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-10912776-B2
Publication Date
2021-02-09
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 invention relates to treating cancer in a subject by administering a therapeutically effective amount of an adenosine-A2A receptor antagonist of formula (I) and/or formula (II) together with a therapeutically effective amount of atezolizumab. The combination is presented as a cancer treatment regimen targeting adenosine-A2A signaling in combination with PD-1/PD-L1 pathway inhibition through atezolizumab.
The document further describes immunological endpoints associated with the combination, including activation of CD4 T cells and CD8 T cells, shifts in CD45RA-negative CD4, changes in memory T-cell and effector T-cell relative amounts, increased PD-1 positive cells, and increased TCR repertoire diversity via increased TCR recombination. It also recites pharmacodynamic and biomarker monitoring using phosphorylated CREB (pCREB) as a readout of adenosine receptor pathway blockade.
The overall disclosed core is the concurrent administration of an adenosine-A2A receptor antagonist of the specified formulas with atezolizumab to achieve enhanced anti-tumor immune activity, anti-tumor immune memory, and immune activation. The document also describes restoring IL-2 and IFN-gamma and cAMP pathway inhibition, and relates the combination to anti-PD-1 refractory cancer subjects.
Claims Coverage
The independent claim coverage centers on a method of treating cancer by administering an adenosine-A2A receptor antagonist of the stated formulas together with atezolizumab. The inventive features repeatedly include the combined administration relationship and restriction to specified cancer types, with dependent refinements adding synergistic amount and treatment parameters.
Combined adenosine-A2A receptor antagonist and atezolizumab treatment of cancer
A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of an adenosine-A2A receptor antagonist of formula (I) and/or formula (II) and a therapeutically effective amount of atezolizumab.
Cancer type restriction to multiple specified cancers
The method wherein 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.
Combined synergistic amount
The therapeutically effective amounts are administered together in a combined synergistic amount.
Specific administration parameters
The adenosine-A2A receptor antagonist is administered at 100 mg, twice daily, and atezolizumab is administered once every two weeks.
Overall claim coverage centers on administering an adenosine-A2A receptor antagonist of formula (I) and/or formula (II) together with atezolizumab for the listed cancer types, with dependent claims further specifying combined synergistic amount and particular dosing and dosing intervals.
Stated Advantages
Enhances anti-tumor immune memory.
Increases global immune activation.
Strong efficacy is reported for the combination in established MC38 colon tumors, including full elimination in the described preclinical setting.
The combination promotes T-cell activation markers, including PD-1+ CD8+ and a memory/effector phenotype.
The combination induces TCRβ repertoire changes associated with clone expansion (Morisita Index changes).
CPI-444 blocks A2A→CREB phosphorylation signaling (pCREB inhibition).
Efficacy requires CD8+ T cells, with CD8 depletion abrogating the effect.
Increasing anti-tumor immune response.
Increasing anti-tumor memory.
Increasing CD8-positive cell numbers.
Decreasing tumor volume.
Documented Applications
Treating cancer in a subject, including lymphoma and multiple solid tumors such as colon cancer, non-small cell lung cancer, triple negative breast cancer, melanoma, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, and renal cancer, using an adenosine-A2A receptor antagonist together with atezolizumab.
Established MC38 colon tumor models, with reported tumor elimination and immune/TCRβ biomarker effects.
Phase 1/1B clinical trial design linking dosing to biomarker readouts (pCREB and immune activation markers) and exploring relationships between biomarker changes and efficacy across cohorts including PD-L1 status and prior anti–PD-1 refractoriness.
Anti-PD-1 refractory cancer subjects treated by contacting T cells, including effector T cells, natural killer cells, CD8 T cells, and CD4 T cells, with an A2A antagonist together with PD-1/PD-L1 inhibitors including atezolizumab.
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