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| REVIEW |
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| Year : 2023 | Volume
: 6
| Issue : 1 | Page : 3-8 |
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Current status of clinical application of immunotherapy in the treatment of glioma: A narrative review
Qiuzi Chen1, Peng Ren1, Guohao Huang1, Zuoxin Zhang1, Jean-Philippe Hugnot2, Shengqing Lv1
1 Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
2 INSERM U 1191 – CNRS UMR 5203, University of Montpellier, Montpellier, France
| Date of Submission | 30-Jan-2023 |
| Date of Decision | 14-Mar-2023 |
| Date of Acceptance | 15-Mar-2023 |
| Date of Web Publication | 30-Mar-2023 |
Correspondence Address:
Prof. Jean-Philippe Hugnot
INSERM U 1191 – CNRS UMR 5203, Université de Montpellier, Montpellier 34094
France
Prof. Shengqing Lv
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), No. 183 Xinqiao Street, Shapingba District, Chongqing 400037
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/glioma.glioma_2_23
Glioma is a common type of brain tumor. Current treatment for glioma includes surgical resection, radiotherapy, chemotherapy, and tumor-treating fields. The application of immunotherapy to treat glioma is still far from satisfactory in the clinic. Here, we review the mechanisms of immunotherapy for glioma (including immune checkpoint inhibitor, chimeric antigen receptor-T-cell, tumor vaccine, and oncolytic virus) and the results of completed clinical trials, and will discuss the current status of immunotherapy and possible future directions.
Keywords: Chimeric antigen receptor-T-cell, glioma, immune checkpoint inhibitor, oncolytic virus, tumor vaccine
How to cite this article:
Chen Q, Ren P, Huang G, Zhang Z, Hugnot JP, Lv S. Current status of clinical application of immunotherapy in the treatment of glioma: A narrative review. Glioma 2023;6:3-8 |
How to cite this URL:
Chen Q, Ren P, Huang G, Zhang Z, Hugnot JP, Lv S. Current status of clinical application of immunotherapy in the treatment of glioma: A narrative review. Glioma [serial online] 2023 [cited 2023 Oct 2];6:3-8. Available from: http://www.jglioma.com/text.asp?2023/6/1/3/372822 |
| Introduction | |  |
Glioma is the most common adult primary malignant brain tumor. Representing 6% of primary central nervous system tumors in adults, low-grade glioma typically has a more promising prognosis. GBMs have the worst prognosis and are most likely to cause death among all solid malignancies, with a median survival time of <2 years.[1] Magnetic resonance imaging (MRI) is the main and most accurate means to diagnose GBM, but the lack of obvious signs in the early stage often leads to the irreversibility of the disease when the patient is diagnosed. According to the 5th edition of the WHO Classification of Neoplasms of the Central Nervous System (WHO CNS5) – the first of these editions – there may be significant differences in the treatment criteria and prognosis of gliomas. Circumscribed gliomas are recommended for early excision and adjuvant chemotherapy if necessary, and the prognosis is usually good.[2] Diffuse gliomas and other high-grade gliomas are highly refractory depending on their molecular subtype and require chemotherapy.[2] However, in the case of GBM, feasible postexcisional radiotherapy plus temozolomide chemotherapy defines the current standard of care.[2]
The traditional view of the CNS as an “immune privileged” environment has been denied. In the intracranial immune system, immune cells and lymphatic drainage play an important role.[3] The flow of cerebrospinal fluid into the nasal and cervical lymph nodes of the body makes the intracranial immune system not isolated. Infiltrating immune cells in glioma consist mainly of macrophages, followed by lymphocytes, especially CD4+ and CD8+ T-lymphocytes. Notably, microglia and resident macrophages outnumber infiltrating T-cells in glioma, and the lack of T-cells in the tumor microenvironment contrasts with observations in other types of tumors such as melanoma or lung cancer.[4]
A complex series of mechanisms have evolved in the human immune system to inspect and eradicate cancer cells. The immune system tries to kill tumor cells by presenting tumor antigen to T-cells, activating T-cells, and playing an antitumor function.[5] These CD8+ cytotoxic T-lymphocytes migrate to tumor and infiltrate there, to recognize cancer cells, and to trigger tumor cell death. Then, the cancer cells recognized by T-cells release tumor-associated antigens and enhance the immune response cycle. During the cycle, signal regulation is carried out between immune cells and between immune cells and tumor cells through various ligand–receptor bindings. In these signals, the immune checkpoint signal controls the stimulation or inhibition of T-cells. However, tumor cells have the capacity for immune escape. Tumor immunotherapy is a treatment targeted to activate the body's own immune response to overcome the immune evasion of tumor cells.