Innovative immunotherapies

Group leader

Monica Casucci

Immunotherapy with T cells engineered to express chimeric antigen receptors (CAR-T cells) is an emerging treatment modality that has demonstrated unprecedented results against hematological tumors refractory to standard treatments. Most commonly, CARs are synthetic-biology constructs generated by fusing an antigen-binding moiety with the CD3 zeta chain combined with costimulatory endo-domains. Genetic modification with CAR constructs converts T cells into potent serial killers of tumor 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.

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Research activity

Our unit is focused on the development of novel CAR-T cell products to be applied in different tumor indications, especially solid malignancies. We exploit optimized CAR design and ex vivo manufacturing to enrich early memory T-cell subsets, which have been associated with improved antitumor efficacy in patients. Different approaches are being explored, including combination with known drugs and/or logic-gating strategies, to reach an optimal balance between efficacy and safety.

Our group has recently demonstrated that aberrant tumor glycosylation hinders CAR-T cell activity by interfering with the formation of a proper immunological synapse and promoting the interaction between inhibitory ligand-receptor pairs1. We are currently investigating the impact of glycosylation on other cell populations within the tumor microenvironment that can shape CAR-T cell responses. Moreover, we are building on these results to develop a strategy, based on structural design of new agents and genetic engineering, to be translated into the clinic.

Our unit has also extensive experience on advanced animal models to evaluate the performance of CAR-T cell products. We have previously developed a mouse model reconstituted with a human immune system that allows the in-depth analysis of efficacy determinants and CAR-related toxicities. We have demonstrated the sensitivity of the model in appreciating fine differences between CAR-T cell products obtained with different manufacturing procedures2,3 and to test strategies to mitigate CRS severity and onset4. The group is now actively exploiting this model to deepen the pathophysiological understanding of additional adverse events after CAR-T cell therapy, such as ICANS and late cytopenias.

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