====== Glioblastoma immunotherapy ====== {{rss>https://pubmed.ncbi.nlm.nih.gov/rss/search/1POHEZD9YUqDw56e0D1a7NwBBrpgsYYg1ctiqFwKSqzMbWK9W1/?limit=15&utm_campaign=pubmed-2&fc=20230531170411}} ---- ---- ====== 💉 Glioblastoma Immunotherapy ====== **Glioblastoma (GBM)** is the most aggressive and lethal form of primary brain tumor in adults. Conventional therapies — surgery, radiation, and chemotherapy — offer limited survival benefit. **Immunotherapy** offers a promising approach by engaging the patient's immune system to recognize and eliminate tumor cells. ===== 🎯 Goals of Immunotherapy ===== * Enhance immune system recognition of tumor-specific antigens * Overcome the immunosuppressive tumor microenvironment * Induce durable, systemic anti-tumor immunity * Cross the blood-brain barrier effectively ===== 🧬 Immunotherapy Strategies in GBM ===== ==== 1. Cancer Vaccines ==== * Aim to trigger T cell responses against glioma-specific antigens * Types: - **Peptide vaccines** (e.g., Rindopepimut – EGFRvIII) - **Dendritic cell vaccines** (e.g., DCVax-L) - **mRNA vaccines** (e.g., NOA-16) - **Neoantigen vaccines** (e.g., personalized vaccines from tumor sequencing) ==== 2. Immune Checkpoint Inhibitors ==== * Block inhibitory pathways like **PD-1/PD-L1** and **CTLA-4** * Goal: prevent T cell exhaustion and restore activity * Limited success as monotherapy; better in **combinatorial regimens** ==== 3. CAR-T Cell Therapy ==== * Engineering patient’s T cells to express **chimeric antigen receptors** * Targets like **EGFRvIII**, **IL13Rα2**, or **HER2** * Early trials show promise, but challenges include antigen loss and immune suppression ==== 4. Oncolytic Virus Therapy ==== * Genetically modified viruses that selectively infect and kill tumor cells * Also induce an **in situ vaccine effect** by releasing tumor antigens * Example: **DNX-2401 (Delta-24-RGD)** and **G47Δ (Japan)** ==== 5. Adoptive T Cell Therapy and TILs ==== * Transfer of **tumor-infiltrating lymphocytes (TILs)** or modified T cells * Under investigation; may complement vaccines or viral therapy ==== 6. Cytokine and Adjuvant Therapies ==== * Use of **IL-2**, **IFN-γ**, or **poly-ICLC** to boost immune responses * Often used alongside vaccines ===== ❗ Challenges in GBM Immunotherapy ===== * **Immunosuppressive tumor microenvironment** (Tregs, MDSCs, TAMs) * **Blood-brain barrier** limits immune cell access * **Antigen heterogeneity** → tumor cells escape immune recognition * **Low mutational burden** → fewer neoantigens compared to other cancers * **Corticosteroid use** suppresses immune responses during treatment ===== 🔬 Clinical Trials & Key Studies ===== ^ Trial ^ Type ^ Notes ^ | **NOA-16** | Personalized mRNA vaccine | Targeted IDH1 R132H in glioma | | **AMPLIFY-NEOVAC** | Vaccine + checkpoint combo | Builds on NOA-16 | | **DCVax-L** | Dendritic cell vaccine | Phase III showed survival benefit | | **CheckMate-143** | Anti–PD-1 monotherapy | No OS benefit vs bevacizumab | | **G47Δ (Japan)** | Oncolytic herpesvirus | Received conditional approval | ===== 🚀 Future Directions ===== * Personalized **neoantigen vaccines** using mRNA platforms * **Combination therapies** (vaccines + checkpoint inhibitors) * Enhanced **biomarker selection** for patient stratification * **AI-based prediction** of immunogenic epitopes * Local delivery methods (e.g., **intratumoral injection**, hydrogel scaffolds) ===== 🧾 Summary ===== **Immunotherapy for glioblastoma** is a rapidly evolving field. Despite challenges like immune evasion and the brain's unique environment, strategies such as **personalized vaccines**, **CAR-T cells**, and **oncolytic viruses** are advancing through clinical trials and showing potential to improve long-term outcomes. ===== 🔗 Related Pages ===== * [[Glioblastoma]] * [[NOA-16 Trial]] * [[AMPLIFY-NEOVAC Trial]] * [[Personalized mRNA Neoantigen Vaccine]] * [[Cancer Vaccine for Glioma]] * [[Checkpoint Inhibitor]]s * [[CAR-T]] Therapy ---- [[Immunotherapy]] has shown promising success in a variety of [[solid tumor]] types, but efficacy in [[glioblastoma]] is yet to be demonstrated. Barriers to the success of immunotherapy in glioblastoma include a heterogeneous tumor [[cell]] [[population]], a highly immunosuppressive [[microenvironment]], and the [[blood-brain barrier]], to name a few. Several immunotherapeutic approaches are actively being investigated and developed to overcome these limitations ((Zaidi SE, Moelker E, Singh K, Mohan A, Salgado MA, Essibayi MA, Hotchkiss K, Shen S, Lee W, Sampson J, Khasraw M. Novel Immunotherapeutic Approaches for the Treatment of Glioblastoma. BioDrugs. 2023 May 31. doi: 10.1007/s40259-023-00598-2. Epub ahead of print. PMID: 37256535.)) ---- Immunotherapy approaches include the use of [[checkpoint inhibitor]]s, [[chimeric antigen receptor]] (CAR) T-Cell therapy, [[vaccine]]-based approaches, [[viral vector]] therapies, and [[cytokine]]-based treatment ((Sener U, Ruff MW, Campian JL. Immunotherapy in Glioblastoma: Current Approaches and Future Perspectives. Int J Mol Sci. 2022 Jun 24;23(13):7046. doi: 10.3390/ijms23137046. PMID: 35806051; PMCID: PMC9266573.)) ---- Future strategies to ameliorate the efficacy of immunotherapy and facilitate clinical translation will be provided to address the unmet medical needs of GBM ((Bausart M, Préat V, Malfanti A. Immunotherapy for glioblastoma: the promise of combination strategies. J Exp Clin Cancer Res. 2022 Jan 25;41(1):35. doi: 10.1186/s13046-022-02251-2. PMID: 35078492; PMCID: PMC8787896.)). ---- With the success of immunotherapy in other aggressive cancers such as advanced [[melanoma]] and advanced [[non-small cell lung cancer]], glioblastoma has been brought to the forefront of immunotherapy research ((Yu MW, Quail DF. Immunotherapy for Glioblastoma: Current Progress and Challenges. Front Immunol. 2021 May 13;12:676301. doi: 10.3389/fimmu.2021.676301. Erratum in: Front Immunol. 2021 Oct 07;12:782687. PMID: 34054867; PMCID: PMC8158294.)). ---- [[Immunotherapy]], has become a promising strategy with the ability to penetrate the [[blood-brain barrier]] since the pioneering discovery of [[lymphatic]]s in the [[central nervous system]]. ---- The anti-tumoral contribution of [[Gamma delta T cell]]s depends on their activation and differentiation into effectors. This depends on different [[molecule]]s and [[membrane receptor]]s, which conditions their physiology. Belghali et al. aimed to determine the phenotypic characteristics of γδT cells in [[glioblastoma]] (Glioblastoma) according to five layers of membrane receptors. Among ten Glioblastoma cases initially enrolled, five of them who had been confirmed by pathological examination and ten healthy controls underwent phenotyping of peripheral γδT cells by [[flow cytometry]], using the following staining: αβTCR, γδTCR, CD3, CD4, CD8, CD16, CD25, CD27, CD28, CD45, CD45RA, CD56, NKG2D, CD272(BTLA) and CD279(PD-1). Compared to controls, the results showed no significant change in the number of γδT cells. However, they noted a decrease of double-negative (CD4- CD8- ) Tγδ cells and an increase of naive γδT cells, a lack of [[CD25]] expression, a decrease of the expression of [[CD279]], and a remarkable, but not significant increase in the expression of the CD27 and CD28 costimulation markers. Among γδT cell subsets, the number of Vδ2 decreased in Glioblastoma and showed no significant difference in the expression of CD16, CD56, and NKG2D. In contrast, the number of Vδ1 increased in Glioblastoma with overexpression of CD16, CD56, and NKG2D. The results showed that γδT cells are prone to adopt a pro-[[inflammatory]] profile in the Glioblastoma's context, which suggests that they might be a potential tool to consider in [[T cell]]-based [[glioblastoma immunotherapy]]. However, this requires additional investigation on a larger sample size ((Belghali MY, El Moumou L, Hazime R, Brahimi M, El Marrakchi M, Belaid HA, Benali SA, Khouchani M, Ba-M'hamed S, Admou B. Phenotypic characterization of human peripheral γδT-Cell subsets in glioblastoma. Microbiol Immunol. 