Editors' ChoiceCancer

JAK-ing up antibody delivery to cancer

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Science Translational Medicine  03 Apr 2019:
Vol. 11, Issue 486, eaax1720
DOI: 10.1126/scitranslmed.aax1720

Abstract

The pan-JAK inhibitor tofacitinib improves the delivery of therapeutic antibodies in cancer.

Monoclonal antibodies and antibody-drug conjugates (ADCs) directed against tumor antigens are increasingly used for therapy in a variety of cancers. However, access of therapeutic antibodies to malignant cells is restricted by the tumor microenvironment, thereby limiting their efficacy. Fitzgerald and colleagues now report a preclinical study demonstrating modulation of the tumor microenvironment and improved therapeutic antibody delivery to tumors using a Janus kinase (JAK) inhibitor. Tofacitinib is a U.S. Food and Drug Administration–approved small molecule pan–JAK inhibitor that is licensed for use in autoimmune diseases, such as rheumatoid arthritis, but has no direct anticancer effects. However, given the role of JAK pathway in modulating tumor microenvironment, the authors hypothesized that tofacitinib could facilitate antibody access to malignant cells. Using mouse xenograft models of breast and pancreatic cancer, they demonstrate that tofacitinib increased uptake of immunotoxins and conjugated antibodies by tumors, resulting in increased tumor regression. Down-regulation of JAK-mediated inflammatory cytokine expression by tofacitinib decreased numbers of tumor-associated neutrophils and macrophages, which are “sinks” for the uptake of therapeutic antibodies. The authors therefore postulate that tofacitinib could be repurposed for use in cancer in combination with therapeutic antibodies and ADCs.

These findings point to several possible lines of clinical research. Positron emission tomography could be used to study the effect of JAK inhibitors on distribution of radiolabeled antibodies in patients. Tofacitinib is approved for use in humans and has a known pharmacokinetic profile, allowing a fast progression to clinical trials evaluating the safety and efficacy of combinations of tofacitinib with monoclonal antibodies. However, a limitation of this paper is the choice of models used, since monoclonal antibodies and ADCs are not the current standard of care for treatment of either triple-negative breast cancer or pancreatic ductal adenocarcinoma cancer. Further preclinical studies are therefore required first to stress test the effect of tofacitinib on approved anticancer antibodies in clinically relevant scenarios. Nonetheless, if these findings hold up to experimental and clinical validation, the discovery of tofacitinib as a facilitator of antibody-based therapy for cancer could herald an exciting new phase of immuno-oncology.

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