A biophysical approach to improve CAR T cell efficacy against diffuse midline gliomas
Diffuse midline glioma (DMG) is an uncurable pediatric brain tumor with extremely limited treatment options. The Krenciute Lab at St. Jude is working to develop new types of treatments known as immunotherapy for children with DMGs, in which the patient’s own immune system is harnessed to fight the cancer. Specifically, we are interested in developing chimeric antigen receptor (CAR) T cells, a form of immunotherapy where a patient’s T cells are re-engineered to better target and attack the cancer cell. Recently, CAR T cell therapies have provided encouraging clinical results against DMGs – motivating us to continue improving CAR T cell strategies. This project will take a unique approach towards achieving this goal. In a DMG tumor, CAR T cells are tasked with a physically taxing job. CAR T cells must get to the tumor site, infiltrate through the tumor environment, and engage with the DMG cells. In each step of this process, CAR T cells experience significant physical resistance. In response, CAR T cells must attempt to overcome these physical obstacles and attack the DMG cell; however, they ultimately fail to survive long enough to clear the tumor. Within the field, it remains unknown how these physical obstacles within the tumor cause CAR T cells to fail. This project will seek to address this question and develop new approaches that can help CAR T cells better function within the physically demanding tumor environment.
Project Goals
The overarching goal of this project is to improve CAR T cell efficacy against diffuse midline gliomas (DMGs) by understanding how CAR T cells are negatively impacted by the physical obstacles they face in the tumor. The first goal is to study how DMG cells physically avoid CAR T cells at the cellular level. CAR T cells need to strongly bind to the target cancer cell to effectively kill it. However, in the presence of CAR T cells, my preliminary data suggest that DMGs form bubble like bulges along the cell surface called blebs to physically prevent CAR T cells from binding, thereby, avoiding CAR T cell killing. By disrupting DMG cells from blebbing, I hypothesize that CAR T cells will be able to better engage and kill the DMG cells. The second goal is to study how CAR T cells respond when challenged by a mechanical property presented by the entirety of the DMG tumor (the bulk tissue level). This property is known as viscoelasticity, and given my preliminary data, I hypothesize that DMG viscoelasticity is a source of mechanical resistance that impairs CAR T cell function. Completion of both goals will inform the development of new strategies capable of overcoming the physical obstacles CAR T cells face in the DMG tumor at two different levels - the cellular and bulk tumor level. Broadly, findings from this proposal would highlight the importance of considering how to overcome physical obstacles for the design of next-generation immunotherapies.
