Next-generation immuno-oncology agents: current momentum shifts in cancer immunotherapy

Abstract

Cancer immunotherapy has reached a critical point, now that immune checkpoint inhibitors and two CAR-T products have received market approval in treating 16 types of cancers and 1 tissue-agnostic cancer indication. Accompanying these advances, the 2018 Nobel Prize was awarded for the discovery of immune checkpoint pathways, which has led to the revolution of anti-cancer treatments. However, expanding the indications of immuno-oncology agents and overcoming treatment resistance face mounting challenges. Although combination immunotherapy is an obvious strategy to pursue, the fact that there have been more failures than successes in this effort has served as a wake-up call, placing emphasis on the importance of building a solid scientific foundation for the development of next-generation immuno-oncology (IO) agents. The 2019 China Cancer Immunotherapy Workshop was held to discuss the current challenges and opportunities in IO. At this conference, emerging concepts and strategies for IO development were proposed, focusing squarely on correcting the immunological defects in the tumor microenvironment. New targets such as Siglec-15 and new directions including neoantigens, cancer vaccines, oncolytic viruses, and cytokines were reviewed. Emerging immunotherapies were discussed in the areas of overcoming primary and secondary resistance to existing immune checkpoint inhibitors, activating effector cells, and targeting immunosuppressive mechanisms in the tumor microenvironment. In this article, we highlight old and new waves of IO therapy development, and provide perspectives on the latest momentum shifts in cancer immunotherapy.

Keywords: CAR-T; CTLA-4; Immune checkpoint inhibitor; Neoantigen; PD-1; PD-L1; Tumor microenvironment.

Fig. 1

The cancer-immunity cycle, immune-resistant mechanisms and strategies for anti-cancer immunotherapy. The anti-cancer immunity cycle (innermost circle) starts when cancer cells release tumor antigens. Antigen-presenting cells take up tumor antigens and present antigen-derived peptides to immune cells, which in turn activate the immune cells to migrate through the circulation, enter tumor sites, and kill cancer cells. The death of cancer cells induces the release of additional tumor antigens, which initiates another cancer-immunity cycle. The immune system has developed complex negative feedback loops to rein in the anti-pathogen response. These negative feedback loops have been exploited by cancer cells to evade anti-cancer immunity (middle circle). Current anti-cancer immunotherapy approaches (outermost circle) have been targeting and harnessing various mechanisms along this cancer-immunity circle. There are two major approaches for cancer immunotherapy: (1) the enhancement approach, which aims to augment “normal” anti-cancer immune mechanisms. Strategies in this category range from the traditional non-specific enhancement of IL-2 signaling to the more recent cancer-specific CAR-T cell therapy; and (2) the normalization approach, which aims to restore defective anti-cancer immunity in the tumor microenvironment. Strategies include FDA-approved immune checkpoint inhibitors and other drugs in development (e.g., inhibitors of the adenosine pathway)

Fig. 2

TIME classification based on PD-L1 expression and infiltration of immune cells, mainly tumor-infiltrating lymphocytes (TIL), in the tumor microenvironment. TIME, tumor immunity in the microEnvironment