Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma

After several unsuccessful attempts to effectively apply immune checkpoint inhibitors (ICIs) in the treatment of glioblastoma, a case report published in Nature Medicine by Georgina Long et al. has renewed hope for this type of immunotherapy (IO) in patients with gliomas.

A 56-year-old right-handed man was diagnosed with glioblastoma (IDH-wild-type, grade 4, RTK2 subtype) in the left temporal lobe after biopsy. The tumor had stable microsatellite status, low mutational burden (2 mutations/megabase) and was unmethylated at the MGMT promoter region. The patient then underwent intravenous application of nivolumab, relatlimab and ipilimumab followed by maximal safe resection after 2 weeks. Radiotherapy at the standard dose of 60Gy in 30 fractions was initiated 2 weeks after surgery.

The timing (neoadjuvant therapy) and the addition of an anti-LAG3 mechanism (relatlimab) to the anti-PD1 (nivolumab) and anti-CTLA4 (ipilimumab) combo were the differentiating aspects in relation to strategies already tested – and failed - in previous trials with IO in high-grade gliomas.

Additionally, analysis of tumor material collected 4 days before the start of treatment (biopsy) and 13 days after (resection) enabled analysis of infiltration by T lymphocytes, which was significantly higher in the second sample, a finding consistent in different sections beyond the biopsy area - this phenomenon was not seen in another patient with glioblastoma who underwent diagnostic biopsy and surgery 14 days apart. Other analyses revealed different markers of immune activation in the post-treatment specimen, including high expression of immune checkpoints (LAG3, CTLA-4, TIM3, TIGIT, CD39) in tumor-infiltrating T cells. 

Immune markers in peripheral blood (collected pre- and post-treatment), such as the higher expression of effector and memory T lymphocytes post-treatment, corroborated the impression of anti-tumor immune activation. 

To make the IO more feasible, some doses of ICI were administered only as monotherapy and, even in the face of immune-mediated toxicities, corticosteroids were avoided. In the case of an unmethylated glioblastoma, temozolomide, a cytotoxic and known lymphosuppressive therapy, was not offered either during or after radiotherapy. The absence of signs of recurrence after 17 months for this ominous subtype of glioblastoma was considered an encouraging outcome.

Despite this, it is worth noting that a personalized peptide vaccine was administered from the 3rd month of treatment, which characterizes a concomitant mode of IO. While this does not change the conclusions about safety, it certainly compromises the accuracy of impact estimation of the triple neoadjuvant regimen on survival. Caution is necessary in any case when analyzing an individual case.

The publication is also memorable for the participation of the research subject himself, the notable melanoma pathologist Richard Scolyer, as one of the authors, and the extensive repercussion of the case on social media even before publication. 

A trial evaluating the use of the combination nivolumab (anti-PD1) and relatlimab (anti-LAG3) in the neoadjuvant regimen for glioblastoma (in which temozolomide will be omitted only in cases of tumor without MGMT methylation) is about to begin recruitment – ​​its results will be more enlightening. On his page on X, the author (and patient) himself corroborated the importance of the controlled study with multiple subjects, while recognizing that the survival benefit he enjoyed may be related to the strategy tested and/or the personalized peptide vaccine. 

A week after the publication, Dr. Scoyler reported tumor recurrence after a new surgery. While hoping for the best possible evolution for the brilliant scientist turned subject, the Neuro-oncology community awaits the results of the randomized study – may they fulfill what, for now, is basically renewed hope.

Journal: Nature Medicine

Long, G.V., Shklovskaya, E., Satgunaseelan, L. et al. Neoadjuvant triplet immune checkpoint blockade in newly diagnosed glioblastoma. Nat Med (2025).