Waite et al. demonstrated that two different “costimulatory bispecifics” cross-linking CD28 to a tumor-specific antigen (PSMA or EGFR) improved the antitumor efficacy of PD-1 blockade. In immunocompetent mice, the combination eradicated tumors and greatly improved survival, with long-term immunity compared to monotherapy. Fluorescence microscopy showed that a PD-1 blocking antibody reduced the level of CD28 at the immune synapse. Unlike CD28 superagonists, TSAxCD28 bispecifics, alone or in combination with anti-PD1, caused no systemic T cell activation in primates, potentially providing an off-the-shelf combination approach.
Contributed by Katherine Turner
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.