Author: Cui, Yuanbin ; Tang, Zhaoyang ; Wong, Nathalie ; Zheng, Yongfang ; Li, Peng ; Zheng, Diwei ; Li, Yao ; Zhou, Linfu ; Peng, Dongdong ; Long, Youguo ; Lau, James ; Wu, Qiting ; Qin, Le ; Yao, Yao

Chimeric antigen receptor (CAR) T cell therapy has demonstrated robust efficacy against hematological malignancies, but there are still some challenges regarding treating solid tumors, including tumor heterogeneity, antigen escape, and an immunosuppressive microenvironment. Here, we found that SNU398, a hepatocellular carcinoma (HCC) cell line, exhibited high expression levels of fibroblast activation protein (FAP) and Glypican 3 (GPC3), which were negatively correlated with patient prognosis. The HepG2 HCC cell line highly expressed GPC3, while the SNU387 cell line exhibited high expression of FAP. Thus, we developed bispecific CAR-T cells to simultaneously target FAP and GPC3 to address tumor heterogeneity in HCC. The anti-FAP-GPC3 bispecific CAR-T cells could recognize and be activated by FAP or GPC3 expressed by tumor cells. Compared with anti-FAP CAR-T cells or anti-GPC3 CAR-T cells, bispecific CAR-T cells achieved more robust activity against tumor cells expressing FAP and GPC3 in vitro. The anti-FAP-GPC3 bispecific CAR-T cells also exhibited superior antitumor efficacy and significantly prolonged the survival of mice compared with single-target CAR-T cells in vivo. Overall, the use of anti-FAP-GPC3 bispecific CAR-T cells is a promising treatment approach to reduce tumor recurrence caused by tumor antigen heterogeneity.

15 Dec 2022·Clinical Cancer Research

Monitoring Therapeutic Response to Anti-FAP CAR T Cells Using [18F]AlF-FAPI-74

Article

Author: Song, Decheng ; Noguera-Ortega, Estela ; Edwards, Kimberly J. ; Liousia, Maria ; Xiao, Zebin ; Xu, Kexiang ; Puré, Ellen ; Scholler, John ; Lee, Iris K. ; Lohith, Katheryn ; Todd, Leslie ; Albelda, Steven M. ; Farwell, Michael D. ; Sellmyer, Mark A. ; June, Carl H.

AbstractPurpose:Despite the success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies, successful targeting of solid tumors with CAR T cells has been limited by a lack of durable responses and reports of toxicities. Our understanding of the limited therapeutic efficacy in solid tumors could be improved with quantitative tools that allow characterization of CAR T–targeted antigens in tumors and accurate monitoring of response.Experimental Design:We used a radiolabeled FAP inhibitor (FAPI) [18F]AlF-FAPI-74 probe to complement ongoing efforts to develop and optimize FAP CAR T cells. The selectivity of the radiotracer for FAP was characterized in vitro, and its ability to monitor changes in FAP expression was evaluated using rodent models of lung cancer.Results:[18F]AlF-FAPI-74 showed selective retention in FAP+ cells in vitro, with effective blocking of the uptake in presence of unlabeled FAPI. In vivo, [18F]AlF-FAPI-74 was able to detect FAP expression on tumor cells as well as FAP+ stromal cells in the tumor microenvironment with a high target-to-background ratio. We further demonstrated the utility of the tracer to monitor changes in FAP expression following FAP CAR T-cell therapy, and the PET imaging findings showed a robust correlation with ex vivo analyses.Conclusions:This noninvasive imaging approach to interrogate the tumor microenvironment represents an innovative pairing of a diagnostic PET probe with solid tumor CAR T-cell therapy and has the potential to serve as a predictive and pharmacodynamic response biomarker for FAP as well as other stroma-targeted therapies. A PET imaging approach targeting FAP expressed on activated fibroblasts of the tumor stroma has the potential to predict and monitor therapeutic response to FAP-targeted CAR T-cell therapy.See related commentary by Weber et al., p. 5241

01 Nov 2019·Nature ImmunologyQ1 · MEDICINE

CAR T cells for heart disease

Q1 · MEDICINE

Article

Author: Visan, Ioana

A review discussing about chimeric antigen receptor (CAR) T cells for heart disease.The endogenous glycoprotein FAP was not expressed in healthy hearts or other tissues in mice and humans but is expressed in cardiac fibroblasts in patients with cardiomyopathy.FAP CAR T cell therapy shows no evidence of systemic or cardiac toxicity and does not delay wound healing in a model of skin injury.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	US	Tmunity Therapeutics, Inc.Startup	-
Solid tumor	Preclinical	US	University of Pennsylvania	-

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