CAR-T cell therapy — a cancer treatment pioneered at Penn — has recently shown promising results in shrinking and preventing growth in glioblastomas.
According to The Philadelphia Inquirer, an early stage Penn clinical trial found that CAR-T therapy reduced the size of tumors of glioblastoma — a rapidly growing and aggressive form of brain cancer. Currently, there is no cure for glioblastoma, but patients are often treated with surgery, chemotherapy, and radiation.
Chimeric antigen receptor T cell therapy involves the removal of T cells — a type of white blood cell — from a cancer patient. The T cells are then genetically modified to attack cancerous cells and reinserted into the patient’s bloodstream. This treatment was first developed by Penn researcher Carl June, the director of the Center for Cellular Immunotherapies at the Perelman School of Medicine.
CAR-T cell therapies have been approved by the United States Food and Drug Administration for treating blood cancers such as lymphoma, leukemia, and multiple myeloma.
Stephen Bagley, the principal investigator for the clinical trial and an assistant professor of hematology-oncology and neurosurgery, told The Daily Pennsylvanian that the new treatment is personalized with each patient receiving "an autologous product manufactured only from them.”
While blood cancers are uniform and produce one specific protein target, solid tumors like glioblastoma produce multiple protein targets, according to the Inquirer. Because glioblastomas are such a diverse species of tumors, they are especially difficult to treat.
In a Penn Medicine news release, Bagley said that glioblastomas “can evade a patient’s immune system and block immune cells — both engineered CAR-T cells and a patient's own immune cells — that might otherwise fight the tumor.”
"Our challenge is getting our treatment around the tumor’s defenses so we can kill it,” he added.
Six patients were involved in this trial, their treatment beginning in June 2023. The patients underwent MRI scanning one to two days after receiving the treatment, and all of the enrolled patients experienced reduction in the size of their tumors.
It is unclear if these methods will lead to long-lasting results. One of the patients treated went seven months without tumor growth after the administering of the treatment. Two others, however, saw their tumors begin growing again after a few months.
For this study, the treatment was injected into the patient’s spinal cords through a port installed in the skull. The CAR-T cells targeted two proteins commonly found in brain tumors in what is known as a dual-target approach.
According to Bagley, this is the first time CAR-T cell therapy with two targets, rather than just one, has been administered to patients with glioblastoma. He said that, prior to this study, two clinical trials using CAR-T cells on glioblastomas were conducted at Penn — but, in both, only one antigen was targeted.
“The efficacy of that approach was limited by two key factors: not getting enough of the cells into the tumor and not addressing tumor heterogeneity,” he said.
Injecting cells into the spinal fluid allows this modified fluid to wash over the patient’s whole brain and reach tumors more directly, according to Bagley. He said that this new approach helps overcome the “heterogeneity” of these tumors and could be the key to developing therapies that outsmart the complicated defense systems of glioblastomas.
All patients treated for this study have experienced neurotoxicity, meaning their brain cells and nervous system have had a negative reaction due to exposure to a toxic substance — resulting in additional symptoms such as confusion, achiness, and fatigue. While patients have remained in the hospital for seven days afterwards, symptoms typically subside within three days.
The Penn Med news release said that neurotoxicity was recorded for all of the patients to be “substantial but manageable.”
The treatment was intended to reduce the size of these tumors rather than completely eliminate them, according to the Inquirer. In order to establish statistical significance, researchers would have to prove six months of delay of tumor growth.
In the ongoing Phase I clinical trial, Bagley said that Penn plans to enroll 18 patients. If treatment continues to show sustained efficacy, Phase II will likely begin, in which researchers “are considering moving the treatment up earlier in the course of the disease … rather than waiting until there is a tumor recurrence,” he said.
Bagley said that himself and and other researchers involved — including Donald O’Rourke, director of Glioblastoma Translational Center of Excellence at the Abramson Cancer Center, and Zev Binder, research assistant professor in the Department of Neurosurgery — are optimistic that improved outcomes for glioblastoma may emerge from this study and other immunotherapies.
Bagley said that hopes that these early results will provide clues for other doctors using versions of CAR-T therapy for solid tumors as well.
“This project is the definition of team science, and we wouldn't be successful without the hard work of our entire team,” Bagley said.
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