Immunotherapy for High-Grade Gliomas
Simple Summary
Abstract
1. Introduction
2. Challenges and Considerations for Immunotherapy Efficacy
2.1. Immunosuppressive Tumor Microenvironment
2.2. Immunosuppressive Molecules and Markers
2.3. Systemic Immunosuppression
2.4. Antigen Escape
2.5. Intratumoral Heterogeneity
2.6. Adaptive and Acquired Resistance
2.7. Longitudinal Response Assessment
2.8. Blood–Brain Barrier Penetration
3. Methods for Clinical Trial Selection
4. Checkpoint Inhibitors
5. Oncolytic Viruses
5.1. Background
5.2. Herpes Simplex Virus
5.3. Adenoviruses
5.4. Reoviruses
5.5. Murine Leukemia Virus
5.6. Poliovirus
5.7. Measles
6. Vaccine Therapy
6.1. Dendritic Cell Vaccines
6.2. Peptide Vaccines
6.3. Nucleic Acid Vaccines
6.4. Heat Shock Proteins
7. CAR-T
7.1. IL-13Rα2
7.2. EGFRvIII
7.3. Bivalent Therapy
7.4. GD2
8. Targeted Cytokines
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Trial Identifier | Official Study Title | Phase | Additional Interventions | Tumor Types | Current Status |
---|---|---|---|---|---|
NCT05463848 | Surgical Pembro ± Olaparib W TMZ for RGBM | 2 | Surgery | Recurrent GBM | Recruiting |
NCT04977375 | Trial of Anti-PD-1 Immunotherapy and Stereotactic Radiation in Patients With Recurrent Glioblastoma | 1/2 | Surgery | Recurrent GBM | Recruiting |
NCT05084430 | Pembrolizumab and M032 (NSC 733972) in Treating Patients with Newly Diagnosed or Recurrent/Progressive Glioblastoma, Anaplastic Astrocytoma, or Gliosarcoma | 1/2 | Surgery | Newly Diagnosed GBM, Recurrent GBM, Anaplastic Astrocytoma, Gliosarcoma | Recruiting |
NCT06556563 | EF-41/KEYNOTE D58: Phase 3 Study of Optune Concomitant With Temozolomide Plus Pembrolizumab in Newly Diagnosed Glioblastoma | 3 | - | Newly Diagnosed GBM | Recruiting |
NCT02658279 | Pembrolizumab (MK-3475) in Patients With Recurrent Malignant Glioma With a Hypermutator Phenotype | 2 | - | Recurrent Malignant Glioma | Active, Not Recruiting |
NCT03576612 | GMCI, Nivolumab, and Radiation Therapy in Treating Patients With Newly Diagnosed High-Grade Gliomas | 1 | AdV-tk (oncolytic virus), valacyclovir (GMCI), SOC | Newly Diagnosed High-Grade Glioma | Completed (results pending) |
NCT03277638 | Laser Interstitial Thermotherapy (LITT) Combined With Checkpoint Inhibitor for Recurrent GBM (RGBM) | 1/2 | Stereotactic biopsy | Recurrent GBM | Recruiting |
NCT06160206 | Retifanlimab With Bevacizumab and Hypofractionated Radiotherapy for the Treatment of Recurrent Glioblastoma | 2 | - | Recurrent GBM | Recruiting |
NCT05465954 | Efineptakin alfa (NT-I7) Plus Pembrolizumab for the Treatment of Recurrent Glioblastoma | 2 | Surgery | Recurrent GBM | Recruiting |
Trial ID | Virus Species | Product/Strain | Additional Treatments | Phase | Tumor Type(s) | Outcomes |
---|---|---|---|---|---|---|
NCT02062827 | HSV | M032 | - | 1 | Recurrent/progressive GBM, AA, gliosarcoma | Tolerable safety. Preliminary median post-treatment survival: 9.38 months; trial ongoing. |
NCT05084430 | HSV | M032 | Pembrolizumab | 1/2 | Recurrent/progressive and newly diagnosed GBM, AA, gliosarcoma | Ongoing |
UMIN000002661 | HSV | G47Δ | - | 1/2 | rGBM | Tolerable safety. mOS: 7.3 months, 1-year survival rate: 38.5%. pFS: 8 days from last administration (due to enlargement of enhancing region). |
UMIN000015995 | HSV | G47Δ | - | 2 | Residual or rGBM | mOS: 20.2 months. 1-year survival rate: 84.2%. |
NCT00751270 | Adenovirus | AdV-tk | Valacylovir, SOC | 1b | nGBM, nAA | Tolerable safety. Median post-therapy survival: 10.9 months |
NCT00589875 | Adenovirus | AdV-TK | Valacyclovir, SOC | 2a | nGBM, nAA, nAO | Median post-treatment survival for GBM patients: 16.7 months |
NCT00870181 | Adenovirus | AdV-TK | Ganciclovir, Mannitol | 2 | rHGG | mOS for GBM patients: 10.4 months |
