Combination Treatment of Cancer
The present disclosure relates to combination therapies useful for the treatment of cancer. In particular, the disclosure relates to the combined use of a PD-1 inhibitor, a TGFbeta inhibitor, and a PARP inhibitor to treat cancer.
1 . A PD-1 inhibitor, a TGFβ inhibitor and a PARP inhibitor for use in a method of treating a cancer in a subject,
wherein the method comprises administering the PD-1 inhibitor, the TGFβ inhibitor and the PARP inhibitor to the subject.
2 . The compounds for use according to claim 1 , wherein the PD-1 inhibitor is an anti-PD-L1 antibody, or a fragment thereof capable of binding PD-L1, and the TGFβ inhibitor is a TGFβRII, or a fragment thereof capable of binding TGF-β, or an anti-TGFβ antibody, or a fragment thereof capable of binding TGFβ.
3 . The compounds for use according to claim 1 or 2 , wherein the anti-PD-L1 antibody or fragment thereof comprises a heavy chain sequence, which comprises a CDRH1 having the sequence of SEQ ID NO: 1, a CDRH2 having the sequence of SEQ ID NO: 2 and a CDRH3 having the sequence of SEQ ID NO: 3, and a light chain sequence, which comprises a CDRL1 having the sequence of SEQ ID NO: 4, a CDRL2 having the sequence of SEQ ID NO: 5 and a CDRL3 having the sequence of SEQ ID NO: 6; or
wherein the anti-PD-L1 antibody or fragment thereof comprises a heavy chain sequence, which comprises a CDRH1 having the sequence of SEQ ID NO: 19, a CDRH2 having the sequence of SEQ ID NO: 20 and a CDRH3 having the sequence of SEQ ID NO: 21, and a light chain sequence, which comprises a CDRL1 having the sequence of SEQ ID NO: 22, a CDRL2 having the sequence of SEQ ID NO: 23 and a CDRL3 having the sequence of SEQ ID NO: 24.
4 . The compounds for use according to any one of claims 1 to 3 , wherein the TGFβ inhibitor is an extracellular domain of TGFβRII or a fragment thereof capable of binding TG93.
5 . The compounds for use according to any one of claims 1 to 4 , wherein the PD-1 inhibitor and the TGFβ inhibitor are fused as an anti-PD(L)1:TGFβRII fusion protein.
6 . The compounds for use according to claim 5 , wherein the light chain sequences and the heavy chain sequences of the anti-PD(L)1:TGFβRII fusion protein have at least 90% sequence identity to the light chain sequence and the heavy chain sequence selected from the group consisting of: (1) SEQ ID NO: 7 and SEQ ID NO: 8, (2) SEQ ID NO: 15 and SEQ ID NO: 17, and (3) SEQ ID NO: 15 and SEQ ID NO: 18.
7 . The compounds for use according to claim 5 , wherein the amino acid sequence of the anti-PD(L)1:TGFβRII fusion protein corresponds to the amino acid sequence of bintrafusp alfa.
8 . The compounds for use according to any one of claims 5 to 7 , wherein the anti-PD(L)1:TGFβRII fusion protein is administered intravenously at a dose of 1200 mg Q2W or at a dose of 2400 mg Q3W.
9 . The compounds for use according to any one of claims 1 to 8 , wherein the PARP inhibitor is a small molecule.
10 . The compounds for use according to claim 9 , wherein the PARP inhibitor is a nicotinamide analog.
11 . The compounds for use according to claim 9 , wherein the PARP inhibitor is selected from the group consisting of olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, nicotinamide and theophylline.
12 . The compounds for use according to any one of claims 1 to 11 , wherein the PARP inhibitor is administered orally at a dose of 0.1 to 1000 mg QD or BID.
13 . The method for use according to any one of claims 1 to 12 , wherein the method further comprises administering the compounds in combination with radiotherapy.
14 . The compounds for use according to any one of claims 1 to 13 , wherein the cancer is selected from the group consisting of squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, biliary tract cancer, and head and neck cancer.
15 . The compounds for use according to any one of claims 1 to 14 , wherein the cancer has defects in homologous recombination repair.