[6] Antibodies that block programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4 have been shown to have activity in many types of solid tumors and are now the standard treatment for advanced melanoma, non-small cell lung cancer, and more other malignant tumors.[7] In the case of melanoma, the presence and density of tumor-infiltrating lymphocytes affect the outcome of treatment and patient prognosis.[8] Special composition of immune cells in gliomas may be an obstacle to immunotherapy.[9] While over the past decade or so of relentless research and exploration into the treatment of glioma, numerous treatments have been proposed, since 2005, only three new therapies have been approved by the Food and Drug Administration for GBM: temozolomide, bevacizumab, and tumor-treating fields.[10] The application of immunotherapy for glioma treatment has not been fully recognized. Until now, immunotherapy has shown promise, but many challenges and obstacles remain in glioma.[11]
In this review, we provided an introduction of the latest researches and clinical trials on immunotherapy for glioma treatment including immune checkpoint inhibitor, chimeric antigen receptor (CAR)-T-cell, tumor vaccine, and oncolytic virus and to discuss the limitation and the prospect of the future directions of immunotherapy applied to treat glioma, aiming at providing a comprehensive summary of clinical trials according to the currently available literature for better application of immunotherapy for glioma treatment.
| Retrieval Strategy | | |
Literature for this review was searched and obtained from the PubMed database. We searched literature using the following keywords: glioma, immune checkpoint inhibitor, CAR-T-cells, tumor vaccines, and oncolytic virus. Literature covered in this review (80% of all references) was published from 2016 to 2022. A publication of 1999 was included in consideration of its significance and relevance in the application of virus for glioma treatment.
| Immune Checkpoint Inhibitor | | |
T-cell activation and response requires the major histocompatibility complex to present antigens to T-cells, and then checkpoint molecules determine whether T-cells are stimulated or inhibited. The following checkpoint molecules have been recognized as stimulatory or inhibitory: CD28, CD80, CD86, CD40 L, CD137, TNFRSF4 (also known as OX40), and CD58 promote immune activation, while cytotoxic T-lymphocyte-associated protein 4, PD1, lymphocyte activation gene 3, T-cell Ig and ITIM domains (TIGIT, also known as WUCAM, Vstm3, or VSIG9), and T-cell immunoglobulin and mucin domain-3 (TIM-3; also known as hepatitis A virus cellular receptor 2) suppress immune activation.[12] In melanoma and other types of solid tumor models, immune checkpoints have been found to be used by tumor cells to evade immune detection. Immune checkpoint inhibitor therapy has been applied for treatment of other solid tumors in the clinic. However, the exact function of most of these checkpoint molecules has not been demonstrated in glioma models.[13]
Clinical trials of immune checkpoint inhibitors in glioma have focused attention on pembrolizumab, nivolumab, and ipilimumab. A phase III clinical trial compared the efficacy, toxicity, and safety of treatment with bevacizumab and nivolumab (NCT02017717).[14] Nivolumab is a fully human immunoglobulin G4 monoclonal antibody targeting the programmed cell death protein 1 immune checkpoint receptor. Overall survival (OS) was comparable between the bevacizumab and nivolumab groups. The progression-free survival and objective response rate were better in the bevacizumab group based on the data. Durations of response were longer in the nivolumab group based on the data. Toxic effects were not different from the known safety profiles of nivolumab and bevacizumab. It suggests the possibility of immune checkpoint inhibitors for the treatment of glioma. In a phase I clinical trial, investigators used pembrolizumab (NCT02054806) to treat patients.[15] Pembrolizumab is a fully human monoclonal antibody targeting programmed cell death protein 1 immune checkpoint receptor. Pembrolizumab demonstrated sustained antitumor activity, but the effect of pembrolizumab could not be linked to receptor expression levels. In a phase I clinical trial (NCT02017717), investigators compared the efficacy and safety of the combination of ipilimumab and nivolumab.[16] Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 immune checkpoint receptor. Ipilimumab affects patient tolerance and has no positive indicators combined with nivolumab.[16] Overall, pembrolizumab, nivolumab, and ipilimumab demonstrated differences in survival, intensity, and duration of antitumor effects in clinical studies, but their therapeutic effects did not achieve expectations.
