Immunotherapy with T cells engineered to express chimeric antigen receptors (CAR-T cells) is an emerging treatment modality that has demonstrated unprecedented results against B-cell tumors refractory to standard treatments. CARs are synthetic-biology constructs generated by fusing the scFv of a tumour- reactive monoclonal antibody (mAb) with the TCR CD3 zeta chain from the TCR complex combined with costimulatory endodomains, e.g. CD28, 4-1BB or OX40. Genetic modification with CAR constructs converts T cells into potent serial killers of tumour cells expressing the target antigen. Deeping the knowledge on the biological determinants of CAR-T cells activity will be crucial for improving their efficacy and safety profile and to widen their application to other diseases indications including solid malignancies.
Our group developed a novel CAR specific for the CD44v6 antigen from its first conception to imminent clinical testing in patients with acute myeloid leukaemia and multiple myeloma.
Moreover, we recently developed the first humanized animal model that allows the in-depth analysis of efficacy determinants and, for the first time, CAR-related toxicities, like the cytokine release syndrome and neurotoxicity. The group is now using this innovative model to answer to biological questions related to CAR-T cell performances.
We are currently investigating strategies to improve CAR-T cell activity against solid tumors, which represent a great challenge in the field nowadays. We are also developing new CAR specificities to tackle multiple tumor types and trying to increase CAR-T cell fitness by optimizing ex vivo manufacturing, CAR constructs and gene transfer technologies.
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Consonni M, Garavaglia C, Grilli A, de Lalla C, Mancino A, Mori L, De Libero G, Montagna D, Casucci M, Serafini M, Bonini C, Häussinger D, Ciceri F, Bernardi M, Mastaglio S, Bicciato S, Dellabona P, Casorati G. Human T cells engineered with a leukemia lipid-specific TCR enables donor-unrestricted recognition of CD1c-expressing leukemia. Nat Commun. 2021 Aug 11;12(1):4844
Arcangeli S, Mestermann K, Weber J, Bonini C, Casucci M, Hudecek M. Overcoming key challenges in cancer immunotherapy with engineered T cells. Curr Opin Oncol. 2020
Arcangeli S, Falcone L, Camisa B, De Girardi F, Biondi M, Giglio F, Ciceri F, Bonini C, Bondanza A, Casucci M. Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients. Front Immunol. 2020
Casucci M, Falcone L, Camisa B, Norelli M, Porcellini S, Stornaiuolo A, Ciceri F, Traversari C, Bordignon C, Bonini C, Bondanza A. Extracellular NGFR spacers allow efficient tracking and enrichment of fully functional CAR-T cells coexpressing a suicide gene. Front Immunol, 9:507, 2018.
Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, Sanvito F, Ponzoni M, Doglioni C, Cristofori P, Traversari C, Bordignon C, Ciceri F, Ostuni R, Bonini C, Casucci M, Bondanza A. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine release syndrome and neurotoxicity by CAR-T cells. Nat Med, 2018
Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, Gentner B, Gullotta F, Ponzoni M, Bernardi M, Marcatti M, Saudemont A, Bordignon C, Savoldo B, Ciceri F, Naldini L, Dotti G, Bonini C, Bondanza A. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood, 122:3461-72, 2013.
Casucci M, Perna S, Falcone L, Camisa B, Magnani Z, Bernardi M, Crotta A, Tresoldi C, Fleischhauer K, Ponzoni M, Gregori S, Caligaris Cappio F, Ciceri F, Bordignon C, Cignetti A, Bondanza A, Bonini C. Graftversus- leukemia effect of HLA-haploidentical central-memory T-cells expanded with leukemic APCs and modified with a suicide gene. Mol Ther, 21:466-75, 2013.