Designing Leading-Edge Immunotherapy for Brain Cancer
In This Article
- Massachusetts General Hospital brain tumor neurosurgeon Bryan Choi, MD, PhD, and Director of Cell Therapy Marcela Maus, MD, PhD created a cell therapy that uses chimeric antigen receptor (CAR) T-cells to target multiple antigens
- This unique approach addresses the issues of tumor heterogeneity and the harsh local environment of tumors to effectively eliminate glioblastoma
- Successful preclinical models have progressed toward the first cell therapy clinical trial for brain tumors at Mass General, currently under FDA review
- Brain cancer immunotherapy research continues to explore a variety of approaches, which may be translated for other solid and blood tumors
Massachusetts General Hospital neurosurgeons and scientists have advanced neuro-oncology treatments using an innovative cell therapy approach that combines chimeric antigen receptor (CAR) T-cells and bispecific monoclonal antibodies.
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"Our goal is to develop the next generation of cell therapies and clinical trials for brain tumors using CAR T-cells and the immune system in general," says Bryan Choi, MD, PhD, associate director, Center for Brain Tumor Immunology and Immunotherapy in the Department of Neurosurgery at Massachusetts General Hospital. "My lab is focused on what we can achieve in preclinical models to new clinical trials for patients with brain tumors."
Overcoming Barriers to Brain Tumor Cell-based Gene Therapy
Immunotherapy for brain cancer faces unique challenges, including the ability of peripheral immune responses to pass the blood-brain barrier, cell survival in the harsh local environment of brain tumors, and the elimination of multiple types of tumor antigens at once.
Successful immunotherapy for brain cancer needs to strike a delicate balance to overcome these challenges. It redirects the body's potent immune system to attack the antigens expressed on tumor cells while limiting the toxicity in healthy tissues with those same antigens. CAR T-cells often target epidermal growth factor receptor variant III (EGFRvIII), a mutated antigen only expressed on tumors. However, tumors express more than one kind of antigen, introducing the challenge of tumor heterogeneity. A CAR T-cell with a single target allows remaining antigens to survive and continue growing, a concept known as antigen escape.
Glioblastoma, the deadliest and most common brain tumor, highly expresses wild-type EGFR in addition to EGFRvIII. However, wild-type EGFR antigens also exist in healthy tissue throughout the body, making them difficult to target without widespread toxicity. "Addressing tumor heterogeneity and antigen escape is one of the primary goals for the next generation of CAR T-cells for brain tumors," Dr. Choi says.
Striving to overcome these challenges and the harsh immunosuppressive local environment of tumors spurred Dr. Choi and Marcela V. Maus, MD, PhD, director of the Cellular Immunotherapy Program at the Mass General Cancer Center, to develop a new cell therapy approach.
CAR TEAM Antibodies: Experimental Immunotherapy for Glioblastoma
Cell therapy predominantly employs two different technologies: CAR T-cells and bispecific monoclonal antibodies (also called bispecific T-cell engagers). Bispecific antibodies bind to both the antigen and the body's own T-cells. While pursuing his doctorate, Dr. Choi developed the first bispecific T-cell engager for brain tumors. By integrating CAR T-cells with this molecule, Drs. Choi and Maus created a new therapeutic approach: CAR TEAM.
"We wanted to combine these two competing technologies so their synergy would be stronger than the parts," Dr. Choi explains. "This construct, down to the DNA, was conceived, engineered, and designed in Mass General's laboratories."
The genetically modified CAR T-cells target EGFRvIII while secreting TEAM molecules to target wild-type EGFR in the tumor microenvironment.
"We defined the secretion and biological activity of the wild-type EGFR TEAM to wherever the CAR goes," Dr. Choi explains. "In doing so, we had a broad impact on the tumor but minimized the systemic toxicity. This localized effect allows us to mitigate antigen escape but create a really pro-inflammatory environment."
The success of the preclinical model is published in Nature Biotechnology.
Launching the First CAR T-cell Clinical Trial for Brain Tumors at Mass General
This new approach to CAR T-cell therapy has led to the development of one of the first cell therapy clinical trials for brain tumors worldwide. Dr. Choi predicts the phase I trial, currently undergoing FDA review, will open in 2023. Investigators plan to enroll up to 18 patients with glioblastoma to receive the novel, home-grown CAR TEAM cell therapy. Investigators leading the trial include neurosurgeon William Curry, MD, and neuro-oncologist Elizabeth Gerstner, MD.
"One of my greatest passions is trying to build technologies that bridge the gap from bench to bedside," Dr. Choi says. "This will be the first CAR T-cell trial for brain tumors at Mass General. We have a lot of excitement about that."
Forging Ahead in Immunotherapy Research
Dr. Choi continues to focus on developing a wide range of experimental immunotherapy for brain cancer. His research explores a variety of approaches, including:
- Building CAR T-cells that secrete different molecules or integrate precise gene editing techniques, such as CRISPR-Cas9
- Combining CAR T-cell therapy with other treatments, including checkpoint inhibition, oncolytic virus, and peptide vaccines
- Creating "off-the-shelf" therapies to increase accessibility and cost-effectiveness
- Designing CAR constructs that target multiple antigens at once
- Modifying additional cells with innate immunity, such as myeloid and NK cells
"My desire is to design a whole array of therapies that address different forms of tumors, not only targeting single antigens, but also changing the microenvironment," Dr. Choi says.
His interests have helped build the Center for Brain Tumor Immunology and Immunotherapy at Mass General. The Center unites investigators interested in improving the field's understanding of brain tumor immunology to ultimately create clinical trials and treatment options using immunotherapy for brain cancer patients.
Investigators at Mass General Cancer Centerhave started exploring the CAR TEAM platform for use in other cancers. "My hope is that it addresses many forms of tumor heterogeneity, not only in brain tumors but across all malignancies," shares Dr. Choi.
Finding Unique Opportunities at Mass General
Access to the unparalleled hub of collaborative investigators and resources at Mass General has played a key role in fulfilling Dr. Choi's research aims. "What makes Mass General unique is that it's actually a research hospital," he continues. "I'm primarily a neurosurgeon, but I run a lab. Mass General is really a unique environment to be an investigator in. At Mass General, we have the investigators and resources who want to push the bounds and create new therapies for patients who otherwise don't have choices."
Learn more about the Stephen E. and Catherine Pappas Center for Neuro-Oncology
Refer a patient to the Department of Neurosurgery at Mass General