Efficacy of CAR-T immunotherapy in MET overexpressing tumors not eligible for anti-MET targeted therapy

• DOI: 10.1186/s13046-022-02479-y
• Publication Date: 2022-10-21T06:05:45Z
• Authors: Cristina Chiriaco; Chiara Donini; Marco Cortese; Stefano Ughetto; Chiara Modica; Ilaria Martinelli; Alessia Proment; Letizia Vitali; Lara Fontani; Monica Casucci; Paolo Maria Comoglio; Silvia Giordano; Dario Sangiolo; Valeria Leuci; Elisa Vigna
• Keywords: Receptors, Chimeric Antigen; Research; T-Lymphocytes; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Xenograft Model Antitumor Assays; CAR; 3. Good health; Targeted therapy; Mice; 03 medical and health sciences; 0302 clinical medicine; CAR; Gastric cancer; Immunotherapy; MET oncogene; Targeted therapy.; MET oncogene; Cell Line, Tumor; Humans; Animals; Heterografts; Immunotherapy; CAR; Gastric cancer; Immunotherapy; MET oncogene; Targeted therapy; Humans; Mice; Animals; Immunotherapy; T-Lymphocytes; Cell Line, Tumor; Heterografts; Xenograft Model Antitumor Assays; Receptors, Chimeric Antigen; Gastric cancer; RC254-282

Aberrant activation of the MET receptor in cancer is sustained by genetic alterations or, more frequently, transcriptional upregulations. A fraction MET-amplified or mutated tumors are sensible to targeting agents, but their responsiveness typically short-lasting, as secondary resistance eventually occurs. Since absence usually not a tumor driver, overexpressing not/poorly responsive targeted therapies. Consequently, vast majority exhibiting still represent an unmet medical need.Here we propose immunotherapy strategy based on T lymphocytes expressing Chimeric Antigen Receptor (CAR) different histotypes. We engineered two MET-CAR constructs and tested MET-CAR-T cell cytotoxic activity against models, including lines, primary cells, organoids, xenografts immune-deficient mice.We proved that exerted specific cells. Cell killing was proportional level expressed surface. While CAR-T cytotoxicity minimal versus cells carrying at physiological levels, essentially sparing normal robust, significantly controlling growth vitro vivo. Notably, were also able brake acquired agents amplified mutations downstream signal transducers.We set validated pre-clinical potentially beneficial for cancers eligible therapy with inhibitory molecules, those resistance.