2022 Jun 19. doi: 10.1111/1348-0421.13016. Epub ahead of print. PMID: 35718749.)). ---- A limited number of phase III trials have been completed for [[checkpoint inhibitor]], [[vaccine]], as well as gene therapies, and have been unable to show improvement in [[survival]] [[outcome]]s. Nevertheless, these [[trial]]s have also shown these strategies to be safe and promising with further adaptations. Further large-scale studies for [[chimeric antigen receptor]]s T cell therapies and viral therapies are anticipated. Many current trials are broadening the number of antigens targeted and modulating the micro[[tumor microenvironment]] to abrogate early mechanisms of resistance. Future Glioblastoma treatment will also likely require synergistic effects by combination regimens ((Zhang M, Choi J, Lim M. Advances in Immunotherapies for Gliomas. Curr Neurol Neurosci Rep. 2022 Feb 2. doi: 10.1007/s11910-022-01176-9. Epub ahead of print. PMID: 35107784.)). ---- As the pioneer and the main effector cells of immunotherapy, [[T cell]]s play a key role in tumor immunotherapy. For glioblastoma, immunotherapy has not been as effective ((Bovenberg MS, Degeling MH, Tannous BA. Cell-based immunotherapy against gliomas: from bench to bedside. Mol Ther. 2013 Jul;21(7):1297-305. doi: 10.1038/mt.2013.80. Epub 2013 May 7. PMID: 23648695; PMCID: PMC3702108.)) , the T cells in Glioblastoma microenvironment are inhibited by the highly immunosuppressive environment of Glioblastoma, ([[cold tumor microenvironment]]) posing huge challenges to T cell-based Glioblastoma immunotherapy ((Wang H, Zhou H, Xu J, Lu Y, Ji X, Yao Y, Chao H, Zhang J, Zhang X, Yao S, Wu Y, Wan J. Different T-cell subsets in glioblastoma multiforme and targeted immunotherapy. Cancer Lett. 2020 Oct 3:S0304-3835(20)30498-5. doi: 10.1016/j.canlet.2020.09.028. Epub ahead of print. PMID: 33022290.)) ((Lim M., Xia Y., Bettegowda C., Weller M. Current state of immunotherapy for glioblastoma. Nat. Rev. Clin. Oncol. 2018;15:422–442. doi: 10.1038/s41571-018-0003-5.)) ((Reardon D.A., Wucherpfennig K., Chiocca E.A. Immunotherapy for glioblastoma: On the sidelines or in the game? Discov. Med. 2017;24:201–208.)). As these tumors do not attract and activate immune cells, approaches based on educating immune cells on killing tumor cells, utilized in “hot” immuno-activating cancers, have not been successful in brain tumor clinical trials. In this context, the use of immune-stimulatory approaches, like therapy with oncolytic viruses (OV), is promising ((Iorgulescu JB, Reardon DA, Chiocca EA, Wu CJ. Immunotherapy for glioblastoma: going viral. Nat Med. 2018 Aug;24(8):1094-1096. doi: 10.1038/s41591-018-0142-3. PMID: 30082860; PMCID: PMC6443579.)) ---- Xu et al. detailed the management of gliomas and previous studies assessing different immunotherapies in gliomas, despite the fact that the associated [[clinical trial]]s have not been completed yet. Moreover, several drugs that have undergone clinical trials are listed as novel strategies for future application; however, these clinical trials have indicated limited efficacy in glioma. Therefore, additional studies are warranted to evaluate novel therapeutic approaches in glioma treatment ((Xu S, Tang L, Li X, Fan F, Liu Z. Immunotherapy for glioma: current management and future application. Cancer Lett. 2020 Feb 7. pii: S0304-3835(20)30056-2. doi: 10.1016/j.canlet.2020.02.002. [Epub ahead of print] PubMed PMID: 32044356. )). ---- Earlier forms of immune-based platforms have now given way to more current approaches, including [[chimeric antigen receptor]] [[T-cell]]s, personalized [[neoantigen]] [[vaccine]]s, oncolytic viruses, and checkpoint blockade ((Fecci PE, Sampson JH. The current state of immunotherapy for gliomas: an eye toward the future. J Neurosurg. 