NCT03072134 | Adenovirus | NSC-CRAd-S-pk7 | SOC | 1 | nGBM, nAA | Tolerable safety. mPFS for all patients: 9.1 months; mOS: 18.4 months. |
NCT05139056 | Adenovirus | NSC-CRAd-S-pk7 | Surgery | 1 | rHGG | Ongoing |
** | Adenovirus | DNX-2401 | - | 1 | rGBM | Tolerable safety. 4 patients with radiographic response, 1 with complete regression. |
** | Adenovirus | DNX-2401 | TMZ | 1 | rGBM (1st recurrence) | Tolerable safety. mPFS: 51 days; mOS: 282 days. |
NCT02197169 | Adenovirus | DNX-2401 | Interferon gamma | 1b | rGBM | Addition of interferon not well-tolerated, not associated with survival benefit. DNX-2401 well-tolerated as monotherapy. |
NCT02798406 | Adenovirus | DNX-2401 | Pembrolizumab | 1/2 | rGBM | Tolerable safety. Primary efficacy endpoint not met (ORR 10.4%, vs. prespecified endpoint of 5%. Secondary endpoint of OS-12: 52.7%, vs. prespecified control rate of 20%. Durable response n = 3 (alive at 45, 38, and 60 months). |
T03896568 | Adenovirus | DNX-2401 | - | 1 | rHGG | Ongoing. |
NCT00528684 | Reovirus | Reolysin | - | 1 | rGBM, rAA | Tolerable safety. mOS: 140 days. Note that IDH mutation status was not published within original 2014 data. |
CTIS#: 2016-001632-35 | Reovirus | Pelareorep | GM-CSF, SOC | 1 | nGBM | Tolerable safety. mOS: 13.1 months; 12.6 months in the lower dose group, 16.1 months in the higher dose group. |
EudraCT: 2011-005635-10 | Reovirus | Orthoreovirus | - | 1b | rHGGs, brain metastases | Tolerable safety. Median post-treatment survival: 469 days (range 118 to 1079 days) |
NCT01156584 | Murine Leukemia Virus | Toca 511 | 5-FC | 1 | rHGG | Tolerable safety. |
NCT01470794 | Murine Leukemia Virus | Toca 511 | FC | 1 | rHGG | Tolerable safety. mOS 11.9 months. |
NCT02414165 | Murine Leukemia Virus | Toca 511 | FC | 2/3 | rGBM, rAA | mOS: 11.1 months for the study arm vs. 12.2 months for the standard of care arm. Study terminated for futility. |
NCT01491893 | Poliovirus/Rhinovirus | PVSRIPO | - | 1 | rGBM | Tolerable safety. mOS: 12.5 months, vs. 11.3 months in the historical control group |
NCT02986178 | Poliovirus/Rhinovirus | PVSRIPO | - | 2 | Recurrent Grade 4 glioma | Completed early 2024, data unavailable. |
NCT04479241 | Poliovirus/Rhinovirus | PVSRIPO | Pembrolizumab | 2 | rGBM | Completed early 2024, data unavailable. |
NCT00390299 | Measles | MV-CEA | - | 1 | rGBM | Tolerable safety. mOS: 11.6 months. 1 year survival: 45.5% |
Trial ID | Vaccine Class | Product | Additional Treatments | Phase | Tumor Type(s) | Outcomes |
---|---|---|---|---|---|---|
NCT00045968 | DC | DCVax-L | SOC (for nGBM) | 3 | nGBM, rGBM | Newly diagnosed GBM: mOS 19.3 months DCVax-L vs. 16.5 months for external controls; Recurrent GBM: mOS 13.2 months DCVax-L vs. 7.8 months external controls |
NCT01957956 | DC | Optimized DC vaccine | SOC | 1 | nGBM | Tolerable safety. mPFS: 9.7 months; mOS: 19 months |
** | Peptide: EGFRvIII | Rindopepimut | SOC, with standard or dose-intensified adjuvant TMZ. | 2 | nGBM | Tolerable safety. mPFS: 15.2 months; mOS: 23.6 months |
NCT01480479 | Peptide: EGFRvIII | Rindopepimut | SOC | 3 | nGBM | mOS: 20.1 months rindopepimut, vs. 20.0 months control. Study terminated for futility. |
NCT02455557 | Peptide: Survivin | SurVaxM | SOC | 2a | nGBM | mPFS: 11.4; mOS: 25.9 months |
NCT05163080 | Peptide: Survivin | SurVaxM | SOC | 2b | nGBM | Ongoing. |
NCT00639639 | Peptide: CMV pp65 | CMV-ALT, CMV-DC | SOC +/− GM-CSF | 1 | nGBM | mPFS: 25.3 months; mOS: 41.1 months |
ACTRN126150-00656538 | Peptide: CMV pp65 | CMV-specific ACT | SOC | 1 | nGBM | Tolerable safety. mOS: 23 months for treated patients, vs. 14 months for patients who progressed prior to ACT treatment |
NCT03299309 | Peptide: CMV pp65 | PEP-CMV | - | 1 | rHGG, rMB (children/young adults) | Tolerable safety. mPFS: 2.5 months; mOS: 6.4 months |
