Research ArticleCancer

Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy

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Science Translational Medicine  24 Jun 2020:
Vol. 12, Issue 549, eaba2325
DOI: 10.1126/scitranslmed.aba2325

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Immunotherapies combining forces

Although immunotherapy has been achieving increasing prominence in cancer treatment, these methods are not perfect, and many tumors still do not respond to treatment. One approach used for cancer immunotherapy is bispecific antibodies, which recognize a receptor on the surface of T cells and a tumor antigen, helping to bring the two types of cells together and activate the T cells. Building on recent advances in this field, Waite et al. used bispecific antibodies targeting CD28 on T cells and one of two different tumor antigens and then combined them with immune checkpoint therapy, showing that the two treatments reinforce each other.

Abstract

Monoclonal antibodies that block the programmed cell death 1 (PD-1) checkpoint have revolutionized cancer immunotherapy. However, many major tumor types remain unresponsive to anti–PD-1 therapy, and even among responsive tumor types, most of the patients do not develop durable antitumor immunity. It has been shown that bispecific antibodies activate T cells by cross-linking the TCR/CD3 complex with a tumor-specific antigen (TSA). The class of TSAxCD3 bispecific antibodies have generated exciting results in early clinical trials. We have recently described another class of “costimulatory bispecifics” that cross-link a TSA to CD28 (TSAxCD28) and cooperate with TSAxCD3 bispecifics. Here, we demonstrate that these TSAxCD28 bispecifics (one specific for prostate cancer and the other for epithelial tumors) can also synergize with the broader anti–PD-1 approach and endow responsiveness—as well as long-term immune memory—against tumors that otherwise do not respond to anti–PD-1 alone. Unlike CD28 superagonists, which broadly activate T cells and induce cytokine storm, TSAxCD28 bispecifics display little or no toxicity when used alone or in combination with a PD-1 blocker in genetically humanized immunocompetent mouse models or in primates and thus may provide a well-tolerated and “off the shelf” combination approach with PD-1 immunotherapy that can markedly enhance antitumor efficacy.

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