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 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).