Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma

Sunitha Kakarla, Kevin K.H. Chow, Melinda Mata, Donald R. Shaffer, Xiao Tong Song, Meng Fen Wu, Hao Liu, Lisa L. Wang, David R. Rowley, Klaus Pfizenmaier, Stephen Gottschalk

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98 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1611-1620
Number of pages10
JournalMolecular Therapy
Volume21
Issue number8
DOIs
StatePublished - Aug 2013

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ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Kakarla, S., Chow, K. K. H., Mata, M., Shaffer, D. R., Song, X. T., Wu, M. F., Liu, H., Wang, L. L., Rowley, D. R., Pfizenmaier, K., & Gottschalk, S. (2013). Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. Molecular Therapy, 21(8), 1611-1620. https://doi.org/10.1038/mt.2013.110