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.
Highlights
Cancer immunotherapy has been a game changer in cancer treatment since the approval of the immune checkpoint inhibitor (ICI) ipilimumab in 2011
Nobel Prize in Physiology or Medicine was awarded to James Allison, who conceptualized cancer immunotherapy by targeting the immunosuppressive signal mediated by Cytotoxic T Lymphocyte-Associated Protein 4 (CTLA-4) [1, 2]
ICIs had been approved for microsatellite instability (MSI)-high colorectal cancers, which constitute approximately 5% of metastatic colorectal cancers, as well as other MSI-high gastrointestinal malignancies which constitute less than 1‐2% of their respective types of tumors [60, 61]
Summary
Cancer immunotherapy has been a game changer in cancer treatment since the approval of the immune checkpoint inhibitor (ICI) ipilimumab in 2011. Clinical trials using these approaches to prime the melanoma TIME and enhance the sensitivity of anti-PD-1 antibodies have been conducted Preliminary results from these studies support using this novel strategy in overcoming the resistance to ICIs through activating T cells directly by activating type-I cytokine receptors or indirectly through activating innate immune responses. A Phase-I/Ib clinical trial with oral CPI-444 alone or CPI-444 in combination with atezolizumab is currently ongoing in patients with renal cell carcinoma, non-small cell lung cancer, melanoma, triple-negative breast cancer, or other cancer types (unpublished data) These patients have exhibited progressive disease on prior therapy, including immunotherapy, and they were not selected based on PD-L1 expression. It will be interesting to see the expression levels of PCBP1 in ICI-resistant, cold tumors, and examine how this plays a role in the TeffTreg commitment program and ICI resistance
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