Our Research
Cancer is the leading cause of death by disease in children in the United States, with 1 in 285 children being diagnosed with cancer before their 20th birthday. Underinvestment in pediatric cancer research has limited the treatments available to patients in the clinic, particularly those with refractory or resistant disease.
Chimeric antigen receptor T cells (CAR-T) have demonstrated striking efficacy in both pediatric and adult hematologic malignancies; however, their efficacy in solid tumors is limited. This is in part due to the lack of CAR-T trafficking, survival and persistence in the hostile tumor microenvironment. To this end, our lab is dedicated to improving the safety and efficacy of CAR-T for patients with solid tumors through a strategic fusion of basic immunology and synthetic biology. Specifically, we will primarily focus on three target areas: optimal cell selection, tackling the tumor microenvironment and strategic combination therapies.
Optimal cell selection
Despite significant advancements in gene editing and engineering, generating CAR-T capable of surviving and functioning in the tumor microenvironment has been difficult. Our prior work has highlighted the potential to improve CAR-T persistence and efficacy in solid tumor models through the identification and selection of inherently superior T cell subsets. With this in mind, we are focused on better understanding the basic biology of various classic and invariant T cell subsets, in addition to their crosstalk within the tumor microenvironment, to inform and improve future cell therapies for patients in the clinic.
Tackling the tumor microenvironment
The lack of CAR-T efficacy in patients with solid tumors is due, in part, to the inability to access, survive and function in an immunosuppressive tumor microenvironment (TME). Our previous work demonstrated that strategic manipulation of signaling pathways can improve CAR-T survival with an added potential for possibly skewing the TME to a more antitumorigenic microenvironment. Moving forward, our lab will continue to identify extrinsic and intrinsic regulators of CAR-T resistance within the TME and leverage gene editing and engineering to overcome these hurdles. This will include CAR-T trafficking, infiltration, survival and metabolism.
Combination therapies
Despite the success of CAR-T as a monotherapy in patients with B-cell malignancies, it has become increasingly evident that combination therapies are needed for patients with solid tumors. Our lab is focused on bolstering CAR-T through combination with alternative therapies, such as metabolic regulators, immune checkpoint blockades and focused ultrasound. We strive to identify the mechanisms by which these approaches will best synergize with CAR-T therapy in an effort to design rational combination therapies that will improve clinical outcomes without increasing toxic side effects.