Chimeric Antigen Receptor (CAR) T cell therapy is a method that alters a patient's immune system to target and destroy tumor cells. While CAR T cell therapy has shown remarkable success in blood cancer treatment, relapse is frequent. Moreover, achieving success with CAR T cell treatment in solid tumors poses a significant obstacle. To address these challenges, we are utilizing high-throughput genome editing to identify new mechanisms of resistance to CAR T cell therapy in solid tumors, particularly focusing on pancreatic ductal adenocarcinoma (PDAC). Additionally, we are developing non-invasive imaging tools to track CAR T cells, aiming to improve our ability to predict patients' responses to CAR T cell therapy.

Cancer genome sequencing studies have contributed to the development of targeted therapies and laid the foundation for precision medicine paradigms. Still, intratumoral and inter-patient variability presents a roadblock to achieving durable treatment responses and preventing drug resistance. Until recently, comprehensive studies examining the impact of distinct allelic variants on cancer progression and therapy response were not feasible due to technological limitations. In collaboration with the Sánchez-Rivera Lab at MIT, we are applying high-throughput precision genome editing technology to elucidate how diverse types of genetic variants influence cancer development and progression, as well as response and resistance to cancer therapies.

Cellular Immunotherapy approaches, particularly Chimeric Antigen Receptor (CAR) T cell immunotherapy has revolutionized how we treat different forms of white blood cell cancers such as B cell leukemias. While this new therapy can be highly effective, different forms of cancers will recur in a significant percentage of patients. To understand mechanisms of treatment failure and cancer relapse, I set out to investigate the dynamic interactions between CAR-T cells and B cell malignancies. These dynamic interactions potentially underlie immune evasion mechanisms that recurring cancer cells utilize. Using different microscopy methods as well as cell, molecular and biochemical approaches I am gaining insight into how cancer cells evade CAR-T therapy. My results will be a driver of new cellular immunotherapy approaches as well as understanding cancer cell immune evasion mechanisms.

Acute Myeloid Leukemia (AML) is a difficult cancer to treat effectively. By utilizing in vitro and in vivo approaches, we plan to identify the mechanism by which hypoxia and stromal cell populations uniquely induces resistance in response to frontline therapy of AML cells. Furthermore, we are interested in understanding how treatment of AML with frontline therapy leading to MRD could lead to unique sensitivities to subsequent treatment with alternative therapies, especially to Bcl-2 inhibitors such as Venetoclax.

T cell-based immunotherapies have shown striking efficacy in treating blood cancers; however, relapse occurs in a significant number of patients. There is growing evidence that mechanics plays a key role in T cell-mediated cytotoxicity. To better understand this interaction and characterize the physical mechanisms of therapeutic resistance, we are performing high-throughput measurements of cancer cells' biophysical properties in collaboration with the Manalis Lab at MIT.

Acute Myeloid Leukemia (AML), unlike many other cancer types, is a malignancy for which the primary clinical obstacle lies not in achieving remission, but in preventing relapse. The rarity, genetic heterogeneity and poorly-defined phenotype of residual leukemia has made mere identification of minimal residual disease (MRD) challenging, and as such little is known about the specific biology of this relapse-initiating population.