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

   


Authors: Jaspers, J. E.; Khan, J. F.; Godfrey, W. D.; Lopez, A. V.; Ciampricotti, M.; Rudin, C. M.; Brentjens, R. J.
Article Title: 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.
Keywords: genetics; t lymphocyte; t-lymphocytes; mouse; animal; animals; mice; cancer immunotherapy; lung neoplasms; lung cancer; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; oncology; lung tumor; immunology; tumor cell line; adoptive immunotherapy; immunotherapy, adoptive; neuroendocrine carcinoma; carcinoma, neuroendocrine; small cell lung cancer; small cell lung carcinoma; interleukin 18; interleukin-18; cellular immune response; humans; human
Journal Title: Journal of Clinical Investigation
Volume: 133
Issue: 9
ISSN: 0021-9738
Publisher: American Society for Clinical Investigation  
Date Published: 2023-05-01
Start Page: e166028
Language: English
DOI: 10.1172/jci166028
PUBMED: 36951942
PROVIDER: scopus
PMCID: PMC10145930
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85159243442&doi=10.1172%2fJCI166028&partnerID=40&md5=66bed21f326a30145884235ec6f5fc42
Notes: Article -- Export Date: 1 June 2023 -- Source: Scopus
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MSK Authors
  1. Charles Rudin
    495 Rudin
  2. Janneke Elisabeth Jaspers
    3 Jaspers
  3. Andrea V Lopez
    11 Lopez
  4. Metamia Ciampricotti
    16 Ciampricotti
  5. William Darius Godfrey
    2 Godfrey
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