INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

FIELD

The present application relates generally to cancer treatments.

BACKGROUND

Due to the wide variety of cancers presently observed, numerous anticancer agents have been developed to destroy cancer within the body. These compounds are administered to cancer patients with the objective of destroying or otherwise inhibiting the growth of malignant cells while leaving normal, healthy cells undisturbed.

Anticancer agents have been classified based upon their mechanism of action. One promising new class of chemotherapeutic are referred to as a Vascular Disrupting Agents (VDAs) (or alternatively, Vascular Damaging Agents, Vascular Targeting Agents (VTAs) or Anti-vascular agents). The primary mechanism of action of VDAs is “vascular targeting”, in which the neovasculature of solid tumors is selectively disrupted, resulting in a transient decrease or complete shutdown of tumor blood flow that results in secondary tumor cell death due to hypoxia, acidosis, and/or nutrient deprivation (Dark et al.,Cancer Res.,57: 1829-34, (1997); Chaplin et al., Anticancer Res., 19: 189-96, (1999); Hill et al., Anticancer Res., 22(3):1453-8 (2002); Holwell et al., Anticancer Res., 22(2A):707-11, (2002). Vascular disrupting agents (VDAs) cause acute shutdown of the established tumor vasculature, which is followed by massive intratumoral hypoxia and necrosis. While VDAs have strong activity against a variety of tumors, a viable rim of tumor tissue typically surrounds a massive necrotic tumor center after treatment. Rapid tumor regrowth can resume from this residual viable rim, driven by an acute systemic mobilization of bone marrow derived circulating endothelial precursor cells (CEPs) which home to the viable tumor rim and stimulate revascularization.

Improved therapies for treating cancer, including therapies that prevent tumor revascularization and regrowth are desired.

SUMMARY OF THE DISCLOSURE

The present invention relates to methods for treating cancer. The methods can include producing an anti-tumor effect in a subject suffering from cancer or a tumor. The methods can include administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody, programmed cell death protein 1 (PD-1) antibody, programmed death-ligand 1 (PD-L1) antibody, and programmed death-ligand 2 (PD-L2) antibody in amounts effective therefor. The combination of the combretastatin agent and the antibodies can produce a synergistic effect against the cancer or tumor.

In general, in one embodiment, a method for producing an anti-tumor effect in a subject suffering from cancer or a tumor, the method including administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in amounts effective therefor.

In general, in one embodiment, a method for preventing tumor regrowth in a subject suffering from cancer or a tumor, the method including administering to the patient a Vascular Disrupting Agent (VDA) that is a combretastatin agent and one or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in amounts effective therefor.

In general, in one embodiment, a method for inhibiting tumor-associated angiogenesis in a subject that is treated with a Vascular Disrupting Agent (VDA) that is a combretastatin agent, the method including administering to the patient one or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in amounts effective therefor.

In general, in one embodiment, a method for the treatment of cancer, including: administering to a subject in need of a synergistic, therapeutically effective amount of (1) a Vascular Disrupting Agent that is a combretastatin agent; and (2) one or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody.

This and other embodiments can include one or more of the following features. The method can include administering two or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody. The method can include administering a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in a therapeutically effective amount. The combretastatin agent can be combretastatin A1 diphosphate (CA1P) or combretastatin A4 phosphate (CA4P). The CTLA-4 antibody, PD-1 antibody, PD-L1 antibody, and a PD-L2 antibody can be selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL328OA, and AMP-224. The compounds can be simultaneously or sequentially administered. The combretastatin agent can be administered prior to the antibody. The combretastatin agent can be administered more than about 12 hours prior to the antibody. Said cancer can be selected from the group consisting of: ovarian cancer, fallopian tube cancer, cervical cancer, breast cancer, lung cancer, melanoma, kidney, and primary cancer of the peritoneum. The tumor can be a solid tumor selected from the group consisting of: a melanoma, an ovarian tumor, a cervical tumor, a breast tumor, small cell lung tumor, a non-small cell lung tumor, a fallopian tube tumor, a primary tumor of the peritoneum, a glioblastoma multiforme, gliomas, astrocytomas, thyroid carcinoma, neuroendocrine tumors, soft tissue sarcomas, hepatocellular carcinoma, and gastrointestinal stromal tumors. Said cancer can be selected from the group consisting of: hematologic malignancies, acute leukemias, chronic leukemias, lymphomas, and myelomas. The tumor can have a diameter or length that can be greater than about 5 cm. The tumor can have a diameter or length that can be greater than about 7 cm. The tumor can have a diameter or length that can be greater than about 10 cm. The combretastatin agent can be a compound of Formula II:


