Cited by 58CAR-T cell therapy researchImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy

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Smith, Jenessa B, Lanitis, Evripidis, Dangaj, Denarda, Buza, Elizabeth, Poussin, Mathilde, Stashwick, Caitlin, Scholler, Nathalie, Powell, Daniel J·2016·Molecular Therapy

Abstract

B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CARs) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed antitumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6-8 weeks after therapy. Comprehensive assessment of murine B7-H4 protein distribution uncovered expression in ductal and mucosal epithelial cells in normal tissues. Postmortem analysis revealed the presence of widespread histologic lesions that correlated with B7-H4(+) expression, and were inconsistent with graft versus host disease. Lastly, expression patterns of B7-H4 protein in normal human tissue were comparable to distribution in mice, advancing our understanding of B7-H4. We conclude that B7-H4 CAR therapy mediates control of cancer outgrowth. However, long-term engraftment of B7-H4 CAR T cells mediates lethal, off-tumor toxicity that is likely due to wide expression of B7-H4 in healthy mouse organs. This model system provides a unique opportunity for preclinical evaluation of safety approaches that limit CAR-mediated toxicity after tumor destruction in vivo.

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Crossref · 10.1038/mt.2016.149

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Authors
Smith, J. B., Lanitis, E., Dangaj, D., Buza, E., Poussin, M., Stashwick, C., Scholler, N., & Powell, D. J.
Affiliations
  • University of Pennsylvania (US)
  • Ludwig Cancer Research (CH)
  • Lancaster General Hospital (US)
  • SRI International (US)
Corresponding author
Powell, Daniel J
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2016-11
Volume
24
Issue
11
Pages
1987-1999
ISSN
1525-0016 (ISSN-L)
OpenAlex
W2478176079
Cited by
58
References
54
Citations by year
2026: 3 · 2025: 5 · 2024: 6 · 2023: 11 · 2022: 12 · 2021: 1 · 2020: 4 · 2019: 8 · 2018: 2 · 2017: 6
FWCI
2.88
Type
journal article
Language
en
Open access
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • Department of Defense (OC110673)
  • NIH (RO1-CA168900)
  • Immunobiology of Normal and Neoplastic Lymphocytes T32 Training Grant
  • NCI (CA016520)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
B7-H4, chimeric antigen receptor T cells, CAR T-cell therapy, ovarian cancer, on-target off-tumor toxicity, tumor regression, IFN-gamma secretion, xenograft models, preclinical safety
MeSH terms
Animals, Female, Humans, Ovarian Neoplasms, Receptors, Antigen, T-Lymphocytes, Gene Expression Regulation, Neoplastic, Treatment Outcome, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, V-Set Domain-Containing T-Cell Activation Inhibitor 1, Cell- and Tissue-Based Therapy

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