NCT01920191 | Peptide: multipeptide | IMA950 | poly-ICLC | 1/2 | nGBM | Tolerable safety. mOS: 19 months |
NCT03665545 | Peptide: multipeptide | IMA950 | poly-ICLC, Pembrolizumab | 1/2 | rGBM | Updated data and trial status not available. |
NCT04116658 | Peptide: multipeptide | EO2401 | +/− nivolumab; +/− nivolumab + bevacizumab | 1/2 | rGBM | Tolerable safety. EO2401 + nivolumab: mPFS 1.8 months; EO2401 + bevacizumab: mPFS 5.5 months |
NCT02149225 | Personalized peptide | APVAC1, APVAC2 | SOC | 1 | nGBM | Tolerable safety. mPFS: 14.2 months, mOS: 29 months |
NCT02287428 | Personalized peptide | PSLP | RT, pembrolizumab | 1 | nGBM | Ongoing. |
UMIN1426 | Personalized Peptide | AFTV | SOC | 2b | nGBM | mOS: 25.6 months for AFTV vs. 31.5 months for placebo; mpFS 13.3 months in both groups. Total tumor removal: 3-year OS: 80% for AFTV vs. 54% placebo; 3-year PFS 81% for AFTV vs. 46% placebo. |
jRCT2031200153 | Personalized Peptide | AFTV | SOC including GTR | 3 | nGBM | Ongoing. |
NCT02718443 | Nucleic acid | VXM01 | +/− surgery; +/− nivolumab | 1 | rGBM | Tolerable safety. 12-mOS: 7/12 patients (58.3%) |
NCT03750071 | Nucleic acid | VXM01 | Avelumab | 1/2 | rGBM | Tolerable safety. ORR 12% |
NCT00905060 | HSP | HSPPC-96 | SOC | 2 | nGBM | Tolerable safety. mOS: 23.8 months |
NCT00293423 | HSP | HSPPC-96 | GTR | 2 | rGBM | Tolerable safety. mOS: 42.6 weeks |
Trial ID | CAR-T Target | Phase | Tumor Type(s) | Outcomes/Observational Data |
---|---|---|---|---|
NCT02208362 | IL-13Rα2 | 1 | rHGG | Tolerable safety. rGBM: Dual delivery (intra-tumoral/intraventricular) route: mOS 10.2 months, vs. 7.7 months for all patients with recurrent GBM |
NCT02209376 | EGFRvIII | 1 | rGBM | Tolerable safety. mOS: 251 days. |
NCT05660369 | EGFRvIII, wild-type EGFR | 1 | nGBM, rGBM | Tolerable safety. Transient radiographic improvement in 2 patients (n = 3). |
NCT05168423 | EGFR, IL-13Rα2 | 1 | rGBM | Early-onset neurotoxicity was observed but manageable. 1 patient in DL2 developed DLT. None met criteria for ORR. |
NCT04196413 | GD2 | 1 | H3K27 mutant tumors (DIPG, sDPG) | Tolerable safety. Major volumetric reduction (>50%, n = 4/9), CR for >30 months (n = 1), neurological benefit (9/9). |
Trial ID | Cytokine | Additional Treatments | Phase | Tumor Type(s) | Outcomes |
---|---|---|---|---|---|
NCT01765088 | IFN-α | SOC | 3 | nHGG | mOS: 26.7 months for adjuvant TMZ + IFN-α, vs. 18.8 months for SOC with adjuvant TMZ alone |
** | IFN-α | RT + carmustine | 3 | nHGG | No significant difference in survival or response rates. |
NCT04443010 | TNF (L19TNF) | SOC | 1 | nGBM | Ongoing. |
NCT04573192 | TNF (L19TNF) | Lomustine | 1/2 | rGBM | Ongoing. |
NCT03687957 | IL-7 (NT-I7) | SOC | 1 | nHGG | Tolerable safety. |
NCT05465954 | IL-7 (NT-I7) | Surgery + pembrolizumab | 2 | rGBM | Ongoing. |
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© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Karbhari, N.; Frechette, K.M.; Burns, T.C.; Parney, I.F.; Campian, J.L.; Breen, W.G.; Sener, U.T.; Lehrer, E.J. Immunotherapy for High-Grade Gliomas. Cancers 2025, 17, 1849. https://doi.org/10.3390/cancers17111849
Karbhari N, Frechette KM, Burns TC, Parney IF, Campian JL, Breen WG, Sener UT, Lehrer EJ. Immunotherapy for High-Grade Gliomas. Cancers. 2025; 17(11):1849. https://doi.org/10.3390/cancers17111849
Chicago/Turabian StyleKarbhari, Nishika, Kelsey M. Frechette, Terry C. Burns, Ian F. Parney, Jian L. Campian, William G. Breen, Ugur T. Sener, and Eric J. Lehrer. 2025. "Immunotherapy for High-Grade Gliomas" Cancers 17, no. 11: 1849. https://doi.org/10.3390/cancers17111849
APA StyleKarbhari, N., Frechette, K. M., Burns, T. C., Parney, I. F., Campian, J. L., Breen, W. G., Sener, U. T., & Lehrer, E. J. (2025). Immunotherapy for High-Grade Gliomas. Cancers, 17(11), 1849. https://doi.org/10.3390/cancers17111849