2019 Sep 1;131(3):657-666. doi: 10.3171/2019.5.JNS181762. Review. PubMed PMID: 31473668. )). Critical to mapping a path forward will be the systematic characterization of the [[immunobiology]] of [[glioblastoma]] utilizing currently available, state of the art technologies. Therapeutic approaches aimed at driving effector [[immune cell]]s into the glioblastoma microenvironment as well as overcoming immunosuppressive [[myeloid cell]]s, physical factors, and cytokines, as well as limiting the potentially detrimental, iatrogenic impact of [[dexamethasone]], will likely be required for the potential of anti-tumor immune responses to be realized for glioblastoma ((Reardon DA, Wucherpfennig K, Chiocca EA. Immunotherapy for glioblastoma: on the sidelines or in the game? Discov Med. 2017 Nov;24(133):201-208. PubMed PMID: 29278673. )). [[Patient]]s with [[glioblastoma]] (Glioblastoma) exhibit a complex state of [[immunodeficiency]] involving multiple mechanisms of local, regional, and systemic immune suppression and tolerance. These [[pathway]]s are now being identified and their relative contributions explored. Delineating how these pathways are interrelated is paramount to effectively implementing [[immunotherapy]] for Glioblastoma ((Jackson CM, Lim M. Immunotherapy for glioblastoma: playing chess, not checkers. Clin Cancer Res. 2018 Apr 24. pii: clincanres.0491.2018. doi: 10.1158/1078-0432.CCR-18-0491. [Epub ahead of print] PubMed PMID: 29691293. )). ---- Progress in the development of these therapies for [[glioblastoma]] has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas. Trials have revealed promising trends in [[overall survival]] and [[progression free survival]] for patients with glioblastoma, and have paved the way for ongoing randomized controlled trials ((Thomas AA, Fisher JL, Ernstoff MS, Fadul CE. Vaccine-based immunotherapy for glioblastoma. CNS Oncol. 2013 Jul;2(4):331-49. doi: 10.2217/cns.13.29. PubMed PMID: 25054578.)) ((Agrawal NS, Miller R Jr, Lal R, Mahanti H, Dixon-Mah YN, DeCandio ML, Vandergrift WA 3rd, Varma AK, Patel SJ, Banik NL, Lindhorst SM, Giglio P, Das A. Current Studies of Immunotherapy on Glioblastoma. J Neurol Neurosurg. 2014 Apr 5;1(1). pii: 21000104. PubMed PMID: 25346943.)) ---- Some [[clinical trial]]s are reaching phase III. Significant progress has been made in unraveling the molecular and genetic heterogeneity of [[glioblastoma multiforme]] and its implications to disease prognosis. There is now consensus related to the critical need to incorporate tumor heterogeneity into the design of therapeutic approaches. Recent data also indicates that an efficacious treatment strategy will need to be combinatorial and personalized to the tumor genetic signature ((Kamran N, Calinescu A, Candolfi M, Chandran M, Mineharu Y, Assad AS, Koschmann C, Nunez F, Lowenstein P, Castro M. Recent advances and future of immunotherapy for glioblastoma. Expert Opin Biol Ther. 2016 Jul 13. [Epub ahead of print] PubMed PMID: 27411023. )). ---- A recurrent theme of this work is that immunotherapy is not a one-size-fits-all solution. Rather, dynamic, tumor-specific interactions within the tumor microenvironment continually shape the immunologic