Novel directions for advancing glioblastoma care

Aug. 29, 2025

Mayo Clinic is committed to finding new ways to treat primary glioblastoma. Physician-scientists are exploring a number of approaches that could shift the treatment paradigm and improve survival, including:

Neoadjuvant immunotherapy.
Stem cell and chimeric antigen receptor (CAR)-T cell immunotherapies.
Better drug delivery across the blood-brain barrier.
Augmented reality.
Intraoperative tumor monitoring.

"We've made very limited progress in improving survival outcomes over the past few decades. Novel directions are needed to advance clinical care," says Gelareh Zadeh, M.D., Ph.D., chair of Neurosurgery at Mayo Clinic in Rochester, Minnesota.

The current standard of care — maximal safe surgical resection followed by radiotherapy and chemotherapy — offers patients a median overall survival of about 18 months. "This is the most devastating cancer that affects humanity," says Alfredo Quinones-Hinojosa, M.D., a neurosurgeon at Mayo Clinic in Jacksonville, Florida. "The handful of approved therapies prolong survival for only about 10 to 12 months, and they are extremely expensive. The economic effects and the emotional toll for patients and families are extraordinary."

Mayo Clinic's efforts are led by researchers with access to the latest technology. Translating their findings into patient care and finding scalable therapies are top priorities.

"We always want to be on the cutting edge of treatment," says Bernard R. Bendok, M.D., chair of Neurosurgery at Mayo Clinic in Phoenix/Scottsdale, Arizona. "There's a lot going on at Mayo Clinic that puts us in a front row seat on the innovation train towards a better destination."

Neoadjuvant immunotherapy

Immune checkpoint inhibitors (ICIs) have revolutionized outcomes in cancers such as melanomas but haven't shown similar benefit for treating glioblastoma. "Several factors might explain glioblastoma's resistance to immunotherapy — not just the brain's biological barriers but also tumor-specific characteristics such as low mutational burden," Dr. Zadeh says. "Low mutational burden can result in a highly immunosuppressive tumor microenvironment."

"There's a lot going on at Mayo Clinic that puts us in a front row seat on the innovation train towards a better destination."

— Bernard R. Bendok, M.D.

A commentary co-written by Dr. Zadeh and published in Nature Medicine suggests that neoadjuvant immunotherapy — in combination with other therapies — might be more beneficial than typical adjuvant immunotherapy. "Individual case reports have shown that neoadjuvant immunotherapy for glioblastoma can activate antitumor immunity," she says. "Contrary to current understanding, that response can occur in glioblastoma with low tumor mutational burden."

In one case report, a patient received neoadjuvant triple ICI therapy followed by tumor resection. The patient subsequently had adjuvant ICIs and a personalized peptide vaccine along with adjuvant radiation. After 17 months of follow-up, the patient remained free from disease progression or recurrence. Analysis of the resected tumor confirmed the ICI's penetrance to the tumor site.

"If the neoadjuvant phase proves pivotal for establishing robust antitumor responses, those findings should prompt a transformation in glioblastoma management paradigms," Dr. Zadeh says.

She continues to work closely with colleagues in neuro-oncology to pursue the potential benefits of immunotherapy, in combination with viral therapeutics. The researchers have identified a gene signature that is predictive of response to this approach and are planning clinical trials to further explore and validate this biomarker.

Using cancer to fight cancer

Several potential cell-based immunotherapies are under development at Mayo Clinic. Led by Dr. Quinones-Hinojosa, researchers in the Brain Tumor Stem Cell Research Laboratory are investigating the use of allogenic adipose-derived mesenchymal stem cells (AMSCs) to treat recurrent glioblastoma. The stem cells are delivered into the surgical cavity during tumor resection.

"When in direct contact with tumor cells, AMSCs affect tumor growth, residual tumor cell death and chemotherapy resistance," Dr. Quinones-Hinojosa says. "Delivering those cells directly into the surgical cavity could decrease the disease progression rate and the invasiveness of malignant cells."

Mayo Clinic researchers also have developed a novel solid tumor CAR-T cell therapy and demonstrated its potential effectiveness against glioblastoma in preclinical models. As described in Molecular Therapy: Oncology, the therapy — known as MC9999 — attacks both tumor and immunosuppressive cells. "Our proof-of-concept data establish MC9999 as a foundation for the development of effective CAR-T cell therapies against solid tumors, including glioblastoma," Dr. Quinones-Hinojosa says.

Another, early-stage effort involves removing cancer tissue from patients and isolating tumor-infiltrating lymphocytes (TILs) in the laboratory. "We engineer the TILs with advanced technology to bypass the tumor heterogeneity that is a big challenge in glioma immunotherapy," Dr. Quinones-Hinojosa says. "What is amazing is that we are using cancer to fight cancer."

Breaching the blood-brain barrier

One of the major challenges of glioblastoma treatment is delivering therapy across the blood-brain barrier. Mayo Clinic researchers are planning clinical trials of a new approach that uses low-intensity pulsed ultrasound and microbubbles.

An ultrasound device, implanted in the patient's skull after tumor resection, periodically generates pulses. Microbubbles are concomitantly injected into the bloodstream. The ultrasound waves cause the microbubbles to oscillate, applying pressure to cell walls.

"That allows us to temporarily break down the blood-brain barrier and deliver chemotherapy or immunotherapy intravenously or through an endovascular catheter," Dr. Bendok says.

Endovascular drug delivery targets the tumors' extensive microvasculature. "We can go right up to the vessels that feed the tumor and deliver much higher doses of drugs," Dr. Bendok says. "Endovascular neuro-oncology is a new field we are establishing at Mayo Clinic, alongside a blood-brain barrier breakdown program. We want to be sure that drugs reach the target."

Surgical innovations

Mayo Clinic has long been at the forefront of efforts to map patients' brains to enhance the safety and efficacy of tumor resections. "We've pushed the envelope by having a brain mapping program that incorporates functional imaging and augmented reality," says Dr. Bendok, who leads Mayo Clinic's Neurosurgery Simulation and Innovations Laboratory.

"We're moving into faster technologies that are easier to implement and scalable."

— Alfredo Quinones-Hinojosa, M.D.

Patient-specific simulations of surgeries can be superimposed on the surgical field to guide the procedure. "Merging the avatar with the real patient allows us to create a surgical approach designed for each person's needs. That can result in better outcomes," Dr. Bendok says.

Other techniques offer potential for assessing tumors intraoperatively. Mayo Clinic researchers developed a deep learning-based approach for delineating cancer and noncancerous tissue in the operating room. As described in Biomedical Optics Express, the technique uses optical coherence tomography. Another new approach, described in Scientific Reports, uses distortion electrospray ionization mass spectrometry to rapidly analyze tumor microarrays.

"We're moving into faster technologies that are easier to implement and scalable," Dr. Quinones-Hinojosa says. "We can now think of a future when we might resect a tumor and know right then and there in the operating room what therapies it might be susceptible to."

Advanced glioblastoma research requires tumor samples. With patients' permission, Mayo Clinic neurosurgeons routinely collect and deposit these samples in biobanks. "A biobank goes beyond just collecting tissue. It symbolizes a partnership between an institution and a patient," Dr. Quinones-Hinojosa says. "Tissue samples are essential to helping us understand the biology of cancer and how it grows. These studies undoubtedly will help us find cures. Our patients are part of history."