How Mass General Brigham Researchers Are Navigating Glioblastoma’s Biggest Challenges

Glioblastoma is one of the most aggressive forms of brain cancer. Despite decades of research, the disease remains difficult to treat, with only about 6% of adults age 40 and older surviving five years after diagnosis.

Part of the challenge is that glioblastoma seems to have a workaround for nearly every treatment. The brain's protective barrier, known as the blood brain barrier (BBB), is great at preventing harmful invaders from entering the brain, but can also prevent drugs from reaching tumors. Cancer cells have also found remarkably clever ways to evade the immune system. And different groups of cells within the same tumor can respond differently to treatment, preventing the complete elimination of the tumor and helping the disease return.

Researchers at the Mass General Brigham Cancer Institute Open external link in a new window are tackling each of these obstacles from different angles, hoping to improve the effectiveness of treatments, reduce disease recurrent and increase patient longevity.

Getting treatments into the brain

One of the biggest challenges in treating glioblastoma is getting drugs where they're needed. The brain is protected by the BBB, which helps keep harmful substances out but can also block treatments from reaching tumor cells.

In a study published in Device Open external link in a new window , Alexandra Golby, MD, and colleagues studied focused ultrasound, a technique that uses sound waves to temporarily open the BBB.

After analyzing nearly 1,000 target points in patients with high-grade gliomas, the team found that using this ultrasound technology in combination with treatment was effective in increasing drug delivery in a reliable and predictable way.

The findings could help researchers deliver more treatments to brain tumors that have been difficult to reach.

Helping the immune system find the tumor

Glioblastoma can hide from the immune system, making it difficult for the body's natural defense force to recognize the tumor cells as harmful and eliminate them.

One approach Mass General Brigham researchers are exploring uses oncolytic viruses, which are engineered viruses that designed to both infect and kill cancer cells and help to activate the immune system against remaining cancer cells without infecting or harming healthy cells.

In a Cell Open external link in a new window study, Antonio Chiocca, MD, PhD, and colleagues tested an oncolytic virus that was derived from the herpes virus and engineered to infect glioblastoma cells while leaving healthy cells intact. As the virus kills tumor cells, it also helps alert the immune system to the cancer.

In a Phase 1 trial involving 41 patients with recurrent glioblastoma, the treatment attracted immune cells into tumors and helped keep them active. Patients with stronger immune responses tended to live longer after treatment.

The results suggest that oncolytic viruses may help the immune system better recognize and fight glioblastoma.

Making immunotherapy work better

Even when the immune system recognizes glioblastoma, the tumor can find ways to resist treatment.

Mass General Brigham researchers are studying different ways to overcome that resistance. In a study published in Nature Cancer Open external link in a new window , Francisco J. Quintana, PhD, and colleagues engineered a herpes virus to deliver immune-boosting molecules directly into glioblastoma tumors. In preclinical models, the approach increased tumor-fighting immune cells and extended survival.

In a separate study published in PNAS Open external link in a new window , Rakesh K. Jain, PhD, and colleagues found that a pathway known as Wnt signaling may help make glioblastomas rich in cancer stem cells harder to treat and more resistant to immunotherapy. In preclinical models, blocking this pathway changed the tumor environment in ways that improved the response to anti-PD-1 immunotherapy. The findings point to a potential combination strategy for overcoming resistance to current immunotherapies.

Jain and colleagues have also continued to examine strategies for improving cancer treatment, including a 2026 Cell review Open external link in a new window that looks at lessons learned from 25 years of research into normalizing tumor blood vessels.

Together, these studies point to new ways of helping immunotherapies work better against glioblastoma.

Targeting more tumor cells

Glioblastoma tumors are made up of many different types of cancer cells. Some cells may respond to treatment, while others survive and allow the tumor to return.

In a study published in The New England Journal of Medicine Open external link in a new window , Bryan D. Choi, MD, PhD, Marcela Maus, MD, PhD, and colleagues developed a CAR-T cell therapy designed to target more than one type of glioblastoma cell. CAR-T therapy uses a patient's own immune cells, which are engineered to find and attack cancer.

The therapy was designed to recognize two forms of EGFR, a protein found on many glioblastoma cells. By targeting both, researchers hoped to attack more of the tumor at once.

In a phase 1 trial, the first three patients experienced dramatic tumor reductions within days.

Although the tumors later returned, the results showed that CAR-T cells can rapidly attack glioblastoma.

About Mass General Brigham

Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation's leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.