Scientists at the University of Michigan (U-M) Rogel Cancer Center, in collaboration with multiple labs, report they have developed a nanoparticle that delivered an inhibitor in mice to help turn on the immune system to eliminate cancer and trigger immune memory in glioblastoma. Their method may one day help treat and prevent or delay brain cancer recurrences.
Their findings are published in the journal ACS Nano in a paper titled, “Systemic delivery of an adjuvant CXCR4-CXCL-12 signaling inhibitor encapsulated in synthetic protein nanoparticles for glioma immunotherapy.”
“No one could get this molecule into the brain. It’s really a huge milestone. Outcomes for patients with glioma have not improved for the last 30 years,” said Maria G. Castro, PhD, the Richard C. Schneider collegiate professor of neurosurgery at Michigan Medicine.
“Glioblastoma (GBM) is an aggressive primary brain cancer, with a five-year survival of ∼5%. Challenges that hamper GBM therapeutic efficacy include tumor heterogeneity, treatment resistance, immunosuppressive tumor microenvironment (TME), and the blood-brain barrier (BBB),” wrote the researchers. “The C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling pathway is activated in GBM and is associated with tumor progression. Although the CXCR4 antagonist (AMD3100) has been proposed as an attractive anti-GBM therapeutic target, it has poor pharmacokinetic properties, and unfavorable bioavailability has hampered its clinical implementation. Thus, we developed synthetic protein nanoparticles (SPNPs) coated with the transcytotic peptide iRGD (AMD3100-SPNPs) to target the CXCL2/CXCR4 pathway in GBM via systemic delivery.”
“Despite survival gains in many cancer types, glioma remains stubbornly challenging, with only 5% of patients living five years after their diagnosis,” explained study author Pedro R. Lowenstein, MD, PhD, the Richard C. Schneider collegiate professor of neurosurgery at Michigan Medicine.
The Castro-Lowenstein team developed the small molecule inhibitor AMD3100 to block the action of CXCR12, a cytokine released by the glioma cells that builds up a shield around the immune system, preventing it from firing up against the invading tumor.
Researchers demonstrated in mouse models of glioma that AMD3100 prevented CXCR12 from binding with immune-suppressive myeloid cells. However, AMD3100 was having difficulty getting to the tumor.
The Castro-Lowenstein lab collaborated with Joerg Lahann, PhD, the Wolfgang Pauli collegiate professor of chemical engineering at the U-M College of Engineering, to create protein-based nanoparticles to encapsulate the inhibitor, in the hopes of helping it pass through the bloodstream.
Castro also connected with Anuska V. Andjelkovic, MD, PhD, professor of pathology and research professor of neurosurgery at Michigan Medicine, whose research focuses on the blood-brain barrier.
The researchers injected AMD3100-loaded nanoparticles into mice with gliomas. The nanoparticles could then reach their target, where they released the drug, thus blocking the entry of the immune-suppressive myeloid cells into the tumor mass. This allowed the immune cells to kill the tumor and delay its progression.
“If you don’t have blood flow, nothing will get to your target. That’s why tumors are so smart. But AMD3100 restores the conduits, which is what allows the nanoparticles to reach the tumor,” Castro said.
Further studies in mice and patient cell lines demonstrated that coupling the AMD3100 nanoparticle with radiation therapy enhanced the effect beyond either the nanoparticle or radiation alone.
Among the mice whose tumors were eliminated, the researchers then reintroduced the tumor, to simulate a recurrence. Without any additional therapy, 60% of mice remained cancer-free.
This observation suggests that AMD3100 created immune memory.“Every glioma recurs. It’s very important for glioma therapy to have this immunological memory,” Castro explained.
Initial tests showed little to no impact on liver, kidney, or heart function and normal blood counts in the mice after treatment.
Additional safety testing is necessary before moving to a clinical trial. However, their findings may one day help improve survival and prevent glioblastoma recurrence.
