Immune activation may determine success of dual-target CAR T therapy in glioblastoma
New research from Penn Medicine finds that activation of natural killer cells is linked to longer survival, and suppressive immune cells is tied to poor response.
2 min. read
Dual-target CAR T cell therapy for recurrent glioblastoma (GBM), delivered directly into the cerebrospinal fluid (CSF), triggers a broad immune response, with natural killer (NK) cell activation linked to better patient outcomes and longer overall survival. CSF of individuals who did not respond to the therapy exhibited a higher proportion of activated regulatory T cells (Tregs) and high baseline levels of immunosuppressive scavenger myeloid cells, according to new research from the Perelman School of Medicine and Abramson Cancer Center, published in Cell.
Findings from a phase I clinical trial for recurrent GBM published last year in Nature found that a dual-target CAR T cell therapy could trigger tumor reduction and extend survival in some patients, but not all, and relapse remained common.
“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,” says co-senior author Dana Silverbush, an assistant professor of cancer biology.
Glioblastoma is one of the most challenging cancers to treat, in part because the tumor environment helps the cancer evade the body’s natural immune defenses. In this study, researchers took advantage of the unique way the treatment is delivered to monitor the immune response to treatment. The dual-target CAR T cells are infused via intracerebroventricular (ICV) injection, directly to the cerebrospinal fluid surrounding the patient’s brain. This not only allows the therapy to bypass the blood-brain barrier, but also gives researchers the unique opportunity to sample the patient’s CSF in real time.
“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,” says co-senior author Cécile Alanio,an adjunct professor of neurosurgery. “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.”
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