PD-1 blockade synergizes with oxaliplatin-based, but not cisplatin-based, chemotherapy of gastric cancer

Abstract

Preclinical experimentation revealed that established cancers treated with the immunogenic cell death (ICD) inducer oxaliplatin are sensitized to immune checkpoint inhibitors targeting PD-1. In contrast, no such sensitizing effect is observed when cisplatin, a non-immunogenic cell death inducer is used. Two randomized phase III clinical trials targeting unresectable gastric and gastro-esophageal junction carcinomas apparently validate this observation. Thus, oxaliplatin-based chemotherapy (together with capecitabine or 5-fluorouracil plus leucovorin) favorably interacted with nivolumab, yielding improved outcome. In contrast, the outcome of cisplatin-based chemotherapy (together with capecitabine or 5-fluorouracil) failed to be improved by concomitant treatment with pembrolizumab. These clinical findings underscore the importance of choosing appropriate ICD-inducing cytotoxicants for the development of chemoimmunotherapeutic regimens. Unfortunately, the FDA and EMA have approved PD-1 blockade in combination with "platinum-based chemotherapy" without specifying the precise nature of the platinum-containing drug. This is a non sequitur. Based on the available clinical data, such approvals should be restricted to the use of oxaliplatin.

Keywords: Clinical trial; Immunotherapy.

Figure 1.

Synergistic effect of immunogenic chemotherapies and immune checkpoint inhibitors. Cisplatin (CDDP) is a non-immunogenic cell death (ICD)-inducing chemotherapeutic that fails to prime adaptive immunity in tumors, forming a “cold” immune microenvironment that consists more immune suppressive cells like tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDCSs), and regulatory T cells (Tregs), but less antigen presenting cells such as dendritic cells (DCs) or effector cells such as cytotoxic T lymphocytes (CTLs). Thus, CDDP cannot synergize with PD-1 targeting immune checkpoint inhibitors (ICIs). Oxaliplatin (OXA) induces ICD and establishes a primed “hot” tumor immune microenvironment that favors the infiltration and accumulation of DCs and CTLs over immunosuppressive cells, thus sensitizing to the immunotherapeutic effects of PD-1 targeting antibodies.