Abstract 251: Combining Ibrutinib with immune checkpoint blockade to induce therapeutic antitumor immune response in solid tumors

Abstract

Abstract The ability of T-cell responses to effectively attack tumors is restricted by multiple negative checkpoint regulators. Monoclonal antibodies blocking negative regulators of T -cells, such as CTLA-4 and PD-L1 can amplify pre-existing immune responses and evoke new therapeutic responses. Ibrutinib (Imbruvica®), a covalent inhibitor of BTK has shown therapeutic efficacy in several blood cancers, by a mechanism thought to be a direct effect on a critical signaling pathway intrinsic to the malignant B cell. Since BTK is predominantly expressed in hematopoietic cells, solid tumors have not been an obvious target of this drug. An additional target of ibrutinib is the inhibition of ITK, a key enzyme in the survival of Th2 T cells. It has been reported that ibrutinib can alter the balance of Th1 and Th2 T cells leading to enhanced immune responses. Here we report that the combination of ibrutinib and a-PD-L1 antibody suppresses tumor growth, reduces lung metastasis and improves survival of mice bearing solid tumors such as 4T1-triple negative breast cancer and CT26-colon cancer. Moreover, the combination of ibrutinib and a-PD-L1 was able to overcome ibrutinib resistance in mouse models of lymphoma and myeloma. We present evidence that the synergistic therapeutic activity of Ibrutinib with anti PD1 blockade results in enhanced T cell anti-tumor immune responses. In preclinical models, by combining inhibitory checkpoint blockade while shifting the immune response towards CD4 Th1 with ibrutinib, immune tolerance to tumors can be overcome. These results provide rationale for several newly planned clinical trials combining ibrutinib with PD-1 blockade in solid tumor and exploration of such a combination in hematologic malignancies. Citation Format: Idit Sagiv-Barfi, Holbrook Kohrt, Debra Czerwinski, Patrick Ng, Betty Chang, Ronald Levy. Combining Ibrutinib with immune checkpoint blockade to induce therapeutic antitumor immune response in solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 251. doi:10.1158/1538-7445.AM2015-251