Modifying CAR T cell epigenetic programs to improve therapy against aggressive pediatric brain tumors
Safe and effective treatment options are desperately needed for pediatric brain tumor patients. Specifically, I am focused on group 3 medulloblastoma, a lethal brain tumor that often affects infants and has very poor prognosis. The Krenciute lab at St. Jude, in which I do my research, is dedicated to developing immunotherapy treatment options for pediatric brain tumor patients in which a patient’s own immune system is re-engineered to fight their cancer in a way that is effective and safe for all ages. Specifically, we develop T-cell based therapies where the natural ability of a T cell to kill cancer cells is directed and amplified by the addition of a receptor molecule that recognizes only tumor cells. This is known as CAR T cell therapy. CAR T cell therapies have been very successful at curing blood cancers but have struggled against brain tumors. One reason for this is the inability of the CAR T cells to persist and function long enough to completely clear the tumor or prevent relapse. The immunotherapy field at large is interested in finding biological drivers of failed persistence to block or remove negative signals and improve CAR T cell therapy. Many groups have identified single negative regulators and have removed them via gene editing technology and saw improvement of CAR T cell therapies. However, it is not yet understood which targets have the most profound impact on CAR T cell therapy because they have not been directly compared.
Project Goal:
The overarching goal of this project is to improve the persistence of CAR T cells against group 3 medulloblastoma tumor models for improved cancer therapy. This is accomplished via genetic elimination of single proteins that hinder CAR T cell persistence. I will prepare a panel of 6 genetically modified CAR T cell products that we hypothesize will improve persistence and anti-tumor function. I will compare them directly in tests where they are asked to kill group 3 medulloblastoma tumor cells. This project has been designed in such a way that I will stratify the genetic modifications based on how significantly they improve anti-tumor functionality of CAR T cells across a range of tests. Of specific note, a main goal is to test the modifications against group 3 medulloblastoma tumor models in mice that have fully intact natural immune systems. It is standard practice to perform tests in mice that do not have immune systems but can support the growth of patient-derived tumors and can be treated with human CAR T cells. However, this does not fully mimic what would be seen in a patient with an immune system. It is critical to understand the influence of the natural immune system on CAR T cell function, but these tests are not yet well established for pediatric brain tumors. As such, a secondary goal of this proposal is to establish these types of tests for the benefit of the field at large so that more researchers have better tools for the optimization of CAR T cell therapies.
