‘Moving the Needle’ for Glioblastoma

Gene and cell therapy at a crossroads

After glimpsing the promise of gene and cell therapy, Mass General Brigham researchers are now enhancing the technology to drive new treatments for rare and common diseases

Replacing defective genes or cells with healthy ones has been a goal of modern medicine for decades. And while that aspiration may have seemed simple in principle, the practical path toward realization has been longer and more complex than ever imagined. But now, the initial wave of gene and cell therapies has reached the clinic, with remarkable health benefits for a subset of patients that affirms the potential of these precision medicines for more widespread applications. With scores of gene and cell therapies now under development, the field stands at a major crossroads.

At Mass General Brigham, our faculty are at the forefront of this extraordinary revolution. As part of a world-leading healthcare system that spans the full spectrum of the biomedical research enterprise and works collaboratively with industry to fuel innovation, Mass General Brigham scientists and physicians are working to bring the next generation of gene and cell therapies to the clinic. We highlight a few of their stories here, ranging from rare, genetic diseases to more common conditions that lack effective treatments.


Glioblastoma is the most common type of brain cancer in adult patients. Unfortunately, its outlook is too often grim. Most patients die within 12 to 18 months of diagnosis.

“We really haven’t moved the needle for glioblastoma in the last 30 years,” said Khalid Shah, PhD, who is the Vice Chair of Neurosurgery and directs the Center for Stem Cell Therapeutics and Imaging at Brigham Health. “We’re still treating patients with chemo and radiation, and eventually, these tumors just come back — something has to change.”

Now something is changing. Various teams across MGB are harnessing the tools of gene and cell therapy to develop novel treatments for glioblastoma. For example, Shah and his colleagues are wielding cancer cells as weapons against themselves. Their work draws inspiration from a surprising discovery nearly two decades ago, which found that cancer cells that have spread to distant sites in the body can find their way back to the original tumor. Shah’s team has taken this re-homing concept and, with the power of CRISPR genome editing technologies to molecularly rewire patients own tumor cells, designed the cells to be cancer seekers and slayers. Now, Shah’s group has enhanced these cells, giving them dual cancer-killing and immunomodulatory properties, and are gearing up to test their experimental approach in a phase one clinical trial.

“What the glioblastoma field needs is a cell therapy that not only kills tumor cells, but also gives the body long-term immunity against the cancer so it doesn’t return,” said Shah, who is also a professor at HMS. “That’s what we are building.”

Marcela Maus, MD, PhD and her colleagues are also working on a novel cell therapy. Their focus: developing next-generation CAR-T technologies that can target solid tumors like glioblastoma. CAR-T cells, which Maus’ team helped pioneer, first entered the clinic in 2017. The cells are created using patients’ own immune cells and are genetically engineered in the laboratory to give them therapeutic powers. They’ve proven remarkably potent for some forms of difficult-to-treat blood cancers, enabling some patients to survive for years cancer-free. Now, Maus has enhanced the cells, tweaking them to target not just one, but two molecules on glioblastoma cells. Such bispecificity should make the CAR-T cells better able to destroy solid tumors. The team is preparing to launch clinical trials later this year.

“At Mass General Brigham, we’re incredibly lucky to have such amazing scientific and clinical talent right here,” said Maus, who is Director of Cellular Immunotherapy at the MGH Cancer Center and an associate professor of medicine at HMS. “We have all the talent we need to complete the therapeutic lifecycle — to sketch an idea on the whiteboard, test it in preclinical models, and then collaborate with colleagues in the hospital to bring it to patients.”

Another Mass General Brigham team is also working on a new gene and cell therapy strategy to target glioblastoma. Nino Chiocca, MD, PhD, Neurosurgeon-in-Chief and Chairman of Neurosurgery at BWH, is designing specialized cancer-killing viruses to kill these tumors. Such oncolytic viruses have proven to be quite effective against melanoma, and now Chiocca and his colleagues are adapting them to target glioblastoma. Part of the enthusiasm for this approach lies in the observation that oncolytic viruses help recruit certain immune cells into glioblastoma tumors, transforming them from immunologically cold to hot. This transformation is critical for enabling tumors to respond to cancer immunotherapies, like checkpoint inhibitors. Now, in addition to testing oncolytic viruses in clinical trials, Chiocca’s team will also explore potential combinations with immunotherapy drugs.

“As scientists, we do a lot of research in the lab, but it rarely reaches patients,” said Chiocca, who is also the Harvey W. Cushing Professor of Neurosurgery at HMS. “It’s very exciting to see these potential therapies that could really make a difference for glioblastoma.”