Immunotherapy for Glioblastoma

Last updated 4/27/25

Why Immunotherapy?

Glioblastoma (GBM) creates an immune-suppressive micro-environment that allows it to grow unchecked. Immunotherapy aims to tip the balance back toward immune control by (a) exposing the tumor to the immune system and (b) releasing the molecular brakes that stop T cells from attacking.

Therapeutic Vaccines

Vaccines such as DCVax-L, SurVaxM, NeoVax and Gliovac train dendritic cells and T cells to recognise tumour antigens. For full details see our dedicated page: Therapeutic Vaccines for Glioblastoma.

Immune Checkpoints & Inhibitors

T cells have built-in "checkpoints"-molecules such as PD-1 and CTLA-4-that act like ID badges. When these badges engage their ligands (PD-L1, PD-L2 or CD80/CD86) on other cells they send a stop signal that prevents collateral damage to healthy tissue. GBM exploits this by up-regulating PD-L1 on tumour and myeloid cells, effectively hiding in plain sight.

Checkpoint inhibitors are monoclonal antibodies that block the stop-signal, allowing T cells to remain active. The main drugs being tested in GBM are:

  • Nivolumab - anti-PD-1 (trials: CheckMate-143, CheckMate-548, CheckMate-498)
  • Pembrolizumab - anti-PD-1 (KEYNOTE-028, KEYNOTE-716 + TTFields)
  • Atezolizumab - anti-PD-L1 (Impassion-GBM)
  • Durvalumab - anti-PD-L1 (NCT02336165)
  • Ipilimumab - anti-CTLA-4 (used mostly in combination trials)

Key Trial Results

  • CheckMate-143 (NCT02017717): nivolumab vs bevacizumab in recurrent GBM - no OS benefit (9.8 vs 10.0 mo) but durable responses in a small subset.
  • CheckMate-548 (NCT02667587): nivolumab + temozolomide in newly diagnosed MGMT-methylated GBM - median OS 28.9 mo vs 32.1 mo with placebo.
  • NCT03233152: pembrolizumab + TTFields - 1-yr OS 61 % with compliance >75 % vs historical 48 %.

Ongoing studies focus on combinations: checkpoint inhibitor + vaccine, TTFields, oncolytic virus or radiation to convert "cold" tumours into "hot" ones that respond better to blockade.

Oncolytic Viral Therapies

Viruses can be engineered to selectively infect GBM cells and spark an in-situ vaccine effect. Examples include:

  • DNX-2401 - Delta-24-RGD adenovirus (NCT02798406, NCT03714334)
  • G47Δ - triple-mutated HSV-1 (approved in Japan; NCT02209368)
  • Lerapolturev (former PVSRIPO) - recombinant poliovirus (LUMINOS-101, NCT05076513)

CAR-T Cell Therapies

Chimeric Antigen Receptor (CAR) T cells are patient T cells re-programmed to express receptors that bind GBM surface markers. Targets in clinical testing include EGFRvIII, IL13Rα2, HER2 and B7-H3.

  • IL13Rα2 CAR-T (NCT02208362) - intraventricular dosing produced two >7 mo complete responses.
  • B7-H3 CAR-T (NCT04077866) - early safety data show manageable cytokine release.
  • EGFRvIII CAR-T (NCT02664363) - trafficking to tumour proven; combinational strategies underway.

Adjuvants and Immune Modulators

Poly-ICLC (Hiltonol) is a synthetic double-stranded RNA that activates TLR-3 and MDA-5, driving type-I interferon release. Used as:

  • Stand-alone biological response modifier (NCT00262752 - median OS 18 mo newly diagnosed GBM)
  • Adjuvant with peptide vaccines (ITI-1001) or checkpoint inhibitors (NCT04329065)

Gene Therapy Approaches

Gene therapy delivers genetic payloads directly into the tumour to either kill cells or enhance immune visibility. Strategies include IL-12 gene transfer (Ad-RTS-hIL-12 + veledimex, NCT04006119) and herpes-thymidine-kinase suicide gene combined with valganciclovir (Toca 511 studies).

Selected Active Clinical Trials

ModalityTrial IDTitle / Notes
Checkpoint inhibitor + TTFields NCT03233152 Pembrolizumab combined with Tumor Treating Fields for recurrent GBM
Oncolytic virus NCT05076513 Lerapolturev (PVSRIPO) + pembrolizumab - LUMINOS-101
CAR-T (IL13Rα2) NCT02208362 Re-dosing intraventricular IL13Rα2 CAR-T cells
Poly-ICLC + peptide vaccine NCT04329065 Multipeptide vaccine (IMA950) with Poly-ICLC in newly diagnosed GBM
IL-12 gene therapy NCT04006119 Ad-RTS-hIL-12 plus veledimex for recurrent GBM

Outlook

No single immunotherapy has yet delivered a definitive survival advantage in unselected GBM patients, but signals of long-term survival in small sub-groups suggest that the right combination and right patient selection could transform outcomes. Keeping informed about trial options and emerging biomarkers (for example MGMT status, T-cell inflamed gene signature or CSF-ctDNA) is essential.



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