NOVEL IMMUNE CHECKPOINT

Inhibitors May Have Higher Efficacy Or Better Safety Profile

The search for new ICIs has accelerated, in the hope that novel ICIs may have fewer side effects, in combinations or alone, or be more effective—or both Immunotherapies come with many side effects that can limit treatment options for patients. Alternatives that are better tolerated could significantly enhance patient lives and lead to better treatment outcomes as well.

Additionally, 50% of patients with melanoma still do not respond to current immunotherapies Novel therapeutic approaches are therefore needed to expand the success of immunotherapies. LAG-3 is just one of several promising targets for novel ICIs. Others include TIM-3, TIGIT, VISTA, B7-H3, and BTLA Additional molecules that are immunomodulatory and may synergize with one or more ICIs include ICOS, CD40L, OX40, 4-1BB and CD47 Many clinical trials are trying to determine whether blocking these other checkpoints, either alone or in combination with existing ICIs, could lead to better results than current treatment regimes

Similar to LAG-3, these novel ICI targets hold a lot of therapeutic promise. For example, there is currently a phase III trial evaluating the blockade of TIGIT in combination with the PD-1 inhibitor pembrolizumab in patients with resected high-risk melanoma Another example is VISTA, which is still in early clinical trials. VISTA may be particularly interesting to patients with melanoma because about one third of melanomas show high levels of this immune checkpoint protein, which is associated with advanced disease and worse prognosis Additionally, similar to what has been shown with LAG-3, treatment of melanomas with PD-1 blockade leads to increased levels of VISTA, indicating that tumors use immune suppression via VISTA as a back-up mechanism to escape the antitumor effects of blocking the PD-1/PD-L1 interaction. The efficacy of these and other novel ICIs remains to be seen, but patients should look out for new developments in this field

Overall, the discovery of immune checkpoints and their therapeutic blockade has had significant impact on many thousands of melanoma patients, extending survival by years and potentially curing as many as 35-40% of patients with metastatic melanoma Nonetheless, a substantial proportion of patients still does not reap the benefits of immunotherapy, and too many recipients of immunotherapy struggle with debilitating side effects that require treatment discontinuation Therefore, it is important that more research is done on novel immune checkpoint inhibitors and new combination treatments that show increased efficacy and tolerability.

Paul works in the group of Semir Beyaz and focuses his research on the impact of metabolism on immune cells and their ability to fight cancer. With this research, the Beyaz Lab sits at the cutting edge of cancer immunology and hopes to help make better immunotherapies for the future