Improving the efficacy of immunotherapy in small cell lung cancer: Leveraging recent scientific discoveries and tumor-specific antigens

Small cell lung cancer (SCLC) is an aggressive neuroendocrine neoplasm with poor survival outcomes and little change to treatment standards over decades. SCLC is associated with heavy tobacco exposure and a high rate of somatic mutations in tumor cells, leading to hope that immune checkpoint inhibitors would dramatically reshape the treatment landscape of SCLC. Instead, immune checkpoint inhibitors have led to real but modest gains in outcomes, with only a small minority of patients deriving more durable benefit. Furthermore, biomarkers of ICI efficacy that have succeeded in other tumor types have not been validated in SCLC. However, recent research advances have suggested that epigenetic heterogeneity and plasticity play especially key roles in SCLC biology. Leveraging this emerging perspective, a new slate of candidate biomarkers of immune checkpoint inhibitor benefit have been described, and the novel treatment strategies combining rational epigenetic perturbation with immune checkpoint inhibitors are being developed. Finally, other immunotherapy strategies targeting SCLC-specific mechanisms are being tested. Together, these developments may lead to a second generation of much more efficacious immunotherapies in SCLC.