Strategies for Incorporating CD40 Agonists in Cancer Therapy
Fee Bengsch, Yan Li, Mingen Liu, Kristen B. Long, Whitney L. Gladney, Kathleen Graham, Gregory L. Beatty Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA CD40, a member of the TNF receptor superfamily, remains a promising therapeutic target for surmounting immune suppression in cancer. However, as monotherapy, CD40 agonists have not produced significant clinical activity indicating their need to be strategically combined with other therapeutics. Ligation of CD40 in vivo produces an immune cascade defined by systemic cytokine release, bone marrow mobilization, monocyte trafficking to tissues, “licensing” of dendritic cells for T cell priming, activation of B cells and ultimately, induction of T cell immunity. Strategies to harness this cascade for cancer therapy and understanding mechanisms of resistance and response to CD40 agonists have emerged as key questions fundamental for the success of this therapeutic target in cancer. Although the dogma remains that CD40 is a molecule critical to bridging innate and adaptive immunity to stimulate productive antigen-specific T cell responses, CD40 agonists can also condition tumors for enhanced sensitivity to chemotherapy. Here, we discuss preclinical findings revealing strategies for sequencing chemotherapy with CD40 agonists, a role for specific myeloid cell subsets in regulating T cell immunity stimulated by CD40 activation, and rationale for combining additional myeloid-targeted therapies with CD40 agonists. Together, these findings support a role for CD40 agonists in augmenting the efficacy of chemotherapy for tumor debulking as well as in overcoming immune tolerance for restoring productive T cell immunosurveillance in cancer.
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