With V Foundation funding, Assistant Professor Quanyin Hu aims to improve a cancer-killing hydrogel to improve outcomes for pediatric GBM patients

By Susan Smith

A diagnosis of pediatric glioblastoma multiforme (GBM) typically means that the patient has just a few years to live — less than 15 percent of children with GBM will live longer than five years.

But the Cell Inspired Personal Therapy (CIPT) Lab at the helm of Assistant Professor of Pharmaceutical Sciences Quanyin Hu at the University of Wisconsin–Madison School of Pharmacy has developed several promising approaches to treat this difficult and devastating form of brain cancer.

Hu, also a member of the UW Carbone Cancer Center and three-time Highly Cited Researcher, recently received a grant from the V Foundation’s Dick Vitale Pediatric Cancer Research Fund to further this research.

“I applied to this V Foundation grant mechanism with great enthusiasm,” Hu says. “GBM is a leading cause of death in children with cancer, and I think our approach could contribute significantly given the translational potential.”

The problem: GBM tumor recurrence is the main factor driving the disease’s low survival rate.

“It is almost impossible to remove all the tumor cells during surgery,” says Hu. “Neurosurgeons must be conservative, because you don’t want to remove more brain tissue than necessary, but tumor cells have often already spread into nearby healthy brain tissue, which causes the tumor to come back after surgery.”

The new approach: Hu’s CIPT team has developed and tested a hydrogel, equipped with nanoparticles designed to promote the immune system’s cancer-killing response, to be injected into the cavity left behind by the excised tumor. The hydrogel would slowly release nanoparticles that generate glioma stem cell-specific chimeric antigen receptor (CAR) macrophages that would target any remaining cancer cells.

“We envision that we can reprogram the local macrophages, a type of immune cell, to turn these cells from the enemy to an ally in fighting cancer,” says Hu. “Following neurosurgery for glioblastoma, there is a strong inflammatory environment, which attracts these immune cells to the surgery site. They are coming to support the recovery of the glioblastoma tumor — promoting the cancer itself. But we have included nanoparticles in the hydrogel at the surgery site that can reprogram these infiltrated macrophage immune cells to turn them from a pro-tumor phenotype to an anti-tumor phenotype.”

“GBM is a leading cause of death in children with cancer, and I think our approach could contribute significantly given the translational potential.”
—Quanyin Hu

The team’s earlier studies in GBM models showed strong results in keeping the tumor from returning. Building on their established success with the nanoparticle-delivering hydrogel, Hu’s team now plans to use the V Foundation funds to improve the approach.

“We are working on prolonging and strengthening the anti-tumor phenotype through generating the self-stimulating signals, to keep it from converting back to the pro-tumor phenotype of macrophage,” he says. “This will allow the anti-tumor phenotype to eradicate all residue cells to prevent recurrence.”

The benefit: A similar technology has long been used to modify T cells, creating CAR-T cells to recognize and attack cancer cells with a specific antigen on their surfaces — glioma stem cells, in this case. But Hu’s macrophage approach offers several advantages.

“We think that it is much safer and more effective to use the CAR macrophages, for one, because there are a much larger number of macrophages than T cells in the tumor immunosuppressive environment. Second, the cancer killing mechanisms are different,” Hu says. “CAR-T cells kill cancer by generating toxins and cytokines, which can create side effects throughout the body. A macrophage kills cancer cells through phagocytosis, which means they basically just eat all the cancer cells, so this causes much fewer side effects even though macrophages can also produce cytokines.”