Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

Abstract

The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

Keywords: antigen-presenting cell; autophagy; cytotoxic T lymphocyte; damage-associated molecular pattern; dendritic cell; endoplasmic reticulum stress; immune checkpoint blocker; type I interferon.

Figure 1.

Current clinical trials testing immunogenic cell death (ICD)-inducing chemotherapies in oncological indications. A. Distribution by immunological biomarker (biomarkers directly relevant for ICD are in bold). B. Distribution by main chemotherapeutic agent. C. Distribution by oncological indication. D. Number of clinical trials currently testing ICD-inducing chemotherapeutic regimens in combination with immunotherapy. CIK, cytokine-induced killer; CSF1, colony stimulating factor 1; DC, dendritic cell; mAb, monoclonal antibody; MDSC, myeloid-derived suppressor cell; NK, natural killer; TAA, tumor-associated antigen; TLR, Toll-like receptor; T_REG, regulatory T.