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Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK.

ABSTRACT: Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells and by doing so it can shift the balance between Th1 and Th2 T cells and potentially enhance antitumor immune responses. Here we report that the combination of anti-PD-L1 antibody and ibrutinib suppresses tumor growth in mouse models of lymphoma that are intrinsically insensitive to ibrutinib. The combined effect of these two agents was also documented for models of solid tumors, such as triple negative breast cancer and colon cancer. The enhanced therapeutic activity of PD-L1 blockade by ibrutinib was accompanied by enhanced antitumor T-cell immune responses. These preclinical results suggest that the combination of PD1/PD1-L blockade and ibrutinib should be tested in the clinic for the therapy not only of lymphoma but also in other hematologic malignancies and solid tumors that do not even express BTK.

SUBMITTER: Sagiv-Barfi I

PROVIDER: S-EPMC4352777 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK.

Sagiv-Barfi Idit I Kohrt Holbrook E K HE Czerwinski Debra K DK Ng Patrick P PP Chang Betty Y BY Levy Ronald R

Proceedings of the National Academy of Sciences of the United States of America 20150217 9

Monoclonal antibodies can block cellular interactions that negatively regulate T-cell immune responses, such as CD80/CTLA-4 and PD-1/PD1-L, amplifying preexisting immunity and thereby evoking antitumor immune responses. Ibrutinib, an approved therapy for B-cell malignancies, is a covalent inhibitor of BTK, a member of the B-cell receptor (BCR) signaling pathway, which is critical to the survival of malignant B cells. Interestingly this drug also inhibits ITK, an essential enzyme in Th2 T cells a ...[more]

PMID: 25730880

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Project description:Simple Summary Metastatic prostate cancer has a poor clinical prognosis and is incurable. In recent decades, immune checkpoint blockade has revolutionized anticancer therapies and represents a potential way to control metastatic prostate cancer. Unfortunately, due to low immunoreactivity, patients failed to achieve clinical benefits from PD-1/PD-L1 blockade. The underpinning mechanisms involved in the drug resistance of immune checkpoint blockade focus the research for metastatic prostate cancer treatment. In this study, we provide a novel combinational regimen with a kinase inhibitor and PD-1/PD-L1 axis blockade to overcome the above-mentioned drug resistance. We believe that our research will be helpful for the development of novel strategies for metastatic or late-stage prostate cancer immunotherapy. Abstract Metastatic prostate cancer (PCa) remains incurable and causes considerably diminished overall survival. Despite significant progress in pharmacotherapy, the disease prognosis remains unchanged. Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness in treating various advanced malignancies, but their efficacy in metastatic PCa is relatively limited. Previous studies have confirmed the immunosuppressive role of tumor-infiltrating B cells (TIL-Bs) in the PCa microenvironment, which accounts for their poor immunogenic potency. In this study, we demonstrated that an oral kinase agent, ibrutinib, strongly potentiated anti-PD-1 checkpoint blockade efficacy and successfully controlled tumor growth in a murine orthotopic PCa model constructed using a metastatic and hormone-independent cell line (RM-1). We identified close relationships between TIL-Bs, Bruton’s tyrosine kinase (BTK), and immunosuppressive molecules by bioinformatics and histological analysis. An in vitro study showed that a low dose of ibrutinib significantly inhibited B cell proliferation and activation as well as IL-10 production through the BTK pathway. Moreover, ibrutinib-treated B cells promoted CD8+ T cell proliferation and inhibitory receptor (IR) expression. However, the same dose of ibrutinib was insufficient to induce apoptosis in cancer cells. An in vivo study showed that ibrutinib monotherapy failed to achieve tumor regression in murine models but decreased B cell infiltration and inhibited activation and IL-10 production. More importantly, CD8+ T cell infiltration increased with high IR expression. Ibrutinib synergized with anti-PD-1 checkpoint blockade enormously improved antitumor immunity, thereby reducing tumor volume in the same scenario. These data set the scene for the clinical development of ibrutinib as an immunogenic trigger to potentiate anti-PD-1 checkpoint blockade for metastatic PCa immunotherapy.

Dataset Information

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK.

Publications

Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK.

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