Reducing beta-catenin expression to potentiate immunotherapy
Inventors
Ganesh, Shanthi • Abrams, Marc
Assignees
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Publication Number
US-11572559-B2
Publication Date
2023-02-07
Expiration Date
Abstract
Provided herein are methods and compositions for treating cancer, including cancer that is not responsive to immunotherapy. In one aspect, the methods of treatment comprise administering to the subject a therapeutically effective amount of a β-catenin inhibitor and a therapeutically effective amount of an immunotherapeutic agent. Another aspect is directed to pharmaceutical compositions comprising a β-catenin inhibitor for use in treating cancer, wherein the composition is administered in combination with an immunotherapeutic agent. Yet another aspect is directed to a method of potentiating the therapeutic effect of immunotherapy against a cancer using a β-catenin inhibitor, such as a β-catenin nucleic acid inhibitor molecule.
Core Innovation
The document describes combination cancer immunotherapy in which reducing b2-catenin expression converts nonT cell inflamed cold tumors into hot T cell-inflamed tumors. The approach centers on administering a b2-catenin nucleic acid inhibitor molecule, particularly a double stranded RNAi that targets b2-catenin. The method is positioned to potentiate subsequent immunotherapeutic activity by changing the tumor immune contexture toward T cell inflammation.
A therapeutically effective amount of the b2-catenin nucleic acid inhibitor is administered together with an immunotherapeutic agent. The immunotherapeutic agent is described as an immune checkpoint targeting modality, including inhibitory checkpoint antagonists such as anti-CTLA-4, anti-PD-1, and anti-PD-L1, and co-stimulatory agonists. The document also describes patient stratification based on Wnt activation status and a non-T cell inflamed phenotype.
The document supports the conversion and potentiation concept by comparing direct b2-catenin inhibition to indirect Wnt-pathway inhibition, and by describing increased CD8 infiltration and chemokine induction including CCL4 and CXCL10/11. It further describes checkpoint marker upregulation including PD-1/PD-L1 and enhanced tumor growth delay/regression when b2-catenin inhibitor is combined with checkpoint blockade across Wnt-active and non-Wnt-activated tumor models.
Claims Coverage
The provided set includes three independent claims covering three related inventive features: combining a b2-catenin nucleic acid inhibitor RNAi with an immunotherapeutic agent, a specific double-stranded RNAi embodiment with defined SEQ ID NO:1/SEQ ID NO:2 and checkpoint antibodies, and potentiating an immunotherapeutic agent2019s therapeutic effect using the b2-catenin RNAi.
Administering a b2-catenin nucleic acid inhibitor RNAi with SEQ ID NO:1 plus an immunotherapeutic agent
A method of treating cancer in a subject by administering a therapeutically effective amount of a b2-catenin nucleic acid inhibitor molecule, wherein said nucleic acid inhibitor molecule is a double stranded RNAi and the sense strand comprises or consists of SEQ ID NO:1, together with a therapeutically effective amount of an immunotherapeutic agent.
Defined b2-catenin RNAi with SEQ ID NO:1/SEQ ID NO:2 plus checkpoint monoclonal antibodies
A method of treating cancer in a human subject by administering a therapeutically effective amount of a b2-catenin nucleic acid inhibitor molecule, wherein the molecule is a double stranded RNAi inhibitor molecule comprising a sense and an antisense strand with a region of complementarity, the sense strand comprises or consists of SEQ ID NO:1, the antisense strand comprises or consists of SEQ ID NO:2, and the immunotherapeutic agent comprises an anti-CTLA-4 monoclonal antibody, an anti-PD-1 monoclonal antibody, an anti-PD-L1 monoclonal antibody, or a combination of an anti-CTLA-4 monoclonal antibody and an anti-PD-1 monoclonal antibody.
Potentiating immunotherapeutic effect by b2-catenin RNAi sense strand SEQ ID NO:1
A method of potentiating a therapeutic effect of an immunotherapeutic agent against a cancer by administering to a subject having the cancer a b2-catenin nucleic acid inhibitor molecule in an amount sufficient to potentiate the therapeutic effect of the immunotherapeutic agent, wherein the molecule is a double stranded RNAi and the sense strand comprises or consists of SEQ ID NO:1.
Across the independent claims, the coverage centers on combining or using to potentiate immunotherapy with a b2-catenin double stranded RNAi in which the sense strand comprises or consists of SEQ ID NO:1, including a more specific SEQ ID NO:1/SEQ ID NO:2 RNAi embodiment paired with anti-CTLA-4, anti-PD-1, and anti-PD-L1 monoclonal antibodies.
Stated Advantages
Converts non-T cell inflamed cold tumors into hot T cell-inflamed tumors.
Potentiates the therapeutic effect of an immunotherapeutic agent against cancer.
Enhances checkpoint blockade efficacy when combined with b2-catenin inhibition.
Increases CD8 infiltration and chemokine induction including CCL4 and CXCL10/11.
Upregulates checkpoint marker expression including PD-1/PD-L1 and improves tumor growth delay/regression.
Documented Applications
Treating cancer in a subject by administering a b2-catenin nucleic acid inhibitor RNAi with SEQ ID NO:1 together with an immunotherapeutic agent.
Treating cancer in a human subject using a specified double stranded RNAi with sense and antisense sequences SEQ ID NO:1 and SEQ ID NO:2 together with anti-CTLA-4, anti-PD-1, or anti-PD-L1 monoclonal antibodies, or a combination of anti-CTLA-4 and anti-PD-1 monoclonal antibodies.
Potentiating a therapeutic effect of an immunotherapeutic agent against cancer by administering a b2-catenin nucleic acid inhibitor RNAi with SEQ ID NO:1.
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