Using immunogenic cell death to improve anticancer efficacy of immune checkpoint inhibitors: From basic science to clinical application

Abstract

SummaryEven though the discovery of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, a high proportion of patients do not respond. Moreover, some types of cancers are refractory to these treatments. Thus, the need to find predictive biomarkers of efficacy and to evaluate the association with other treatments, such as chemotherapy or radiotherapy, appears to be essential. Because ICIs reactivate or maintain an active status of T cells, one possibility is to combine these treatments with therapies that engage an immune response against tumor cells. Thus, by inducing immunogenic cell death (ICD) of cancer cells, some conventional anticancer treatments induce such immune response and may have an interest to be combined with ICIs. In this review, we explore preclinical studies and clinical trials that evaluate the combination of ICIs with ICD inducers. More than inducing ICD, some of these treatments appear to modulate the tumor microenvironment and more particularly to inhibit immunosuppression, thus improving treatment efficacy.

Harnessing Nanomedicine to Potentiate the Chemo-Immunotherapeutic Effects of Doxorubicin and Alendronate Co-Encapsulated in Pegylated Liposomes

“…Nonetheless, immune checkpoint blockade as a single treatment modality is only efficacious in a small subset of patients, often due to the low tumor immunogenicity and TAM-induced immunosuppression in the tumor microenvironment of most tumors [54,55]. The combination of an immune checkpoint inhibitor with one or more cytotoxic drugs appears to be the most efficacious approach [56,57]. Presumably, as cancer cells are killed by the cytotoxic chemotherapy, they trigger the activation of antigen-presenting cells that synergize with immune checkpoint inhibitors to produce a robust antitumor adaptive immune response.…”

Opaganib (ABC294640) Induces Immunogenic Tumor Cell Death and Enhances Checkpoint Antibody Therapy

“…ICD also involves the autophagy-mediated secretion of ATP, and the extracellular release of the high-mobility group box 1 (HMGB1) protein. Intriguingly, several studies have demonstrated that agents that induce ICD improve the antitumor activity of the antibodies (reviewed in [9,10]). This enhanced efficacy can be seen with antibodies directed against CTLA-4, PD-1 and/or PDL1 [10][11][12][13], providing an opportunity for an effective ICD inducer to be broadly combined with FDA-approved immunotherapy drugs.…”

Mechanisms of programmed cell death

“…If induced in an appropriate fashion, one of the major positive effects of cancer cell stress and death is the induction of immune responses against tumor-associated antigen, thus sensitizing tumors to immunotherapy with immune checkpoint inhibitors. [3][4][5] This has important therapeutic implications because chemotherapeutics that induce immunogenic cell death can be used as first-line treatments to sensitize major cancer types (exemplified by KRAS-mutated colorectal cancer, non-small cell lung cancer and triple-negative breast cancer) to subsequent immunotherapy with antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or PD-1 ligand-1 (PD-L1), as this has been confirmed in several clinical trials.…”