Modern Strategies Improving Immunotherapy in Cancer

In season 2, episode 3 of Targeted Talks, Jason Luke, MD, a medical oncologist and director of the Center for Therapeutics at UPMC Hillman Cancer Center, and an associate professor of medicine, leads a discussion with Sandip Patel, MD, a medical oncologist and associate professor of medicine at the University of California San Diego Health, about the present and future of immunotherapy in cancer.

Many of the available immunotherapy agents, specifically anti–PD-L1 and anti–CTLA-4–directed therapies, were first used for cutaneous and thoracic tumors. A newer option for patients after progression is T cell immunoglobulin and ITIM domain (TIGIT). In the thoracic space, this therapy is being investigated in patients with small cell lung cancer and non–small cell lung cancer (NSCLC). A notable study was the CITYSCAPE (NCT03563716) clinical trial of the anti-TIGIT therapy tiragolumab in combination with atezolizumab (Tecentriq), which achieved anti-tumor activity in patients with metastatic non –NSCLC whose tumors have high PD-L1 expression and no EGFR or ALK genomic aberrations, leading to a breakthrough therapy designation from the FDA. Results from the study led to further exploration of the combination in gastrointestinal and gynecologic malignancies in the SKYSCRAPER clinical trial program (NCT04540211, NCT04300647).

What is unique about how TIGIT works is that it promotes a natural way for the body to limit overactive immune surveillance. Research suggests that there is synergy between TIGIT and PD-1 inhibitors. There has also been early data showing the promise of TIGIT monotherapy. Further pembrolizumab (Keytruda) combinations are promising.

Although clinical trials that include these treatment strategies have shown promise, one of the issues in the immunotherapy space is that most combination strategies automatically include a PD-1 inhibitor. With more biomarker testing, Luke and Patel believe that more beneficially treatment strategies could be discovered for patients who do not derive as much benefit from anti-PD-1 combinations.

Integration of immunotherapy in other diseases has already begun. Luke and Sandip explained that the trend with immunotherapy in areas like genitourinary cancer is to add agents in the later-line setting to start. Then, immunotherapeutic agents are combined with other agents like VEGF inhibitors earlier on in the course of treatment. Notably, the discovery of the LAG3 protein has also inspired biomarker studies.

Looking to the future, the integration of immunotherapy should be more biomarker-focused, the oncologists explain. A more targeted approach to treatment can both improve responses and address progression on immunotherapy agents. Based on the research that has been reported to date, both oncologists agree that anti–PD-L1 agents will continue to lead the immunotherapy landscape as it continues to expand to other malignancies.