Methods of treating cancer
Inventors
Willingham, Stephen • Miller, Richard A. • Ho, Po Y. • McCaffery, Ian • Hotson, Andrew
Assignees
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Publication Number
US-12023337-B2
Publication Date
2024-07-02
Expiration Date
Abstract
Provided herein are, inter alia, methods of treating cancer by administering to a subject a therapeutically effective amount of an adenosine-A2A (A2A) receptor antagonist or a combination of an adenosine-A2A (A2A) receptor antagonist and a programmed cell death protein 1 (PD-1) signaling pathway inhibitor. Further provided are pharmaceutical compositions including an A2A receptor antagonist, a PD-1 signaling pathway inhibitor and a pharmaceutically acceptable excipient. Further provided are methods of detecting cellular effects, for example expression of pCREB, before, after or during adenosine receptor antagonist treatment.
Core Innovation
The subject matter relates to treating cancer in a subject in need thereof by administering a pharmaceutical composition containing 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine together with a pharmaceutically acceptable excipient. The treatment framework includes twice per day administration and effective amount dosing, with oral administration in certain formulations.
The patent also describes anti-cancer immunotherapy in which an adenosine-A2A (A2A) receptor antagonist is administered alone or in combination with PD-1 pathway inhibitors. The combination includes PD-1 antagonists and PD-L1 antagonists, including atezolizumab, and is described in terms of shifting immune responses involving CD4 and CD8 T cells and counteracting adenosine-mediated suppression.
The document further describes treatment intents directed to enhancing anti-tumor immune response and immune memory, increasing CD8-positive cells relative to Treg cells, and reducing tumor volume. It also describes biomarker and pharmacodynamic readouts involving phosphorylated CREB (pCREB) in B and T cells, together with immunophenotyping using CD19/CD20 for B cells and CD3/CD4/CD8 for T cells.
Claims Coverage
The independent claims cover three main treatment frameworks centered on 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine. Across the independent claims, the inventive features are the specified compound, the cancer indication scope, and the administration framework, including twice per day composition dosing, effective-amount administration, and renal cancer specificity.
Twice-per-day administration of a defined pharmaceutical composition for listed cancers
Administering to the subject a pharmaceutical composition twice per day, where the cancer is lymphoma, colon cancer, lung cancer, triple negative breast cancer, melanoma, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, or renal cancer, and where the pharmaceutical composition comprises 100 mg of 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine and a pharmaceutically acceptable excipient.
Effective-amount administration for a listed set of cancers
Administering to the subject an effective amount of 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine, thereby treating the cancer, where the cancer is lymphoma, colon cancer, non-small cell lung cancer, triple negative breast cancer, melanoma, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, or renal cancer.
Renal cancer treatment with effective-amount administration
Administering to the subject an effective amount of 7-(5-methylfuran-2-yl)-3-[[6-[[(3S)-oxolan-3-yl]oxymethyl]pyridin-2-yl]methyl]triazolo[4,5-d]pyrimidin-5-amine, thereby treating renal cancer in the subject.
Overall, the independent claims consistently focus on treating cancer by administering the specified A2A antagonist compound, with coverage distinguished by twice-per-day pharmaceutical composition dosing, effective-amount regimens, and a renal-cancer-specific method.
Stated Advantages
Enhancing anti-tumor immune response.
Providing immune memory.
Increasing CD8-positive cells relative to Treg (regulatory T cells).
Reducing tumor volume.
Increase anti-tumor immune response/global immune activation.
Modulate T-cell/NK cell engagement.
Increase CD8-positive cell numbers relative to regulatory T cells.
Decrease tumor volume.
Enhance anti-tumor memory.
T-cell activation.
Increasing immune activation/memory.
Synergistic outcomes with PD-1 signaling pathway inhibitor regimens referenced as combined synergistic amounts.
Documented Applications
Treating cancer in a subject in need thereof, including lymphoma, colon cancer, lung cancer, non-small cell lung cancer, triple negative breast cancer, melanoma, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, and renal cancer.
Treating renal cancer specifically in a subject in need thereof.
Combination regimens with PD-1/PD-L1 pathway inhibitors, including atezolizumab (MPDL3280A), with simultaneous or sequential timing and time windows.
T-cell modulation concepts involving contacting T cells with an A2A antagonist and a PD-1 inhibitor, and inhibiting A2A receptor activity in cells.
Used with PD-1 pathway inhibitors, including PD-L1 antagonists and PD-1 antagonists, in cancer treatment and immunotherapy regimens.
Applied in anti-PD-1 refractory cancer subjects.
Immune modulation aimed at modulating T-cell/NK cell engagement, including CD8/CD4 T cells and natural killer (NK) cells, and shifting CD8-positive cells relative to regulatory T cells.
Administration with atezolizumab.
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