Immune checkpoint inhibitor therapy is less effective in treating glioma, so it is considered in combination with other treatments. The investigators treated recurrent GBM patients by hypofractionated stereotactic irradiation and pembrolizumab in a phase I clinical trial (NCT02313272).[17] Patients on triple therapy with hypofractionated stereotactic irradiation, pembrolizumab, and bevacizumab had improved survival (progression-free survival and OS) and did not exhibit significant toxic effects. It is worth exploring a combination of immune checkpoint inhibitor therapy with other therapies.
| Chimeric Antigen Receptor-T-cell | | |
CARs are engineered fusion proteins. Following transfection of a CAR construct into autologous or allogeneic T-cells in peripheral blood using plasmid transfection, siRNA, or viral vector transduction, the T-cells are infused into the patient's body, targeting any tumor antigen exposed on surface and identified by the CAR's extracellular targeting moiety.[10] Primary T-cell activation occurs upon binding of CAR to its associated antigen, leading to cytokine release, cytolytic degranulation, and T-cell proliferation. In addition, T-cell effector mechanisms and memory responses also occur in a costimulatory-dependent manner.[18] Therefore, CAR-T-cells continue to produce immune response after binding with corresponding tumor-related antigen. In addition, one of the advantages of CAR-T-cell therapy is to play an antitumor role independently of the autoimmune system. Human epidermal growth factor receptor 2, epidermal growth factor receptor variant III (EGFRvIII), and interleukin-13 receptor alpha 2 (IL-13 Rα2), as the major candidates for the study of tumor-associated antigen targets of CAR-T-cells in glioma, they have been found that can be expressed by glioma stem cells.[10]
A clinical trial (NCT02209376) proved the safety of CART-EGFRvIII product for glioma treatment first. The researcher redirected single-dose autologous T-cells to EGFRvIII mutation through CAR and injected the patients with indications intravenously.[19] One patient required no further treatment for over 18 months following CART infusion. They found no marked tumor regression on MRI in any patient. However, the definitive conclusion about the clinical benefit and potential of CART EGFRvIII products will require larger cohorts.[19] A phase I clinical trial (NCT00730613) utilized a CAR construct, using autologous primary human CD8+ cytolytic T-lymphocytes targeting IL13Rα2 for the treatment of GBM.[20] The investigators demonstrated the safety of repeated intracranial administration clones of the IL13-zetakine+ CD8+ cytolytic T-lymphocyte lineage, and under continuous observation, some patients were found to have no adverse events and to have transient antitumor function.[21] CAR-T-cell therapy is faced with the problem of CAR-T-cell delivery to a designated site. Although no single strategy can allow CAR-T-cells to reach the tumor and enhance their antitumor function once there, a combination of individually targeted delivery combined with checkpoint molecular knockdown and cytokine stimulation should enable multi-stimulated and activated T-cells to persist and generate robust immune responses in a patient's body.[22]
| Tumor Antigen Vaccine | | |
During tumor tumorigenesis, mutations caused by genetic instability typically arise in both noncoding and coding regions of the genome, where changes in DNA of the coding region include nonsynonymous mutations or single-nucleotide variants, mutational frameshifts, gene fusions, posttranslational modifications that alter the amino acid sequence, and intron retention.[23] The changes in amino acid sequence caused by these changes in DNA can result in short peptides that are not found in normal cells, and these short peptides are referred to as neoantigens. Some of these short peptides are transported to the endoplasmic reticulum and loaded on the major histocompatibility complex-I. The major histocompatibility complex-I which is loaded with peptides enters the cell membrane through the Golgi apparatus, thereby inducing antigen presentation and recognition by receptors on CD8+ T-cells and cytotoxic T-cells are activated and exert tumor-killing effects.
