DLL3-targeted IL18-secreting CAR T cells in Small Cell Lung Cancer - Project Summary Small cell lung cancer (SCLC) represents ~15% of all lung cancers and has an exceptionally poor prognosis, (median overall survival 8-9 months and 3-year overall survival of 9-12%). Responses to frontline platinum- based chemotherapies and programmed cell death protein 1 (PD-1) blockade are generally short-lived (median progression-free survival [PFS] 5 months), and later-line treatments have limited efficacy (median PFS 2.6 months) and considerable toxicity. There is a critical need for novel therapeutic approaches in SCLC. The inhibitory Notch ligand Delta-like protein 3 (DLL3) is a promising target for immune-based SCLC therapies. DLL3 plays a critical role in SCLC tumorigenesis, is highly expressed on the surface of at least 85% of SCLCs, and is absent from normal tissue. DLL3 targeting T cell engagers have response rates of 20-40% in the relapsed, refractory setting with a tolerable side effect profile, but many responses are not durable. Extrapolating from other tumor types, chimeric antigen receptor (CAR) T cells have almost double the response rates and increased durability of responses relative to T cell engagers. CAR T cells can also be engineered to secrete cytokines to activate endogenous anti-tumor immunity and potentially overcome antigen heterogeneity and escape. Hence, DLL3-directed CAR T cells are poised to have increased anti-tumor activity and durable responses compared to T cell engagers. Based on this and our preliminary studies, we hypothesize that DLL3-directed SAVVY-IL18 CAR T cells will be safe and effective against chemotherapy and PD-1 blockade resistant SCLC. We will test this hypothesis in the following specific aims: 1. Determine the safety and preliminary efficacy of DLL3-targeted IL18-secreting CAR T cells in a phase 1 trial of relapsed, refractory extensive stage SCLC. 2. Interrogate intratumoral and peripheral immune cell dynamics and capacity of DLL3-targeted IL18-secreting CAR T cells to enhance the expansion of endogenous CAR-negative tumor-targeted T cells. We will conduct a phase I dose escalation trial. Cohorts of 2 will be infused with escalating doses of DLL3-SAVVY-IL-18 CAR T cells to establish the maximum tolerated dose (MTD) of CAR T cells. Dose escalation/de- escalation decisions will be based on the modified continual reassessment method (MCRM). To complement the clinical trial, correlative studies will be carried out to deeply characterize the immune landscape and its evolution during treatment using next-generation sequencing, whole exome sequencing, single-cell 5’ RNA sequencing and T cell receptor CITE sequencing, immunohistochemistry of tumor tissue of pre- and on-treatment biopsies, and T cell receptor sequencing of peripheral blood mononuclear cells. Promising results will lay the foundation for a larger phase 2 trial, advancing this promising approach. The innovative T cell product proposed in this study has the potential to dramatically improve outcomes for patients with SCLC and will also yield important insights into disease biology.
