ANN ARBOR, Michigan — Scientists at the University of Michigan Rogel Cancer Center were optimistic when they identified a small molecule that blocked a key pathway in brain tumors. But there was a problem: how to get the inhibitor through the bloodstream and into the brain to reach the tumor.
Working with multiple labs, the teams fabricated a nanoparticle to contain the inhibitor, and the results were even better than expected.
Not only did the nanoparticles deliver the inhibitor to the tumor in mouse models, where the drug successfully primed the immune system to eliminate the cancer, but the process activated immune memory so that a reintroduced tumor was also eliminated — a sign that this potential new approach is failing. can only treat brain tumors, but can also prevent or delay recurrences.
“Nobody could get this molecule into the brain. It really is a huge milestone. Outcomes for patients with glioma have not improved in the past 30 years,” said Maria G. Castro, Ph.D., RC Schneider Collegiate Professor of Neurosurgery at Michigan Medicine. Castro is the senior author of the study, published in ACS Nano†
“Despite survival gains in many cancer types, glioma remains a persistent challenge, with only 5% of patients living five years after their diagnosis,” said the study’s author. Pedro R. Lowenstein, MD, Ph.D.Richard C. Schneider Collegiate Professor of Neurosurgery at Michigan Medicine.
Gliomas are often resistant to traditional therapies and the environment within the tumor suppresses the immune system, rendering new immune system-based therapies ineffective. Add to that the challenge of crossing the blood-brain barrier, and it becomes even more difficult to provide effective treatments for these tumors.
Castro-Lowenstein’s lab saw an opportunity. The small molecule inhibitor AMD3100 has been developed to block the action of CXCR12, a cytokine released by glioma cells that builds a shield around the immune system, preventing it from firing at the invading tumor. Researchers showed in mouse models of glioma that AMD3100 prevented CXCR12 from binding to immune-suppressing myeloid cells. By disarming these cells, the immune system remains intact and can attack the tumor cells.
But AMD3100 struggled to get to the tumor. The drug didn’t travel well through the bloodstream and cross the blood-brain barrier, a major problem in getting drugs into the brain.
Castro-Lowenstein’s lab collaborated with Joerg Lahann, Ph.D.Wolfgang Pauli Collegiate Professor of Chemical Engineering at the UM College of Engineering, to create protein-based nanoparticles to encapsulate the inhibitor, hoping to help it pass through the bloodstream.
Castro also connected with Anuska V. Andjelkovic, MD, Ph.D., professor of pathology and research professor of neurosurgery at Michigan Medicine, whose research focuses on the blood-brain barrier. They noted that glioma tumors create abnormal blood vessels, disrupting normal blood flow.
The researchers injected AMD3100 loaded nanoparticles into mice with gliomas. The nanoparticles contain a peptide on the surface that binds to a protein usually found on the brain tumor cells. As the nanoparticles traveled through the bloodstream to the tumor, they released AMD3100, which restored the integrity of the blood vessels. The nanoparticles could then reach their target, where they release the drug, blocking the entry of the immune-suppressing myeloid cells into the tumor mass. This allowed the immune cells to kill the tumor and slow its progression.
“If you don’t have blood flow, nothing will reach your goal. That’s why tumors are so smart. But AMD3100 repairs the ducts, allowing the nanoparticles to reach the tumor,” Castro said.
Further studies in mice and patient cell lines showed that coupling the AMD3100 nanoparticle with radiation therapy enhanced the effect beyond the nanoparticle or radiation alone.
Among the mice whose tumors had been eliminated, the researchers then reintroduced the tumor, simulating a recurrence. Without any additional therapy, 60% of the mice remained cancer-free. This suggests that AMD3100, like a vaccine, created immune memory, allowing the immune system to recognize and destroy the reintroduced cells. While it did prevent a recurrence in mice, Castro said it bodes well for at least delaying recurrence in humans.
“Every glioma comes back. It’s very important for glioma therapy to have this immunological memory,” Castro said.
Initial tests showed little to no impact on liver, kidney or heart function and normal blood counts in the mice after treatment. The nanoparticle has a similar basis to those previously tested in humans and shown to be safe. Additional safety testing is needed before moving on to a clinical trial.
Additional authors: Mahmoud S. Alghamri, Kaushik Banerjee, Anzar A. Mujeeb, Ava Mauser, Ayman Taher, Rohit Thalla, Brandon L. McClellan, Maria L. Varela, Svetlana M. Stamatovic, Gabriela Martinez-Revollar, Jason V. Gregory, Padma Kadiyala, Alexandra Calinescu, Jennifer A. Jimenez, April A. Appelbaum, Elizabeth R. Lawlor, Stephen Carney, Andrea Comba, Syed Mohd Faisal, Marcus Barissi, Marta B. Edwards, Henry Appelman, Yilun Sun, Jingyao Gan, Rose Ackermann, Anna Schwendeman , Marianela Candolfi, Michael R. Olin
Financing: National Institutes of Health grants R37-NS094804, R01-NS105556, R01-NS122536, R01-NS124167, R21-NS123879-01, R37-NS094804, R01-NS105556, R01-NS122536, R01-NS124167, R21-NS123879-01, T32 -CA009676, F31CA247104, F31CA247104; Rogel Cancer Center; Michigan Medicine Department of Neurosurgery; Pediatric Brain Tumor Foundation; Leah’s Happy Hearts Foundation; Ian’s Friends Foundation; Chad Tough Foundation; Smiles for the Sophie Forever Foundation; Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina; Instituto Nacional del Cancer Argentina, Asistencia Financiera IV
Cited paper: “Systemic Delivery of an Adjuvant CXCR4-CXCL-12 Signaling Inhibitor Encapsulated in Synthetic Protein Nanoparticles for Glioma Immunotherapy,” ACS Nano† DOI: 10.1021/acsnano.1c07492
University of Michigan Rogel Cancer Center, www.rogelcancercenter.org
Michigan health lab, www.MichiganHealthLab.org
Michigan Medicine Cancer AnswerLine, 800-865-1125
Subject of research
Systemic delivery of an adjuvant CXCR4-CXCL-12 signaling inhibitor encapsulated in synthetic protein nanoparticles for glioma immunotherapy
Article publication date
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