CAR T therapy works best when it activates the tumor microenvironment in a specific way, according to a study published this week in Cell. When natural killer (NK) cells are activated, survival is extended. But if regulatory T cells and immunosuppressive myeloid cells are increased, that may blunt the therapy’s effects.
“We are now working to understand the exact mechanisms underlying response and resistance so we can continue to improve treatment,” Dana Silverbush, PhD, a co-author of the study and an assistant professor of Cancer Biology at University of Pennsylvania and Penn’s Perelman School of Medicine, told Inside Precision Medicine. Other co-authors were Perelman’s Zev Binder, MD, PhD, assistant professor of neurosurgery, and Cécile Alanio, MD, PhD, adjunct professor of neurosurgery.
About a year ago, Phase I clinical trials using this team’s dual-target CAR T-cell therapy improved survival in glioblastoma (GBM) tumor treatment. But the study found that the therapy was triggering tumor reduction and extending survival in some patients, but not all. Relapse remained common.
CAR T-cell therapy is a personalized immunotherapy that uses a patient’s own immune cells to treat their cancer. While successful against blood cancers, it has not yet made significant inroads against solid tumor cancers
In this latest study, a bivalent CAR T-cell therapy was delivered via intracerebroventricular (ICV) injection. This delivers the therapy directly to the cerebrospinal fluid (CSF) surrounding the patient’s brain. As a result, researchers can sample CSF around the infusion at different times and then analyze the levels of immune activation.
“ICV results in greater numbers of CAR T cells reaching the tumor and avoids the need to cross the blood-brain barrier. There are other potential benefits, such as reduced systemic circulation of CAR T cells, which may help reduce the risk of on-target/off-tumor toxicity, that make ICV administration attractive,” Silverbush said.
GBM is a dire diagnosis. It is the most common brain cancer in adults. There are no drugs approved for recurrent disease. Overall survival for newly diagnosed GBM is around 18 months.
These researchers found that while all patients’ immune systems were activated, there were key differences between those who responded to the treatment and those who did not. Patients who responded had strong activation of NK cells, linked to tumor shrinkage and longer survival. Specifically, those favorable outcomes correlated with expansion of CD56dimCD16pos cytotoxic NK cells.
Non‑responders showed increased regulatory T cells and immunosuppressive myeloid cells, which appear to blunt the therapy.
These findings point CAR T-cell therapy towards new approaches, for example, researchers can try priming patients’ immune systems with drugs that deplete regulatory cells, or try to armor the CAR T cells with proteins that shut down regulatory T cells.
“Now that we can see on a cellular level how CAR T-cell therapy significantly changes the composition of the patient’s immune system, we can begin to investigate ways to improve the therapy so that more patients might respond to the treatment and that response will last longer,” said Silverbush.
“A lot of what we know about CAR T-cell therapy comes from treating blood cancers, which behave very differently from solid tumors like glioblastoma,” said Alanio. “We can’t do frequent brain surgery on patients receiving CAR T-cell therapy to monitor the tumor’s immune environment, but the ICV gives a unique window into a patient’s cancer that wouldn’t be available if the treatment were delivered another way.”
“When we look ahead to making our dual-target CAR T-cell therapy even more effective, these findings point us in a few promising directions,” added Binde.
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