CAR T cells targeting Nectin-4 safely overcome resistance to anti-Nectin-4 antibody-drug conjugate in solid tumors

Faivre, A.; Laban, L.; Ferreira, L.; Josselin, E.; Gorvel, L.; Agavnian-Couquiaud, E.; Farina, A.; Chretien, A.-S.; Verhoeyen, E.; Castellano, R.; Nunes, J.; Guittard, G.; Lopez, M.; Olive, D.

doi:10.1101/2025.09.30.679440

bioRxiv · 10.1101/2025.09.30.679440

CAR T cells targeting Nectin-4 safely overcome resistance to anti-Nectin-4 antibody-drug conjugate in solid tumors

Faivre, A.·Laban, L.·Ferreira, L.·Josselin, E.·Gorvel, L.·Agavnian-Couquiaud, E.·Farina, A.·Chretien, A.-S.·Verhoeyen, E.·Castellano, R.·Nunes, J.·Guittard, G.·Lopez, M.·Olive, D.

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Abstract

Chimeric antigen receptor T (CAR T) cells represent a promising therapeutic option for a variety of cancers, including solid tumors. Nectin-4 is a cell adhesion molecule expressed at different levels in many solid tumors, including breast and urothelial carcinoma (UC). Enfortumab vedotin (EV), an antibody-drug conjugate (ADC) against Nectin-4, has significantly improved survival in patients with metastatic UC. Skin adverse reactions are frequently observed due to Nectin-4 expression in the epidermis. Here, we developed second-generation CAR T cells against Nectin-4 (N4CART) with a scFv that does not recognize human Nectin-4 expressed in skin keratinocytes. To study the effects of N4CART cell therapy, we used preclinical models of cell-derived xenografts (CDX) and patient-derived xenograft (PDX) of breast cancer expressing moderate to high levels of Nectin-4. We showed a marked efficacy with induction of remissions. Interestingly, N4CART cells kill Nectin-4-positive breast, urothelial and colon tumor cells, which are resistant to EV. Thus, N4CART cells represent a valuable and safe therapy for the treatment of patients with Nectin-4 expressing tumors, including those that are resistant to EV. Finally, baboon-envelope pseudotyped lentiviral vectors (LV) outperformed VSVG-LVs for Nectin-4 CAR expressing in {beta} T cells resulting in an efficient anti-tumoral response in PDX mice.

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Faivre, A., Laban, L., Ferreira, L., Josselin, E., Gorvel, L., Agavnian-Couquiaud, E., Farina, A., Chretien, A.-S., Verhoeyen, E., Castellano, R., Nunes, J., Guittard, G., Lopez, M., Olive, D.. 2025-10-01. CAR T cells targeting Nectin-4 safely overcome resistance to anti-Nectin-4 antibody-drug conjugate in solid tumors. https://doi.org/10.1101/2025.09.30.679440

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