I obtained my PhD degree in Natural Sciences from the University of Heidelberg in 2013. My research at the German Cancer Research Center/National Center for Tumor Diseases in the laboratory of Prof. von Kalle and Dr. Schmidt focused on utilizing sequencing technologies to characterize the T cell receptor (TCR) repertoire. I investigated the distortions in the TCR repertoire occurring upon infections and tumor development, and explored the molecular mechanisms involved in TCR generation. In 2015, I joined the Experimental Hematology Unit at Ospedale San Raffaele (OSR, Milan) as a postdoctoral researcher in Chiara Bonini’s lab. My objective was to identify new tumor-specific TCRs for T cell engineering. This project led to the identification of over 61 anti-tumor specific TCRs and resulted in six patents. My research has been supported by national and international funding sources, including DKMS, the Italian Ministry of Health, Marie Sklodowska-Curie, iCARE-AIRC and the Helmholtz Alliance Immunotherapy of Cancer, as well as through industrial collaboration with Intellia Therapeutics. I have also received several awards such as the ESGCT Young Investigator Award and the ASGCT Excellence in Research Award. Additionally, I actively evaluate Marie Sklodowska-Curie Individual Fellowship (MSCA-IF) applications and serve as a reviewer for several peer-reviewed journals, including Nature, Nature Medicine, Blood, Frontiers in Immunology, Science Translational Medicine, PLOS ONE, Journal for ImmunoTherapy of Cancer and Cancer Research. Currently, I am a Project Leader in the Experimental hematology unit at OSR, leading my own independent research program.

BRIEF INTRODUCTION

My scientific interests are centered on developing next generation T cell receptor (TCR) cell products for treating cancer. While TCR therapies have been overshadowed by CARs, they possess unique features (recognition of surface and intracellular antigens with remarkable sensitivity; long-term persistence; reduced toxicity) that could address key challenges in T cell therapy, particularly for highly heterogenous and poorly mutated cancers.

RESEARCH ACTIVITY

1) Hunting novel anti-tumor TCRs for the treatment of solid and hematological cancers.  We have recently established robust pipelines for isolating anti-tumor TCRs specific for tumor antigens expressed by solid and hematological tumors. This extensive search has led to the identification of highly effective receptors, demonstrating remarkable functional efficiency in eliminating leukemic blasts and primary cells from colorectal, pancreatic and ovarian cancers both in vitro and in vivo (Ruggiero E. et al. STM 2022; Manfredi F. et al. Science Advances 2023; Potenza A., Balestrieri C. et al. Gut 2023). Moving forward, we are expanding our TCR library and rigorously validating the efficacy and safety of these newly identified receptors for clinical applications.

2) Harnessing of the resistance mechanisms elicited in tumor cells upon treatment with TCR T-cells to generate more tailored and effective therapies. Our aim is to expedite the development of novel engineered T lymphocytes capable of counteracting the immune evasion mechanisms that arise in tumors following TCR-T cell therapy, either as single agents or in combinatorial approaches. To this aim, we are integrating single-cell omics, state-of-the-art T cell engineering, and functional validation techniques.

3) Boosting anti-tumor activity of TCR-redirected T cells. In this project, we aim to enhance the efficacy of TCR-based immunotherapies through 3 complementary strategies: 1) we will test the effectiveness of combinatorial therapies by using TCR-engineered T cell products that target different tumor antigens, thereby overcoming the immune escape mechanism associated with antigen loss; 2) we will improve the trafficking and accumulation of TCR T cells to tumor sites; 3)  we will address and overcome the immunosuppressive tumor microenvironment that hampers T cell functionality.

4) Molecular tracking of the TCR repertoire in patients treated with different immunotherapeutic approaches. In this project, we aim to delineate the fate and transcriptional profile of infused therapeutic T cells using bulk TCR sequencing and multiomics single-cell RNA sequencing technologies. By tracking the TCR repertoire in patients undergoing CAR-T cell therapy or hematopoietic stem cell transplantation, we will gain insights into the dynamics and behavior of these therapeutic cells, enabling us to better understand their role and effectiveness in treatment.

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