Mohanraj Sadasivam, PhD

Small cell lung cancer (SCLC) is an aggressive cancer often diagnosed late with a poor prognosis. Many patients develop resistance to existing treatments. While therapies targeting SCLC have had limited success, a newer class of treatments uses bispecific T-cell engagers (BiTEs), which show promise by directing the body’s immune system to attack cancer cells. However, these treatments can cause serious side effects. To address this, we are evaluating a novel BiTE that targets a protein called DLL3, which is found on SCLC cells but not on healthy tissues, and activates a specific type of immune cell called gamma delta (γδ) T cells. These cells may offer a safer alternative by reducing toxicity compared to conventional T-cell therapies. We are testing this approach in laboratory and animal models to evaluate its safety and effectiveness, and exploring combinations with other immunotherapies to enhance outcomes. Our goal is to develop a more safe and effective treatment for people with SCLC.

Update: Our project is developing a novel immunotherapy for small cell lung cancer (SCLC) using a DLL3-targeted bispecific antibody designed to redirect immune cells to tumors. DLL3 is a protein found on SCLC cells. During the past year, we demonstrated that combining DLL3-targeted therapy with adoptively transferred γδ T cells significantly reduced tumor growth and improved survival in SCLC mouse models. Increasing the dose of the DLL3-targeted therapy further enhanced its anti-tumor effects, indicating a dose-dependent response. We also evaluated an αβ T-cell–based therapy using tarlatamab, which validated our model and further supported the effectiveness of immune cell redirection strategies. These findings support the continued development of DLL3-targeted γδ T-cell immunotherapy as a promising approach for treating aggressive SCLC.