Immune signatures could explain CAR-T response in glioblastoma
Original story from University of of Pennsylvania School of Medicine (PA, USA).
Activation of natural killer cells are linked to longer survival, and suppressive immune cells are tied to poor response.
Dual-target CAR-T therapy for recurrent glioblastoma, delivered directly into the cerebrospinal fluid (CSF), triggers a broad immune response, with natural killer 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 at the University of Pennsylvania, published today in Cell.
Findings from a Phase I clinical trial for recurrent glioblastoma published last year in Nature found that a dual-target CAR-T 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 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 co-senior author Dana Silverbush, an assistant professor of Cancer Biology.
Tracking the immune response in real time
Glioblastoma is the most common brain cancer in adults, and is extremely aggressive, with a median survival time of 6-10 months after recurrence. It 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 (CSF) 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 therapy comes from treating blood cancers, which behave very differently from solid tumors like glioblastoma,” said co-senior author Cécile Alanio, an adjunct professor of Neurosurgery. “We can’t do frequent brain surgery on patients receiving CAR-T 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.”
A key difference between responders and non responders
Using single-cell RNA sequencing, researchers analyzed the CSF of patients before infusion, and then seven, and 21 days following infusion. The researchers found that CAR-T therapy reshaped the immune environment in all patients — but not in the same way.
Patients whose tumors responded to treatment showed activation of natural killer cells, a type of immune cell that can rapidly identify and destroy diseased cells. In contrast, patients whose tumors did not respond showed increased activity of Tregs and immunosuppressive myeloid cells — cells that can dampen the body’s immune response and help tumors evade destruction.
Importantly, the expansion of Tregs was closely linked to treatment outcomes. Patients with higher levels of these cells had less tumor shrinkage, suggesting that an overly suppressive immune response may limit the therapy’s effectiveness.
Building toward next-generation therapies
Together, the results provide a clearer picture of why CAR-T therapies have had mixed success in glioblastoma, and how scientists can engineer the next generation of treatments.
“When we look ahead to making our dual-target CAR-T therapy even more effective, these findings point us in a few promising directions,” said co-senior author Zev Binder, an assistant professor of Neurosurgery. “We could prime the individual’s immune system with existing treatments that can deplete Tregs and immunosuppressive myeloid cells, or even ‘armor’ the CAR-T cells with proteins that shuts down Tregs on their way to destroying tumor cells.”
Researchers also note that the “liquid biopsy” technique of sampling CSF with ICV could guide decisions about using these combination therapies for each patient based on their specific tumor and immune environment.
This article has been republished from the following materials. Material may have been edited for length and house style. For further information, please contact the cited source. Our press release publishing policy can be accessed here.