or a pharmaceutically acceptable salt thereof, wherein Racan be H, phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl; and Rbcan be phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl. The combretastatin agent can be a compound of Formula IIb:


wherein Racan be H or OP(O)(OR3)OR4; and OR1, OR2, OR3and OR4can be each, independently, H, —O-QH+or —O— M+, wherein M+can be a monovalent or divalent metal cation, and Q can be, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, can form a quaternary ammonium cation QH+; or b) an organic amine containing at least one nitrogen atom which, together with a proton, can form a quaternary ammonium cation, QH+. For Formula IIb, R3can be H or OP(O)(OR3)OR4, and R1, R2, R3and R4can be each, independently, an aliphatic organic amine, alkali metals, transition metal, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic. For Formula IIb, R1, R2, R3and R4can be each, independently, Na, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)-ethylamine, choline, or hydrabamine. Formula II or Formula IIb can be represented by a compound of Formula III:


and pharmaceutically acceptable salts thereof.

In general, in one embodiment, a method of treating a tumor in a subject in need thereof by administering to the subject a pharmaceutical composition including combretastatin A1 diphosphate (CA1P) and one or more compound selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL328OA, and AMP-224.

In general, in one embodiment, a method of treating a tumor in a subject in need thereof by administering to the subject a pharmaceutical composition including combretastatin A4 phosphate (CA4P) and one or more compound selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL328OA, and AMP-224.

This and other embodiments can include one or more of the following features. The subject can be a human. The tumor can have a diameter or length that can be greater than about 5 cm. The tumor can have a diameter or length that can be greater than about 7 cm. The tumor can have a diameter or length that can be greater than about 10 cm.

In general, in one embodiment, a pharmaceutical composition for producing an anti-tumor effect in a subject suffering from cancer or a tumor, including a Vascular Disrupting Agent (VDA) including a combretastatin agent and one or more antibodies selected from the group consisting of: a CTLA-4 antibody, a PD-1 antibody, a PD-L1 antibody, and a PD-L2 antibody in amounts effective therefore in a pharmaceutical carrier.

This and other embodiments can include one or more of the following features. The CTLA-4 antibody, PD-1 antibody, PD-L1 antibody, and a PD-L2 antibody can be selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL328OA, and AMP-224. The composition can include two or more antibodies selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL3280OA, and AMP-224. The VDA can be combretastatin A1 diphosphate (CA1P) or combretastatin A4 phosphate (CA4P). The combretastatin agent can be a compound of Formula II:


or a pharmaceutically acceptable salt thereof, wherein Racan be H, phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl; and Rbcan be phosphate, phosphate ester, phosphonate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, phosphordiamidate, cyclic phosphorodiamidate, phosphonamidate or amino acid acyl. The combretastatin agent can be a compound of Formula IIb:


wherein Racan be H or OP(O)(OR3)OR4; and OR1, OR2, OR3and OR4can each, independently, H, —O— QH+or —O— M+, wherein M+can be a monovalent or divalent metal cation, and Q can be, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, can form a quaternary ammonium cation QH+; or b) an organic amine containing at least one nitrogen atom which, together with a proton, can form a quaternary ammonium cation, QH+. For Formula IIb, R3can be H or OP(O)(OR3)OR4, and R1, R2, R3and R4can each, independently, an aliphatic organic amine, alkali metals, transition metal, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic. For Formula IIb, R1, R2, R3and R4can each, independently, Na, TRIS, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)-ethylamine, choline, or hydrabamine. Formula II or IIb can be represented by a compound of Formula III:


and pharmaceutically acceptable salts thereof. The pharmaceutical composition can include CA1P and one or more compounds selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL328OA, and AMP-224. The pharmaceutical composition can include CA4P and one or more compounds selected from the group consisting of: Tremelimumab, Ipilumab, Nivolumab, Pembrolizumab, Pidilizumab, MEDI4736, BMS 936559, MPDL3280OA, and AMP-224.

