Conjoint therapies for immunomodulation
Inventors
Sasikumar, Pottayil Govindan N. • Ramachandra, Muralidhara • Ramachandra, Raghuveer K. • Lazorchak, Adam S. • Wyant, Timothy L.
Assignees
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Publication Number
US-12064418-B2
Publication Date
2024-08-20
Expiration Date
Abstract
The present disclosure relates to methods comprising administering compounds that inhibit VISTA and PD-1 (e.g., PD-1, PD-L1, or PD-L2) pathways with a compound that inhibits TIM-3 and PD-1 (e.g., PD-1, PD-L1, or PD-L2) pathways. The disclosure also relates to treatment of disorders by inhibiting an immunosuppressive signal induced by VISTA, TIM-3, PD-1, PD-L1, and/or PD-L2.
Core Innovation
The invention relates to conjoint immunomodulatory cancer therapy by administering, to a subject in need thereof, a first compound and a second compound for treating cancer. The combination supports cancer treatment strategies in which immune-activating and immunomodulatory agents are used together with immune checkpoint blockade approaches, including PD-1/PD-L1/PD-L2 pathway inhibition.
The disclosed immune checkpoint modulation includes VISTA pathway inhibitor together with TIM-3 pathway inhibitor, each combined with PD-1/PD-L1/PD-L2 pathway inhibition. It further describes immune-activating antibodies including anti-CD40 in combination with PD-1 blockade, and additional immune pathway modulators including CTLA-4, OX-40, 4-1BB, and ICOS agonists.
Additional immunomodulatory agents include anti-CD3, anti-CD20, anti-CD52, and anti-cytokine and tumor-antigen antibodies, as well as tumor vaccine approaches employing neoantigens or tumor antigens. Cancer vaccine strategies described include therapeutic cancer vaccines such as GM-CSF-expressing tumor vaccines, dendritic cell vaccines, and vaccines based on viral, vector, DNA, RNA, peptide, or protein formats, including heat shock protein-based antigens.
The document further reports preclinical efficacy combining immune-modulating small molecules Cmd 1 and Cmd 32 with anti-PD-1 and anti-TIM-3 in syngeneic mouse tumor models, including CT-26 and MC38, with reported immune marker shifts, additive efficacy, and tumor growth inhibition.
Claims Coverage
The independent claims cover a method of treating cancer by conjointly administering a first compound and a second compound to a subject in need thereof. The inventive features are the conjoint administration of two compounds and the provision that each compound may be a compound or a pharmaceutically acceptable salt thereof.
Conjointly administering first and second compounds for treating cancer
A method of treating cancer in a subject in need thereof comprising conjointly administering a first compound and a second compound to the subject.
First compound as compound or pharmaceutically acceptable salt
The first compound is or a pharmaceutically acceptable salt thereof.
Second compound as compound or pharmaceutically acceptable salt
The second compound is or a pharmaceutically acceptable salt thereof.
Using specified chemical structures for first and second compounds
The method characterized in that the first compound is a specified chemical structure and the second compound is a different specified chemical structure.
Selecting the cancer from an enumerated cancer or tumor list
The method applied to a cancer selected from a specified list of many cancer types and tumor or neoplasm categories.
Treating colon cancer
The method for treating colon cancer.
Treating non-Hodgkin's lymphoma
The method further limited such that the cancer treated is non-Hodgkin's lymphoma.
Overall, the claim set primarily covers conjoint administration of two compounds for treating cancer, with refinements that specify chemical structures, allow each agent to be a pharmaceutically acceptable salt, and narrow the indication to cancers selected from enumerated lists, including colon cancer and non-Hodgkin's lymphoma.
Stated Advantages
Additive efficacy.
Changes in tumor CD8+ T-cell subsets.
Immune marker shifts.
Tumor growth inhibition.
Restore and/or augment T-cell responses beyond PD-1-only therapy.
Documented Applications
Cancer treatment in a subject in need thereof, including conjoint immunomodulatory therapy combining VISTA pathway inhibition and TIM-3 pathway inhibition together with PD-1/PD-L1/PD-L2 pathway inhibition.
In vivo tumor efficacy and immunophenotyping results are described for combinations involving Cmd 1 and Cmd 32 in syngeneic mouse tumor models, including CT-26 and MC38.
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