IL-18–secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models
Janneke E. Jaspers, … , Charles M. Rudin, Renier J. Brentjens
Janneke E. Jaspers, … , Charles M. Rudin, Renier J. Brentjens
Published March 23, 2023
Citation Information: J Clin Invest. 2023;133(9):e166028. https://doi.org/10.1172/JCI166028.
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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 3

IL-18 increases activation of both genetically engineered and endogenous T cells.

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IL-18 increases activation of both genetically engineered and endogenous...
(A) Experimental setup for B–E and Figure 4, A–H. See also Supplemental Figure 2, A–C. 2 × 106 murine mCherry-expressing SC16.8m28mz or SC16.8m28mz_mIL18 CAR T cells were administered 7 days after systemic mSCLC injection. 3, 6, or 10 days later livers and spleens were harvested for flow cytometry analysis (day 3 and day 6, n = 6 from 2 independent experiments; day 10, n = 3). (B) Levels of CAR T cells detected in the liver over time. (C) Example (day 3) and quantification of the CD8+ CAR T cell population. (D and E) Example (day 3) and quantification of (D) intracellular IFN-γ and TNF-α in CAR+ T cells and (E) CAR– endogenous T cells in the liver. (F) CD4+ or CD8+ mCherry– endogenous T cells were sorted on day 3 and 6 after CAR T cell treatment and cocultured with mSCLC, and IFN-γ release was measured with an ELISpot assay (n = 3). (B–F) *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (2-way ANOVA). (G) Systemic mSCLC growth curve (left) and survival curve (right). Tumor-bearing mice were treated with low-dose 50 mg/kg cyclophosphamide (day 6) followed by low-dose 0.5 × 106 CAR T cells (day 7). **P < 0.01 (log-rank test, n = 5). (H) Tumor growth of wild-type (n = 3–4) or DLL3KO mSCLC (n = 6, see Supplemental Figure 2D) in long-term surviving mice after cyclophosphamide plus SC16.8m28mz_mIL18 treatment with no evidence of tumor on day 42 (see G) compared with age-matched naive control mice. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (Student’s t test). (I) Survival of mice in H. *P < 0.05 (log-rank test, n = 6).