IL-18–secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models
Janneke E. Jaspers, Jonathan F. Khan, William D. Godfrey, Andrea V. Lopez, Metamia Ciampricotti, Charles M. Rudin, Renier J. Brentjens
Janneke E. Jaspers, Jonathan F. Khan, William D. Godfrey, Andrea V. Lopez, Metamia Ciampricotti, Charles M. Rudin, Renier J. Brentjens
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Research Article Immunology Oncology

IL-18–secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models

Abstract

Patients with small cell lung cancer (SCLC) generally have a poor prognosis and a median overall survival of only about 13 months, indicating the urgent need for novel therapies. Delta-like protein 3 (DLL3) has been identified as a tumor-specific cell surface marker on neuroendocrine cancers, including SCLC. In this study, we developed a chimeric antigen receptor (CAR) against DLL3 that displays antitumor efficacy in xenograft and murine SCLC models. CAR T cell expression of the proinflammatory cytokine IL-18 greatly enhanced the potency of DLL3-targeting CAR T cell therapy. In a murine metastatic SCLC model, IL-18 production increased the activation of both CAR T cells and endogenous tumor-infiltrating lymphocytes. We also observed an increased infiltration, repolarization, and activation of antigen-presenting cells. Additionally, human IL-18–secreting anti-DLL3 CAR T cells showed an increased memory phenotype, less exhaustion, and induced durable responses in multiple SCLC models, an effect that could be further enhanced with anti–PD-1 blockade. All together, these results define DLL3-targeting CAR T cells that produce IL-18 as a potentially promising novel strategy against DLL3-expressing solid tumors.

Authors

Janneke E. Jaspers, Jonathan F. Khan, William D. Godfrey, Andrea V. Lopez, Metamia Ciampricotti, Charles M. Rudin, Renier J. Brentjens

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Figure 1

Selection of scFv for effective CAR T cells against DLL3 on small cell lung cancer.

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Selection of scFv for effective CAR T cells against DLL3 on small cell l...
(A) Schematic of extracellular DLL3 domains with binding location of anti-DLL3 SC16 antibody clones (top), and schematic of CAR design for initial selection of single-chain variable fragments (bottom). LTR, long terminal repeats; CD8SP, CD8 signal peptide; VH, heavy chain; VL, light chain; TM, transmembrane domain; h, humanized. (B) Luciferase killing assay with CAR T cells cocultured with DLL3-expressing H82-SCLC or DLL3– Set2 cells. The Set2 cells overexpress MUC16 as positive control for the MUC16-targeting 4H11 CAR (n = 3). (C and D) DLL3-specific activation of the SC16.8, SC16.125, and SC16.126 CARs in cocultures with DLL3+ 293 cells, (C) as measured by IFN-γ production (see also Supplemental Figure 1 for IL-2, GM-CSF, and TNF-α levels) and (D) 7-day proliferation (n = 3). 3T3-MUC16 cells were used as positive control for the 4H11 CAR. (E and F) Orthotopic or metastatic H82-SCLC tumor growth following administration of the indicated CAR T cells (n = 4–5).