Neoadjuvant Immunotherapy’s Potential as Glioblastoma Treatment: What’s New?

While immunotherapy has been a remarkable success in the treatment of several tumor types, establishing its effectiveness in the central nervous system (CNS) tumor space has been challenging, particularly for glioblastoma (GBM) patients. Several factors are thought to contribute to this lack of progress including the blood-brain barrier limiting penetration of systemic therapies, tumor heterogeneity, relative lymphopenia, and local immune suppression, and immunosuppressive therapies (e.g. steroids, radiation, and chemotherapy) that are currently the standard of care.

However, ongoing research suggests that there may be a role for neoadjuvant immunotherapy in this setting.

“If you remove all the tumor and then give the immunotherapy, there will be less material to educate the immunotherapy to attack the cancer,” Dr. Mustafa Khasraw, a neuro-oncologist and physician scientist at Duke University, tells SurvivorNet Connect. “Based on that observation, that has proven true in diseases like melanoma, we are conducting clinical trials in newly diagnosed patients who have not received any therapy … now, we want to capture these patients before the surgeon has touched them.”

The idea, Dr. Khasraw adds, is that when the tumor is still present, the immunotherapy is more likely to work. This is the thought process behind the GIANT Trial. One of the first prospective trials looking at giving immunotherapy in the upfront setting.

The GIANT Trial

The GIANT trial (Glioblastoma Immunotherapy Advancement with Nivolumab and Relatlimab; ClinicalTrials.gov identifier NCT06816927) is a phase II, multi‑center, perioperative immunotherapy study in patients with newly diagnosed isocitrate dehydrogenase (IDH) wild‑type glioblastoma. It’s currently open for enrollment in the United States.

It’s designed to assess whether immunotherapy given around the time of surgery (i.e., both neoadjuvant and adjuvant) is feasible, safe, and biologically active in GBM, and to generate data that could support further development of these strategies. Dr. Khasaw is the primary contact for this study.

In the GIANT study:

• All participants undergo surgical resection of their tumor after an initial period of immunotherapy.
• Before resection, patients receive nivolumab, a PD‑1 immune checkpoint inhibitor, either alone or in combination with relatlimab, an antibody that blocks LAG‑3, another immune inhibitory receptor.
• Blocking both PD‑1 and LAG‑3 is intended to release inhibitory signals on T cells and promote a more robust antitumor immune response.

The study has two major parts. Early in the trial, a safety lead‑in phase determines whether giving nivolumab with relatlimab prior to surgery — and continuing these agents with standard radiation and temozolomide chemotherapy afterward — is tolerable.

After this run‑in, the trial moves into a randomized portion where patients are assigned in an unbalanced fashion (more to the combination arm) to receive either nivolumab alone or nivolumab plus relatlimab before surgery. Following resection, both groups continue immunotherapy combined with radiation and chemotherapy in the adjuvant phase, and then additional cycles of temozolomide and the immunotherapy drugs.

A key purpose of GIANT is not only to characterize safety and tolerability but also to explore biological effects resulting from perioperative immunotherapy. Researchers are particularly interested in whether neoadjuvant checkpoint blockade can stimulate T‑cell activation, change the immunosuppressive milieu of GBM, and ultimately translate into meaningful clinical benefit for patients with this aggressive brain tumor.

Dr. Khasraw says he is “hopeful that this combination will be more effective than nivolumab alone in the neoadjuvant setting.” The primary completion date is June of 2029 and is currently recruiting at Duke University

Neoadjuvant Immunotherapy in GBM: The Potential

There are several reasons why neoadjuvant immunotherapy is being studied for GBM. First, these tumors contain a wide range of neoantigens. Exposing the immune system to the intact tumor while the tumor is still present may prime T cells more effectively than after resection.

Preoperative therapy may also activate T cells and reduce immunosuppressive signaling, potentially converting a “cold” tumor into a more “hot” and immune-responsive tumor.

Neoadjuvant therapy may trigger T cell expansion in lymph nodes and circulation, which could help target residual microscopic disease after surgery.

Finally, tumor tissue obtained during surgery can be used to study immune activation, biomarkers, and therapy response, guiding future personalization of therapy.

Other Immunotherapy Strategies Under Investigation

Immunotherapy strategies in neoadjuvant GBM focus primarily on leveraging the intact tumor as a source of antigens to prime the immune system before surgical resection.

Checkpoint inhibition

The most studied approach has been checkpoint inhibition, particularly targeting the PD-1/PD-L1 pathway. In these trials, drugs like nivolumab or pembrolizumab are administered prior to surgery. This preoperative exposure has been shown to increase T-cell infiltration within the tumor, upregulate interferon-gamma-related gene signatures, and promote T-cell clonal expansion in both the tumor and the bloodstream.

Early clinical evidence suggests that patients receiving neoadjuvant checkpoint inhibitors may have improved survival compared to those receiving the same therapy only postoperatively, likely because the intact tumor provides a more complete set of antigens to stimulate the immune system.

Vaccines

Vaccine-based strategies are another avenue of investigation. These typically involve dendritic cell vaccines or peptide-based vaccines that prime T cells against tumor-specific antigens before resection. The rationale is that preoperative vaccination can enhance immune recognition, and when surgery disrupts the tumor, it may release additional antigens, further boosting the immune response.

Oncolytic viral therapy

Oncolytic viral therapy is also being explored in the neoadjuvant setting. Modified viruses are injected into the tumor before surgery to selectively infect and lyse tumor cells, releasing tumor antigens and stimulating both innate and adaptive immunity. This can potentially transform the tumor into a kind of in situ vaccine, which may improve post-surgical immune surveillance.

CAR T-cell therapy

Finally, while CAR T-cell therapy has mostly been used postoperatively, there is growing interest in neoadjuvant or perioperative strategies. Administering CAR T cells before surgery, or shortly after, may allow better initial engagement with the tumor and expansion of T cells, although this approach is still largely experimental. Overall, these strategies aim to convert GBM’s immunologically “cold” microenvironment into one that is more receptive to immune attack, with the ultimate goal of improving long-term control and survival.

Challenges in Neoadjuvant Immunotherapy Trials

Timing and safety are also major concerns. Administering immunotherapy before surgery carries the risk of tumor progression or worsening neurological symptoms while waiting for resection.

Immune activation in the tumor can sometimes cause peritumoral edema or inflammation, which could increase intracranial pressure and complicate surgical planning. Moreover, many GBM patients require corticosteroids like dexamethasone to control cerebral edema, but these drugs suppress immune responses and may counteract the benefits of immunotherapy.

“Changing clinical practice to capture patients and identify them to receive an immunotherapy on a clinical trial before surgery is challenging,” Dr. Khasraw explains. “One challenging point is that these patients are super anxious, they’re scared, they want to have their tumor removed as soon as possible. So for me to go and tell them, hang on a minute, you have a very bad tumor, but we are not going to remove it. We’re going to give you an infusion first and you have to wait a couple of weeks until we plan the surgery … that is not easy, so we have to convince the patients that we are not compromising their care.”

Final Thoughts

The GIANT Trial represents a new approach to the treatment of GBM. One that may finally allow patients with these tumor types to enjoy the remarkable benefits of immunotherapy that have been experienced by patients with other tumor types such as lung and breast cancer. Overall, while phase III evidence is still lacking, there is a growing portfolio of clinical investigations exploring neoadjuvant immunotherapy for GBM. These range from checkpoint inhibitors alone to combination immune modulators and adjunctive therapies integrated with surgery and standard treatment, reflecting an active area of research aimed at overcoming the profound immune resistance of glioblastoma.