Immune-based combination therapy to convert immunologically cold tumors into hot tumors: an update and new insights

Abstract

As a breakthrough strategy for cancer treatment, immunotherapy mainly consists of immune checkpoint inhibitors (ICIs) and other immunomodulatory drugs that provide a durable protective antitumor response by stimulating the immune system to fight cancer. However, due to the low response rate and unique toxicity profiles of immunotherapy, the strategies of combining immunotherapy with other therapies have attracted enormous attention. These combinations are designed to exert potent antitumor effects by regulating different processes in the cancer-immunity cycle. To date, immune-based combination therapy has achieved encouraging results in numerous clinical trials and has received Food and Drug Administration (FDA) approval for certain cancers with more studies underway. This review summarizes the emerging strategies of immune-based combination therapy, including combinations with another immunotherapeutic strategy, radiotherapy, chemotherapy, anti-angiogenic therapy, targeted therapy, bacterial therapy, and stroma-targeted therapy. Here, we highlight the rationale of immune-based combination therapy, the biomarkers and the clinical progress for these immune-based combination therapies.

Keywords: biomarkers; combination therapy; immune checkpoint inhibitors; immunotherapy; neoplasms.

Fig. 1. Immune-based combination therapies convert cold tumors into hot tumors by regulating the cancer-immunity cycle.

Immunotherapy is based on the cancer-immunity cycle, including the release and presentation of tumor antigens, the priming and activation of T cells, the trafficking and infiltration of T cells into tumors, and the recognition and killing of tumor cells by activated T cells. However, multiple mechanisms lead to immune evasion. Numerous therapies, including chemotherapy, radiotherapy, targeted therapy, and anti-angiogenic therapy, all regulate the immune microenvironment and complement immunotherapy for stronger antitumor responses. TSA tumor-specific antigen, TLR toll-like receptors, DC dendritic cell, TKI tyrosine kinase inhibitor, CAR-T cell chimeric antigen receptor T cell, BsAbs bispecific antibodies, CAF cancer associated fibroblast, DAMPs damage-associated molecular patterns, APCs antigen presenting cells. Adapted from [1].

Fig. 2. Potential biomarkers for immunotherapy response prediction.

Biomarkers are mainly divided into four categories: tumor, the tumor microenvironment (TME), host factor, and serum/circulating factors from peripheral blood. TIL tumor infiltrating lymphocyte, LDH lactate dehydrogenase, IDO indoleamine 2,3-dioxygenase, ctDNA circulating tumor DNA, TCR T cell receptor.