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

J Clin Invest. 2023 May 1;133(9):e166028. doi: 10.1172/JCI166028.

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.

Keywords: Cancer immunotherapy; Cellular immune response; Immunology; Lung cancer; Oncology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Neuroendocrine*
  • Cell Line, Tumor
  • Humans
  • Immunotherapy, Adoptive
  • Interleukin-18* / pharmacology
  • Interleukin-18* / therapeutic use
  • Lung Neoplasms* / genetics
  • Mice
  • Small Cell Lung Carcinoma* / genetics
  • T-Lymphocytes / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Interleukin-18
  • DLL3 protein, human
  • Dll3 protein, mouse