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Cited by 653CAR-T cell therapy researchImmunotherapy and Immune ResponsesPeptidase Inhibition and Analysis

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Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity without Severe Toxicity

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Wang, Liang-Chuan S., Lo, Albert, Scholler, John, Sun, Jing, Majumdar, Rajrupa S., Kapoor, Veena, Antzis, Michael, Cotner, Cody E., Johnson, Laura A., Durham, Amy C., Solomides, Charalambos C., June, Carl H., Puré, Ellen, Albelda, Steven M.·2014·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-13-0027PMC PMC4007316

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Abstract

The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8+ T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted. Cancer Immunol Res; 2(2); 154–66. ©2013 AACR.

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Metadata

Authors
Wang, L.-C. S., Lo, A., Scholler, J., Sun, J., Majumdar, R. S., Kapoor, V., Antzis, M., Cotner, C. E., Johnson, L. A., Durham, A. C., Solomides, C. C., June, C. H., Puré, E., & Albelda, S. M.
Affiliations
  • Thomas Jefferson University (US)
  • Authors' Affiliations: 1Thoracic Oncology Research Laboratory; 2Abramson Family Cancer Research Institute; 3Department of Pathology and Laboratory Medicine, Perelman School of Medicine; Departments of 4Animal Biology and 5Pathobiology, School of Veterinary Medicine, University of Pennsylvania; and 6Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania
Corresponding author
Puré, Ellen
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-02-01
Volume
2
Issue
2
Pages
154-166
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-13-0027
PMC
PMC4007316
OpenAlex
W2139325323
Cited by
653
References
8
Citations by year
2026: 50 · 2025: 76 · 2024: 71 · 2023: 91 · 2022: 71 · 2021: 76 · 2020: 63 · 2019: 51 · 2018: 35 · 2017: 28 · 2016: 21 · 2015: 14 · 2014: 5
FWCI
7.14
Type
journal article
Language
en
Open access
Locations
  • Cancer Immunology Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Medicine Forum (submittedVersion)
Funders
National Cancer Institute (P01 CA 66726-07, R01CA141144, P01CA066726, R01CA172921, P30CA010815, P30CA016520)
Topics
  • Health Sciences › Medicine › Oncology › CAR-T cell therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
Keywords
fibroblast activation protein, chimeric antigen receptor T cells, tumor stroma, adoptive T cell therapy, single-chain Fv antibody, 4-1BB costimulatory domain, tumor growth inhibition, on-target off-tumor toxicity
MeSH terms
Fibroblast Activation Protein Alpha, Animals, Cytotoxicity, Immunologic, Immunity, Cellular, Membrane Proteins, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Transplantation, Neoplasms, Experimental, Endopeptidases, Receptors, Antigen, T-Cell, Serine Endopeptidases, T-Lymphocytes, Transduction, Genetic, Stromal Cells, Gelatinases, CD8-Positive T-Lymphocytes, Adoptive Transfer, Cancer Vaccines, Protein Transport, Cell Line, Tumor

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