A clinical trial led by Stanford Cancer Institute members Michelle Monje, MD, PhD, the Milan Gambhir Professor in Pediatric Neuro-Oncology and Crystal Mackall, MD, director for the Parker Institute for Cancer Immunotherapy at Stanford and founding director of the Stanford Center for Cancer Cellular Therapy, has demonstrated promising results for chimeric antigen receptor (CAR)-T cell therapy in treating a group of deadly pediatric brain and spinal tumors called diffuse midline gliomas, including a highly lethal type diffuse intrinsic pontine glioma (DIPG), which has a median survival of only 11 months.
“These are the leading cause of brain tumor-related death in children. They are nearly universally fatal, typically within a year,” Monje explained.
DIPG is a brain tumor that originates in the pons, a crucial part of the brainstem that controls vital functions like breathing, heart rate, and swallowing. It is considered highly aggressive due to its location and rapid progression, and it typically affects children, although it can occur at any age.
Monje’s laboratory has been investigating immunotherapeutic approaches for nearly a decade.
“We discovered that these tumors express extraordinarily high and uniform levels of one particular antigen, GD2,” she said. This discovery led her to collaborate with Mackall.
“I remember knocking on her door, holding a FACS plot* in my hand, and saying, ‘Look at this! Do you want to put your GD2-targeting CAR T-cells into our models of DIPG?’ That cured the mice, and we've been working together ever since.”
*FACS plots are visual representations of data generated from Fluorescence-Activated Cell Sorting (FACS), a technique used to measure and sort characteristics of individual cells in a sample.
How does it work?
Lymphocytes are a type of white blood cell that possess a powerful ability to kill cancer cells; however, they face significant challenges in recognizing these cells as targets and overcoming the various mechanisms that cancers use to evade the adaptive immune system. CAR T-cell therapy addresses these challenges by engineering lymphocytes to specifically recognize an antigen that is predominantly found on cancer cells. In this case, Monje identified that the mutation that drives the development of diffuse midline gliomas increases the cancer cells’ expression of the GD2 antigen.
“It's a really good target because it's very lowly expressed on normal tissue and very highly expressed on the cancer,” Monje said.
The CAR T-cells are engineered to recognize GD2 by incorporating an antibody that binds to the target antigen, fused with the machinery that activates the lymphocyte. As a result, when a CAR T-cell encounters a cancer cell expressing GD2, it can quickly recognize and activate itself to kill the targeted cell.
We saw kids go literally from wheelchair-bound to walking, sometimes only within a matter of weeks."
Regenerative Medicine Advanced Therapy designation
The trial involved 11 participants, with nine showing significant benefits, such as tumor reduction, improved neurological function, and reversal of symptoms such as paralysis, neuropathic pain, and incontinence.
“We saw kids literally go from wheelchair-bound to walking, sometimes within only a matter of weeks,” Monje shared. “It was enormously exciting.”
Notably, one patient achieved a complete response, with his tumor disappearing entirely and maintaining good health now over four years since beginning the therapy.
The findings, published in Nature, have led to the therapy receiving a Regenerative Medicine Advanced Therapy designation from the Food and Drug Administration (FDA), recognizing its potential to significantly improve treatment outcomes for patients with these historically incurable brain cancers.
This designation expedites drug development and the FDA approval process by providing researchers access to regulatory experts who help them optimize their research for a faster timeline, such as designing flexible clinical trials and determining appropriate study parameters, allowing more children to benefit from the treatment sooner.
“We're very hopeful that this is going to become part of an effective strategy to treat these horrible cancers,” she said. “We're moving forward in testing iterations of this initial clinical trial protocol to try to make it even more effective and as minimally toxic as possible.”
