title: Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma.
abstract: Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-α (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.
authors.affiliation: Center for Cell and Gene Therapy, Texas Children's Hospital, The Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sunitha
authors.initials: S
authors.lastname: Kakarla
authors.forename: Kevin K H
authors.initials: KK
authors.lastname: Chow
authors.forename: Melinda
authors.initials: M
authors.lastname: Mata
authors.forename: Donald R
authors.initials: DR
authors.lastname: Shaffer
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Song
authors.forename: Meng-Fen
authors.initials: MF
authors.lastname: Wu
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wang
authors.forename: David R
authors.initials: DR
authors.lastname: Rowley
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfizenmaier
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D010450:Endopeptidases; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D018093:Gelatinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D016207:Cytokines; D010450:Endopeptidases; D018093:Gelatinases; D018836:Inflammation Mediators; D008565:Membrane Proteins; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha