Lentiviral-mediated panErbB CAR-T cell therapy against head and neck squamous cell carcinomas for patients with Fanconi anemia

Abstract

CAR-T cells; EGFR; ErbB receptors

Células CAR-T; EGFR; Receptores ErbB

Cèl·lules CAR-T; EGFR; Receptors ErbB

Fanconi anemia (FA) is a DNA repair syndrome characterized by bone marrow failure and cancer predisposition, including acute myeloid leukemia and solid tumors such as head and neck squamous cell carcinoma (HNSCC). Due to the exacerbated toxicity of radio-chemotherapy in FA patients with HNSCC, there is an urgent need of safer and more efficient antitumoral therapies for these patients, such as those based on chimeric antigen receptor (CAR)-T cells. Here, we show that HNSCC cell lines from both the general population and patients with FA express ErbB family members, which can be recognized by the T1E panErbB ligand. The generation of a lentiviral vector encoding for a second-generation T1E-CAR allowed us to generate panErbB CAR-T cells from healthy donors (HDs) and patients with FA. Despite the molecular and cellular defects characteristic of FA cells, a similar efficacy of CAR-T generation was observed, regardless of the donor origin. In all cases, panErbB CAR-T cells exerted potent cytotoxicity against all HNSCC cell lines tested in vitro. In addition, intratumoral administration of these CAR-T cells in HNSCC xenografts markedly reduced tumor growth. These preclinical results suggest that panErbB CAR-T cells would represent a safe, non-genotoxic therapy for HNSCC, with particular applicability for patients with FA.

This work was supported by grants from “Red Española de Terapias Avanzadas RICORS/TERAV (RD21/0017/0027)”, “RICORS/TERAVplus (RD24/0014/0023)” from Instituto de Salud Carlos III (ISCIII), and by grants from the Spanish Government co-financed by Fondo Europeo de Desarrollo Regional (FEDER) PI21/00208 and CIBERONC no. CB16/12/00228 from the Instituto de Salud Carlos III (ISCIII); and a grant from Fundación Anemia de Fanconi to R.G.-E. The work has been conducted within the framework of an Agreement between Instituto de Salud Carlos III and CIEMAT for the creation of a Mixed Unit on Advanced Therapies (Resolution 27/1/2025).