Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity.
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 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.
Authors' Affiliations: Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Liang-Chuan S
LC
Wang
Albert
A
Lo
John
J
Scholler
Jing
J
Sun
Rajrupa S
RS
Majumdar
Veena
V
Kapoor
Michael
M
Antzis
Cody E
CE
Cotner
Laura A
LA
Johnson
Amy C
AC
Durham
Charalambos C
CC
Solomides
Carl H
CH
June
Ellen
E
Puré
Steven M
SM
Albelda
D019264:Adoptive Transfer / Q000009:adverse effects / Q000379:methods*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D010450:Endopeptidases; D018093:Gelatinases / Q000276:immunology*; D007111:Immunity, Cellular; D008565:Membrane Proteins / Q000276:immunology*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D012697:Serine Endopeptidases / Q000276:immunology*; D017154:Stromal Cells / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014161:Transduction, Genetic; D000099167:Fibroblast Activation Protein Alpha
D019496:Cancer Vaccines; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha