . (canceled)
86 . The method of claim 1 , wherein the engineered T cell is a CD4+ T cell, a CD8+ T cell, or a CD4+/CD8+ T cell.
87 . The method of claim 1 , wherein the T cell is a human cell.
88 . The method of claim 1 , wherein the engineered T cell is administered as a composition further comprising a pharmaceutically acceptable excipient.