Tumor-associated antigen (TAA) is a protein expressed by unmutated genes that are significantly highly expressed in tumor cells but rarely expressed in normal cells.[24] Immune cells recognize these overexpressed proteins and activate the immune system response, thereby acting to kill tumor cells. However, targeting TAA can also lead to autoimmune toxicity since TAA is a normal host protein and is subject to immune tolerance. In contrast, neoantigens are only expressed in tumor cells but not in normal cells, including antigens produced by genome-integrated tumor viruses and antigens produced by mutant proteins. It is highly immunogenic and heterogeneous and is unaffected by central tolerance.[25] Moreover, targeting neoantigens is less likely to result in autoimmunity. Therefore, neoantigens are the preferred targets for tumor vaccines. Based on the epigenetic characteristics and immunogenicity of neoantigens, medications can be designed and synthesized to activate the immune system based on the mutation of the tumor cells, which results in antitumor effects.[26]
One of the most anticipated tumor vaccines is rindopepimut, formerly known as CDX-110, which targets EGFRvIII. The vaccine was investigated in a number of clinical trials. In a phase 3 ACT IV trial (NCT01480479), the investigators treated patients with EGFRvIII-positive GBM with rindopepimut in combination with radiotherapy and temozolomide, compared with radiotherapy and temozolomide alone. The result was negative. Rindopepimut did not improve survival.[27] Furthermore, the rindopepimut group did not show significant differences from the control group in terms of progression-free survival, tumor response, or quality of life measurements. Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma.[28] A phase I clinical trial (NCT02454634) investigated the efficacy and the safety of the IDH1 R132H mutant peptide vaccine (NOA-16) in IDH1-mutated high-grade gliomas, which has been shown to lead to T-cell activation and humoral immune response.[29] Whether glioma development is associated with cytomegalovirus (CMV) infection is controversial, but CMV antigen is found overexpressed in glioma. The vaccine is based on CMV and targets pp6537, which is a major CMV structural protein. The safety of CMV pp6537 has been demonstrated. In a sequential clinical trial (NCT00639639) using CMV pp65 DC vaccines in newly diagnosed GBM patients consistently proved an improved OS.[30]
Given the potential for antigen evasion using a single-peptide vaccine, the most recent type of peptide vaccines was designed to have function synergistically with multiple tumor antigens. A phase II clinical trial showed that administration of the ICT-107 vaccine consisting of 6 TAAs (MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2) pulsed in DC resulted in a notable improvement in the progression-free survival of GBM patients.[31]
| Oncolytic Viruses | | |
Colombo et al.[32] completed a clinical trial using retroviruses as vectors for glioma in 1998. Despite the low efficiency of viral transduction and limited therapeutic scope, the team concluded that viral-based gene therapy technology could be used in early, well-defined cases of GBM recurrence. Viruses have been used in the treatment of gliomas for at least 20 years. However, immunotherapy with oncolytic viruses has been widely used in glioma clinical trials over the past 5 years.
Oncolytic viruses are artificially genetically engineered to specifically replicate in tumor cells and lyse tumor cells without harming normal cells. The goal of oncolytic virus immunotherapy is to transform the virus from a covert pathogen into a finely tuned therapeutic vector that can facilitate direct or indirect viral attack on cancer cells.[33] Oncolytic viruses have antitumor activity by especially replicating in and lysing tumor cell and the lysis products are immunogenic and trigger an immune response.
