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Targeting Diffuse Midline Glioma: Q&A With Cassie Kline, MD, MAS, and Jessica Foster, MD
Editor’s Note: Supporting CHOP’s vision to be the global leader in pediatric cell and gene therapy discovery and treatment is the Cell and Gene Therapy Collaborative. The CGTC aims to significantly increase the number of potential new pediatric cell and gene therapies that are the product of CHOP-led research, and to accelerate the pace of clinical development to provide new therapies to children. One way they’re doing this is through the Cell and Gene Therapy Seed Grant program, which is designed to promote early-stage development of new ideas in either the engineered cell therapy or gene therapy space — with the goal of achieving preclinical proof of concept by the end of the grant period.
In this three-part Q&A Cornerstone series, we’re highlighting the 2023 recipients of grant. Today’s post features the partnership of Cassie Kline, MD, MAS, director of clinical research in the Department of Neuro-Oncology at CHOP, and Jessica Foster, MD, assistant professor and physician scientist in the Department of Neuro-Oncology at CHOP, who are researching chimeric antigen receptor T cells (CAR T-cell therapy) for diffuse midline glioma.
How will your seed grant project drive cell and gene therapy science and/or therapeutics forward? What future clinical impact could your research have?
This seed grant project is focused on bringing cellular therapy to a deadly pediatric central nervous system tumor called diffuse midline glioma (DMG). DMGs have no known cure, and most patients only live for about a year after their diagnosis.
Our proposal is to develop a strategy using CAR T cells directed against GD2, a molecule on the surface of DMGs, to attack these tumors using the body’s own immune system primed against the tumor, combined with a new modality of radiation called FLASH radiotherapy that provides a large dose of radiation over a short period of time. We hope this combination will improve outcomes and provide additive or synergistic benefit to CAR T-cell therapy.
We also want to understand how FLASH radiotherapy affects the immune system, tumor cells, and CAR T cells in preclinical models. While radiation has long been known to affect the immune system and cause local inflammation, the effects of FLASH radiotherapy in the brain are not yet known.
We hypothesize that FLASH radiotherapy, more so than conventional radiotherapy, will prime the immune system in the brain for subsequent CAR T cells to be maximally effective. Both modalities — targeted molecular therapy and radiotherapy — can greatly advance the field of pediatric neuro-oncology. Our findings may also be applicable to other tumor types; thus, potential benefit may extend beyond DMG.
Why do you think the pairing of scientists at different levels of their career is important particularly for the cell and gene therapy space, a field that has come a long way in the last few years but is still relatively cutting-edge? How does this type of collaboration enhance your team's work?
Pairing young scientists with more veteran scientists has helped us work through several roadblocks much more quickly and efficiently than would otherwise be possible. We rely on each other to bring multidisciplinary and experiential skill sets together in ways that move us forward as quickly as possible. For this specific project, we have relied on crosstalk between basic scientists, radiation oncologists, and clinical and translational researchers to develop strategies that will ultimately be translated to patient care.
How does the culture, mission, and capabilities of CHOP Research Institute foster collaborative cell and gene therapy projects such as yours?
The Research Institute has been invested in providing services and support to move our project forward. Our work relies heavily on preclinical models and advanced flow cytometry to identify specific immune cells of interest. Through the Research Institute’s Core Facilities and collaboration with researchers across CHOP and the University of Pennsylvania, we accessed these resources and multidisciplinary expertise to fully execute the experiments.
After completion of this pilot grant, what do you see as next steps?
This work will provide the data needed to translate our research to a clinical trial for patients with DMG. In addition, we are developing new CAR T cells to target different markers on a variety of tumors. We will build on the current work to then test these CAR T products in similar combination approaches with FLASH radiotherapy.