E. Antonio Chiocca, MD, PhD, chair of the Department of Neurosurgery at Brigham and Women’s Hospital, has received a $14.5M Program Project grant from the National Cancer Institute (NCI) for his research on glioblastoma. These NCI grants support multidisciplinary research that addresses a major scientific objective. The highly competitive grants are only awarded to a few research programs every five years.
The Brigham has a long tradition of studying T cell immunology, and grant members at the Brigham have led this area of research for many years. Their combined expertise, in coordination with researchers at the Dana-Farber Cancer Institute (DFCI), could yield new approaches to treating glioblastoma. Dr. Chiocca, along with his co-principal investigator, David Reardon, MD, of DFCI, are using their grant to addresses the problem of insufficient T cell activation in glioblastoma by stimulating immunity using a personalized medicine approach. The research project, “Understanding and Overcoming T cell Immunosuppression in Glioblastoma,” will take five years to complete.
Drs. Chiocca and Reardon oversee an interdisciplinary team of 11 faculty members. These include neurosurgeons and neuro-oncologists, T cell immunologists, geneticists, biostatisticians and medical oncologists from the Brigham and DCFI, as well as the Broad Institute of MIT and Harvard. “This research team was assembled in 2017, and some of us have worked together since the 1990s,” said Dr. Chiocca. “Everyone is a leader in their respective field. It’s really a superstar team of scientists.”
Studying T Cell Immunosuppression in Glioblastoma
For decades, physicians have struggled to treat glioblastoma. The cancer, which makes up 45 percent of all malignant brain tumors, is resistant to many common cancer treatments. Glioblastoma typically leads to death in the first 15 months after diagnosis.
“A person diagnosed with glioblastoma has a short life expectancy and rapid neurological deterioration,” said Dr. Chiocca. “It’s an extremely tough cancer to treat. That’s why we’re working hard to discover effective treatments for these patients. To get a handle on this cancer, we still need to know more about the basic biology of glioblastoma.”
The overarching goal of this collaborative Brigham/DFCI research project is to study the mechanisms of T cell immunosuppression in glioblastoma. T cells play a critical role in eliminating cancer cells, but glioblastoma have found ways to suppress the immune system. Glioblastomas are often fatal even with advanced treatment, and most clinical trials that aim to treat these tumors have failed. Moreover, immunotherapy clinical trials that have been successful for other cancers have failed for glioblastoma.
“With our Program Project grant, we aim to understand why glioblastomas are so immunosuppressive,” said Dr. Chiocca. “We want to know how these tumors reduce the activity of T cells. Our research has found ways to make T cells recognize and attack the glioblastoma—in essence, to vaccinate a patient against their own specific tumor.”
The Four Research Projects Studying T Cells in Glioblastoma
The Program Project grant involves four interrelated research projects. The projects are supported by four “cores” that provide the investigators with molecular immunology technologies, biocomputing and biostatistics tools, and glioblastoma mouse models.
In the first project, Dr. Reardon and Cathy Wu, MD, of DFCI, are isolating antigens from glioblastoma tumors to make personalized multi-peptide neoantigen vaccines. This project involves a Phase 1 clinical trial. In the trial, 40 patients have their tumors removed by Dr. Chiocca at the Brigham. After surgery, Drs. Reardon and Wu use a sample from each tumor to create a personalized vaccine for each patient. The vaccine aims to immunize the patient against 20 different proteins in their unique glioblastoma.
In 2019, the results from the first eight patients in this trial were published in Nature. The ongoing clinical trial uses the same personalized vaccine approach in combination with checkpoint inhibition, an immunotherapy that interrupts PD-1 signaling with T cells. This way to treat glioblastoma is being investigated in project 2, led by Gordon Freeman, PhD, an immunologist at DFCI who discovered the role of immune checkpoint signaling in cancers, in collaboration with Arlene Sharpe, MD, PhD, of the Department of Immunology at Harvard Medical School. Drs. Freeman and Sharpe, along with Dr. Chiocca, are studying how oncolytic viruses and CDK4/6 inhibitors increase T cell activation.
Projects 3 and 4 aim to identify the pathways involved in glioblastoma-related immune suppression. Kai Wucherpfennig, MD, PhD, of DFCI, and Mario Suva, MD, PhD, of the Broad Institute, have discovered new molecular targets that help glioblastomas evade tumors. At the Brigham, leading T cell immunologists Vijay Kuchroo, DVM, PhD, and Ana Anderson, PhD, have isolated another pathway that is involved in the making of glucocorticoids. Glucocorticoids are immunosuppressive molecules within the tumor microenvironment of glioblastomas.
Developing Effective Treatments for Glioblastoma
Dr. Chiocca has been studying glioblastoma for more than two decades. His early research advanced the understanding of the use of gene therapy and oncolytic viruses to stimulate the immune system. Today, his research focuses on the epigenetic mechanisms that drive glioblastoma development. Dr. Chiocca hopes the research funded by the NCI grant will lead to new discoveries for this difficult-to-treat cancer.
“This research will help contribute to our understanding of how glioblastoma evades the immune system,” said Dr. Chiocca. “The hope is that the foundational knowledge that the Brigham and others gain from the research will lead to improved patient care.”
In addition to the Brigham’s unique expertise in T cell immunology, their partnership with DCFI and the Broad provides the grant winners with the opportunity to make great advances in glioblastoma research. In the next five years, Dr. Chiocca hopes he and his colleagues will have discovered new treatments for glioblastoma patients.
“If we don’t find a direct treatment, we hope to at least have a molecule we can add to regimens to make glioblastoma treatment more effective,” said Dr. Chiocca.