Julia Carnevale, MD

Our goal is to learn how to rewire immune cells to effectively treat aggressive malignancies. In prior work, we developed novel CRISPR-based technologies that we can leverage to decode the key genes and gene circuits we can target to engineer superior immune cells (Shifrut and Carnevale et al., Cell 2018; Roth et. al, Nature 2018). We developed a new method, sgRNA lentiviral infection with CAS9 electroporation (SLICE) that enabled genome-wide CRISPR screens in primary human T cells. Using this unbiased screening approach, we identified multiple genes that regulate T cell proliferation, activation, and cancer killing capacity. We enhanced the discovery power of this SLICE screening approach to model various suppressive factors that T cells encounter in the tumor microenvironment, and these screens converged on a number of genes that can be edited to confer resistance to suppression. One of the top genes we identified, RASA2, is a RasGAP that had not previously been studied in the immune cell context. We found that knocking out RASA2 in TCR and CAR-T cells endowed these cells with advantages along multiple parameters (antigen sensitivity, potency and persistence in cancer cell killing, metabolic setpoint) and improved tumor control and survival in preclinical models of liquid and solid tumors (Carnevale et al., Nature 2022). We have additionally adapted the SLICE platform to enable pooled CRISPR screens in T cells in vivo, which demonstrated an advantage to targeting the SWI/SNF complex (Belk et al., Cancer Cell 2022). By harnessing new CRISPR-engineering approaches we aim to discover ways we can manipulate the genetic code in different immune cells to drive towards maximally therapeutic biology for cancer treatment. We have built a translationally-relevant research pipeline that begins with these unbiased screens, moves into target validation and mechanistic studies, and then moves into preclinical models of aggressive malignancies. Lastly, top cell therapy strategies are rigorously tested for efficacy and safety to ultimately move to early-phase clinical trials. While much of this pipeline has been built on performing these investigations in T cells, we are also interested in harnessing the therapeutic potential in other cell types, such as by gene engineering in myeloid lineages. In summary, our lab is focused on using the immense potential of genome engineering in immune cells to transform the landscape of available therapies for cancer patients.