Lang et al.[34] conducted a phase I clinical trial using DNX-2401 (Delta-24-RGD; tasadenoturev) for the treatment of glioma. By modifying the E1A gene, the virus is only able to replicate in tumor cells with a malfunctioning Rb pathway. Eighteen of the 25 enrolled patients had a reduction in tumor size with a median OS time of 9.5 months, independent of dose. Remarkably, five patients survived more than 3 years, three of whom had a 95% reduction in an enhancing tumor cross-sectional area. There was no obvious sign of infection. The investigators concluded that DNX-2401 directly induces tumor oncolysis, then an antitumor immune response, and that tumor infection induced a decline in the expression level of TIM-3.[34] TIM-3 is an important checkpoint molecule that inhibits T-cell. Fares et al.[35] conducted a phase I clinical trial (NCT03072134) using NSC-CRAd-S-pk7, a modified oncolytic adenovirus that is delivered by neural stem cells. This is the first-in-human trial to test the delivery of an engineered oncolytic adenovirus to neural stem cells. Trial results demonstrated correlative antitumor activity. One of 12 patients had a partial response to therapy and 10 of 12 patients had stable disease.
In a phase I clinical trial, G207 was used for the treatment of recurrent GBM, which is a type 1 herpes simplex virus mutant.[36] G207 contains deletions in the two loci of the viral gene γ134.5 gene, in addition to a disabling lacZ insertion in UL39. A phase I clinical trial used modified reovirus to treat glioma.[37] Ten patients had stable disease, one had a partial response, and four had progressive disease. Another phase I clinical trial used ONYX-015 for the treatment of glioma.[38] ONYX-015 is an adenovirus mutant. There are evidence that ONYX-015 replicates specifically more efficiently in cells with abnormal p53 pathway. Twenty patients have died as a result of tumor progression, one died of nontumor-related events (ruptured intestine), and three are still alive. A phase I/II clinical trial used NDV-HUJ, the oncolytic HUJ strain of Newcastle disease virus for the treatment of glioma.[39] One of 12 patients improved at trial progression. A clinical trial (UMIN000015995) was run with G47Δ, third-generation oncolytic herpes simplex virus type 1, in 19 adult patients with residual or recurrent, supratentorial GBM after radiation therapy and temozolomide.[40],[41] Within 2 years, 1 patient with adverse reactions and 18 patients without disease progression.
Importantly, the virus is immunogenic. In clinical trials, researchers need to regularly test the concentration of viral antigens and antibodies in a patient's peripheral blood to avoid causing adverse reactions. Different types of viruses were used in oncolytic therapy, but in terms of results, the most common adverse event was fever followed by vomiting, nausea, lymphocytopenia, and leukopenia.
| Limitation | | |
This manuscript has some limitations. It reviews and summarizes the recent progression of immunotherapy for glioma treatment. However, it only discusses the completed clinical trials of immune checkpoint inhibitors, CAR-T-cells, tumor vaccines, and oncolytic virus and it does not summarize the status and progression of the processing clinical trials.
| Conclusion and Future Perspective | | |
Immunotherapy has been applied to solid tumors with great effectiveness, but due to the high heterogeneity of gliomas and the specificity of the immune environment, immunotherapy has not demonstrated significant effects and is difficult to apply in glioma. The solutions are to overcome the immune escape of tumors from the root or by combining multiple therapies to overcome resistance. Understanding the immune response and escape mechanism of glioma and finding specific immunotherapy targets help to find the way to overcome the immune escape of tumors. At present, some researches have explained the immune escape mechanism and drug resistance mechanism of glioma: avoiding the activation of the immune system through the specific screening of escape immune cells; inhibiting immune system activity through checkpoint molecules; having the ability to avoid being cleared when the immune system is activated.[42] Clinical attempts have been made to overcome glioma drug resistance by combining immunotherapy multidrug combinations or with radiotherapy. With the attempts and explorations, clinical trials have shown good results.
Acknowledgments
Nil.
Financial support and sponsorship
This work was supported by the grant (No. 81972360) from the National Nature Science Foundation of China and grant (No. CQYC20200303149) from Chongqing Talents Project.
Conflicts of interest
There are no conflicts of interest.
