Efficacy and safety evaluation of cross-reactive Fibroblast activation protein scFv-based CAR-T cells

Wenhao Niu ¹, Binchen Wang ², Yirui Zhang ¹

⁰Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Frontiers in Immunology +

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August 1, 2024

View abstract on PubMed

Summary

New CAR T cells targeting Fibroblast Activation Protein (FAP) show potent anti-tumor activity against FAP-positive cells and cancer-associated fibroblasts (CAFs). These FAP-CAR T cells demonstrate biological safety with low on-target off-tumor toxicity, warranting further clinical investigation.

Area Of Science

Immunotherapy
Oncology
Cellular Therapy

Background

Fibroblast Activation Protein (FAP) is overexpressed on cancer-associated fibroblasts (CAFs), correlating with poor prognosis.
Targeting FAP+ CAFs with chimeric antigen receptor (CAR) T cells is a potential therapeutic strategy.
Existing FAP-CAR T cells require caution due to potential toxicity and variable efficacy.

Purpose Of The Study

To design and evaluate novel second-generation FAP-CAR T cells with a 4-1BB co-stimulatory molecule.
To assess the efficacy and safety of these FAP-CAR T cells against FAP-positive cells and in preclinical cancer models.

Main Methods

Developed second-generation CAR T cells targeting FAP with a 4-1BB co-stimulatory domain.
Tested cytotoxicity against FAP-positive cell lines and primary CAFs <i>in vitro</i>.
Evaluated <i>in vivo</i> efficacy and safety in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models in mice.

Main Results

The developed FAP-CAR T cells exhibited potent cytotoxicity against human and murine FAP-positive tumor cells and CAFs.
Effective anti-tumor activity was observed across various tumor types and in both CDX and PDX models.
The FAP-CAR T cells demonstrated biological safety with low levels of on-target off-tumor toxicity (OTOT).

Conclusions

Human/murine cross-reactive FAP-CAR T cells are highly effective against FAP-positive tumor cells and CAFs.
These novel FAP-CAR T cells possess a favorable safety profile with minimal OTOT.
The demonstrated potency and safety warrant further clinical investigation for FAP-targeted cancer therapy.

Keywords:

cancer-associated fibroblasts chimeric antigen receptor fibroblast activation protein on-target off-tumor toxicity solid tumor