The recent success of chimeric antigen receptor (CAR) T cell therapy has brought new enthusiasm to this strategy. Although the majority of CAR research has focused on attacking cancer cells, targeting the tumor-promoting, non-transformed stromal cells using CAR T cells may offer several advantages. We developed a CAR construct specific for mouse fibroblast activation protein (FAP), a protein highly expressed on cancer-associated stromal cells. A single chain Fv specific for mouse FAP (mAb 73.3) was expressed in a retroviral CAR construct containing a CD8α hinge and transmembrane regions and human CD3ζ and 4-1BB activation domains. Retrovirally-transduced muFAP-CAR mouse T cells secreted IFNγ and killed FAP-expressing 3T3 target cells, but did not react with FAP-negative parental 3T3 cells. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The anti-tumor effects could be augmented by multiple injections of T cells, by using T cells with enhanced anti-tumor activity due to the loss of diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action was augmentation of endogenous CD8+ T cell anti-tumor responses. Importantly, off-tumor toxicity in our models was minimal following muFAP-CAR T cell therapy. In conclusion, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective. Further development of anti-human FAP-CAR for clinical use may thus be possible.
- Received March 24, 2013.
- Revision received November 5, 2013.
- Accepted November 5, 2013.
- Copyright © 2013, American Association for Cancer Research.