Editor note: SL is an Editorial Board member of Glioma. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.
| References | | |
| 1. | Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011-2015. Neuro Oncol 2018;20 Suppl 4:iv1-86.  |
| 2. | Horbinski C, Berger T, Packer RJ, Wen PY. Clinical implications of the 2021 edition of the WHO classification of central nervous system tumours. Nat Rev Neurol 2022;18:515-29. |
| 3. | Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature 2015;523:337-41. |
| 4. | Dunn GP, Dunn IF, Curry WT. Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human glioma. Cancer Immun 2007;7:12. |
| 5. | Sampson JH, Gunn MD, Fecci PE, Ashley DM. Brain immunology and immunotherapy in brain tumours. Nat Rev Cancer 2020;20:12-25. |
| 6. | Finn OJ. The dawn of vaccines for cancer prevention. Nat Rev Immunol 2018;18:183-94. |
| 7. | Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet 2021;398:1002-14. |
| 8. | Kalaora S, Nagler A, Wargo JA, Samuels Y. Mechanisms of immune activation and regulation: Lessons from melanoma. Nat Rev Cancer 2022;22:195-207. |
| 9. | Klemm F, Maas RR, Bowman RL, Kornete M, Soukup K, Nassiri S, et al. Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 2020;181:1643-60.e17. |
| 10. | Bagley SJ, Desai AS, Linette GP, June CH, O'Rourke DM. CAR T-cell therapy for glioblastoma: Recent clinical advances and future challenges. Neuro Oncol 2018;20:1429-38. |
| 11. | Chen ZP. Perspective on the current treatment strategies for glioma. Glioma 2021;4:2-4. [Full text] |
| 12. | Jiang H, Ni H, Zhang P, Guo X, Wu M, Shen H, et al. PD-L1/LAG-3 bispecific antibody enhances tumor-specific immunity. Oncoimmunology 2021;10:1943180. |
| 13. | Ott M, Prins RM, Heimberger AB. The immune landscape of common CNS malignancies: Implications for immunotherapy. Nat Rev Clin Oncol 2021;18:729-44. |
| 14. | Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, et al. Effect of Nivolumab vs. Bevacizumab in patients with recurrent glioblastoma: The CheckMate 143 Phase 3 Randomized Clinical Trial. JAMA Oncol 2020;6:1003-10. |
| 15. | Reardon DA, Kim TM, Frenel JS, Simonelli M, Lopez J, Subramaniam DS, et al. Treatment with pembrolizumab in programmed death ligand 1-positive recurrent glioblastoma: Results from the multicohort phase 1 KEYNOTE-028 trial. Cancer 2021;127:1620-9. |
| 16. | Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro Oncol 2018;20:674-86. |
| 17. | Sahebjam S, Forsyth PA, Tran ND, Arrington JA, Macaulay R, Etame AB, et al. Hypofractionated stereotactic re-irradiation with pembrolizumab and bevacizumab in patients with recurrent high-grade gliomas: Results from a phase I study. Neuro Oncol 2021;23:677-86. |
| 18. | Wang C, Yu M, Zhang W. Neoantigen discovery and applications in glioblastoma: An immunotherapy perspective. Cancer Lett 2022;550:215945. |
| 19. | O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJ, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med 2017;9:eaaa0984. |
| 20. | Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+T cells in patients with recurrent glioblastoma. Clin Cancer Res 2015;21:4062-72. |
| 21. | Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med 2016;375:2561-9. |
| 22. | Joseph SK, Ahmed NM, Hegde M. Chimeric antigen receptor T-cells for glioblastoma: The journey ahead. Glioma 2019;2:88-95. [Full text] |
| 23. | Davalos V, Esteller M. Cancer epigenetics in clinical practice. CA Cancer J Clin 2022. doi: 10.3322/caac.21765. |
| 24. | Zamora AE, Crawford JC, Thomas PG. Hitting the target: How T cells detect and eliminate tumors. J Immunol 2018;200:392-9. |
