By Michelle Koidin Jaffee
University of Florida researchers have developed a new algorithm to predict which proteins expressed within brain tumor cells could serve as targets to stimulate a potent anti-tumor response. The preclinical study in mice is the latest step toward overcoming common resistance to immunotherapy treatments for brain cancer.
Furthermore, the study, published Jan. 25 in the journal Genome Medicine, detailed a novel high-tech method devised by McKnight Brain Institute researchers to create precise and individualized mRNA-based vaccines along with personalized adoptive T cell therapy treatments to zero in simultaneously on multiple newly identified targets in mouse models of glioblastoma and medulloblastoma.
With median survival of less than 15 months, glioblastoma is the most common and deadliest primary malignant brain tumor in adults and it is notoriously treatment-resistant, while survival of medulloblastoma in children is over 70%. Amid recent advances in genome-wide sequencing technology showing that individual brain tumors are unique in their genetic makeup, researchers are pursuing personalized immunotherapy treatments for patients.
The UF study is a new demonstration of mRNA-based therapeutics — the kind used in the COVID-19 mRNA vaccines. Researchers led by Duane Mitchell, M.D., Ph.D., director of UF’s Brain Tumor Immunotherapy Program, paired gene-sequencing technology with their new computational algorithm as well as bioinformatics, an evolving discipline combining computer science and biology, to address the challenge of tumor uniqueness.
“We start with individual tumor samples,” said Vrunda Trivedi, Ph.D., first author of the paper who completed the work as a graduate student in Mitchell’s lab and is now a postdoctoral associate at Stanford. “We study the genetic makeup of that tumor, and we identify gene alterations which are uniquely expressed by that tumor. We then use that information to develop a personalized vaccine therapy. Our selective gene enrichment strategy gives us the ability to pull all of these tumor alterations into a single vaccine.”
The investigators demonstrated that the therapy prompted an infiltration of T cells, which can fight tumor cells and alter the immunosuppressive tumor microenvironment, and led to improved survival duration in the mouse models.
The newly developed vaccine is the next iteration of a treatment regimen called adoptive cellular therapy, pioneered by Mitchell, co-director of UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy. That treatment, which is being tested in a current pediatric clinical trial, involves the amplification of tumor-reactive “killer T cells” in significant quantities outside the patient, followed by administering these robust immune cells to children with resistant brain tumors.
“To me, the most exciting thing about our study is this observation that we can redirect the nature of the tumor microenvironment,” Trivedi said. “It’s a significant development in the field of vaccine therapy where you can target a multitude of antigens in a single vaccine. With our technology, we go up to 300 tumor antigens from a single tumor sample.”
Antigens are toxins or substances foreign to the body that evoke an immune response. The algorithm at the heart of the study was designed to identify mutations and tumor-associated genes that serve as antigens, among other key information. Dubbed Open Reading Frame Antigen Network (O.R.A.N.), the software was developed by co-author Changlin Yang, M.D., an associate scientist in Mitchell’s lab.
As a next step in the line of research, the investigators additionally tested the algorithm on human glioblastoma tumor samples as a proof of concept and identified tumor-specific and associated genes — results that laid the groundwork for a future clinical trial.
Trivedi said the study showed their novel approach is capable of being expanded to produce personalized treatments for resistant brain tumors.
The study was supported by the V Foundation, the Cure Group 4 Consortium, the Adam Michael Rosen Foundation, the ReMission Alliance Against Brain Tumors Research Fund, the UF Clinical and Translational Science Institute and the UF Health Cancer Center Predoctoral Award.