Journal
CANCER IMMUNOLOGY RESEARCH
Volume 2, Issue 2, Pages 154-166Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-13-0027
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Funding
- National Cancer Institute (NCI) [P01 CA 66726-07, R01 CA 141144, R01 CA 172921]
- Cancer Research Institute
- Mesothelioma Applied Research Foundation (MARF) award
- START fellowship from the Cancer Research Institute
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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 CD8 alpha hinge and transmembrane regions, and the human CD3 zeta and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-gamma and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAP(hi) 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. (C) 2013 AACR.
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