| 25. | Nagasaki J, Togashi Y, Sugawara T, Itami M, Yamauchi N, Yuda J, et al. The critical role of CD4+T cells in PD-1 blockade against MHC-II-expressing tumors such as classic Hodgkin lymphoma. Blood Adv 2020;4:4069-82. |
| 26. | Li L, Zhou J, Dong X, Liao Q, Zhou D, Zhou Y. Dendritic cell vaccines for glioblastoma fail to complete clinical translation: Bottlenecks and potential countermeasures. Int Immunopharmacol 2022;109:108929. |
| 27. | Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): A randomised, double-blind, international phase 3 trial. Lancet Oncol 2017;18:1373-85. |
| 28. | Waitkus MS, Diplas BH, Yan H. Biological role and therapeutic potential of IDH mutations in cancer. Cancer Cell 2018;34:186-95. |
| 29. | Platten M, Bunse L, Wick A, Bunse T, Le Cornet L, Harting I, et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature 2021;592:463-8. |
| 30. | Batich KA, Mitchell DA, Healy P, Herndon JE 2 nd, Sampson JH. Once, twice, three times a finding: Reproducibility of dendritic cell vaccine trials targeting cytomegalovirus in glioblastoma. Clin Cancer Res 2020;26:5297-303. |
| 31. | Wen PY, Reardon DA, Armstrong TS, Phuphanich S, Aiken RD, Landolfi JC, et al. A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma. Clin Cancer Res 2019;25:5799-807. |
| 32. | Palù G, Cavaggioni A, Calvi P, Franchin E, Pizzato M, Boschetto R, et al. Gene therapy of glioblastoma multiforme via combined expression of suicide and cytokine genes: A pilot study in humans. Gene Ther 1999;6:330-7. |
| 33. | Zhu Z, McGray AJ, Jiang W, Lu B, Kalinski P, Guo ZS. Improving cancer immunotherapy by rationally combining oncolytic virus with modulators targeting key signaling pathways. Mol Cancer 2022;21:196. |
| 34. | Lang FF, Conrad C, Gomez-Manzano C, Yung WK, Sawaya R, Weinberg JS, et al. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: Replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol 2018;36:1419-27. |
| 35. | Fares J, Ahmed AU, Ulasov IV, Sonabend AM, Miska J, Lee-Chang C, et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: A first-in-human, phase 1, dose-escalation trial. Lancet Oncol 2021;22:1103-14. |
| 36. | Markert JM, Razdan SN, Kuo HC, Cantor A, Knoll A, Karrasch M, et al. A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther 2014;22:1048-55. |
| 37. | Kicielinski KP, Chiocca EA, Yu JS, Gill GM, Coffey M, Markert JM. Phase 1 clinical trial of intratumoral reovirus infusion for the treatment of recurrent malignant gliomas in adults. Mol Ther 2014;22:1056-62. |
| 38. | Chiocca EA, Abbed KM, Tatter S, Louis DN, Hochberg FH, Barker F, et al. A phase I open-label, dose-escalation, multi-institutional trial of injection with an E1B-Attenuated adenovirus, ONYX-015, into the peritumoral region of recurrent malignant gliomas, in the adjuvant setting. Mol Ther 2004;10:958-66. |
| 39. | Freeman AI, Zakay-Rones Z, Gomori JM, Linetsky E, Rasooly L, Greenbaum E, et al. Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 2006;13:221-8. |
| 40. | Todo T, Ino Y, Ohtsu H, Shibahara J, Tanaka M. A phase I/II study of triple-mutated oncolytic herpes virus G47 Δ in patients with progressive glioblastoma. Nat Commun 2022;13:4119. |
| 41. | Todo T, Ito H, Ino Y, Ohtsu H, Ota Y, Shibahara J, et al. Intratumoral oncolytic herpes virus G47 Δ for residual or recurrent glioblastoma: A phase 2 trial. Nat Med 2022;28:1630-9. |
| 42. | Jackson CM, Choi J, Lim M. Mechanisms of immunotherapy resistance: Lessons from glioblastoma. Nat Immunol 2019;20:1100-9. |
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