Fibroblast Activation Protein (FAP)-Targeted CAR-T Cells: Launching an Attack on Tumor Stroma

Abstract

Fibroblast activation protein (FAP) is a membrane protease that is highly expressed by cancer-associated fibroblasts (CAFs). FAP can modulate the tumor microenvironment (TME) by remodeling the extracellular matrix (ECM), and its overexpression on CAFs is associated with poor prognosis in various cancers. The TME is in part accountable for the limited efficacy of chimeric antigen receptor (CAR)-T cell therapy in treatment of solid tumors. Targeting FAP with CAR-T cells is one of the strategies being researched to overcome the challenges in the TME. This review describes the role of FAP in the TME and its potential as a target in CAR-T cell immunotherapy, summarizes the preclinical studies and clinical trials of anti-FAP-CAR-T cells to date, and reviews possible optimizations to augment their cytotoxic efficiency in solid tumors.

Keywords:

• CAR T-cells
• immunotherapy
• tumor microenvironment
• fibroblasts
• fibroblast-activating-protein
• solid tumors
• stroma

Acknowledgments

We thank Prof Steven M Albelda (University of Pennsylvania) for supplying the microscopy figure included in the manuscript.

Author Contributions

RB and AK conceptualized, wrote and edited the manuscript. PD and RRD wrote and edited the manuscript. RB and AK designed and edited the figures. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

AK is funded by the Cris Cancer Foundation.