balance between tumor elimination and escape. High-grade gliomas are a particularly fascinating example. These aggressive, universally fatal tumors are highly resistant to radiation and chemotherapy and inevitably recur after surgical resection. Located in the immune-privileged central nervous system, high-grade gliomas also employ an array of defenses that serve as direct impediments to immune attack. Despite these challenges, vaccines have shown activity against high-grade gliomas and anecdotal, preclinical, and early clinical data bolster the notion that durable remission is possible with immunotherapy. Realizing this potential, however, will require an approach tailored to the unique aspects of glioma biology ((Jackson CM, Lim M, Drake CG. Immunotherapy for Brain Cancer: Recent Progress and Future Promise. Clin Cancer Res. 2014 Apr 25. [Epub ahead of print] PubMed PMID: 24771646.)). ---- Clinical experiences with active specific immunotherapy demonstrate feasibility, safety and most importantly, but incompletely understood, prolonged long-term survival in a fraction of the patients. In relapsed patients, Van Gool et al developed an immunotherapy schedule and categorized patients into clinically defined risk profiles. He learned how to combine immunotherapy with standard multimodal treatment strategies for newly diagnosed glioblastoma multiforme patients. The developmental program allows further improvements related to newest scientific insights. Finally, he developed a mode of care within academic centers to organize [[cell therapy]] for experimental clinical trials in a large number of patients ((Van Gool SW. Brain Tumor Immunotherapy: What have We Learned so Far? Front Oncol. 2015 Jun 17;5:98. eCollection 2015. Review. PubMed PMID: 26137448. )). ---- Immunostimulating oligodeoxynucleotides containing unmethylated [[cytosine]]-[[guanosine]] motifs (CpG-ODN) have shown a promising efficacy in several cancer models when injected locally. A previous phase II study of CpG-ODN in patients with [[Glioblastoma recurrence]] (Glioblastoma) has suggested some activity and has shown a limited toxicity. This multicentre single-blinded randomised phase II trial was designed to study the efficacy of a local treatment by CpG-ODN in patients with de novo glioblastomas. Patients with a newly diagnosed glioblastoma underwent large surgical resection and CpG-ODN was randomly administrated locally around the surgical cavity. The patients were then treated according to standard of care (SOC) with radiotherapy and temozolomide. The primary objective was 2-year survival. Secondary outcomes were progression free survival (PFS), and tolerance. Eighty-one (81) patients were randomly assigned to receive CpG-ODN plus SOC (39 patients) or SOC (42 patients). The 2-year overall survival was 31% (19%; 49%) in the CpG-ODN arm and 26% (16%; 44%) in the SOC arm. The median PFS was 9 months in the CpG-ODN arm and 8.5 months in the SOC arm. The incidence of adverse events was similar in both arms; although fever and post-operative haematoma were more frequent in the CpG-ODN arm. Local immunotherapy with CpG-ODN injected into the surgical cavity after tumour removal and followed by SOC, although well tolerated, does not improve survival of patients with newly diagnosed Glioblastoma ((Ursu R, Carpentier A, Metellus P, Lubrano V, Laigle-Donadey F, Capelle L, Guyotat J, Langlois O, Bauchet L, Desseaux K, Tibi A, Chinot O, Lambert J, Carpentier AF. Intracerebral injection of CpG oligonucleotide for patients with de novo glioblastoma-A phase II multicentric, randomised study. Eur J Cancer. 2017 Jan 28;73:30-37. doi: 10.1016/j.ejca.2016.12.003. [Epub ahead of print] PubMed PMID: 28142059. )). ---- [[Epidermal growth factor receptor 3]] (EGFRvIII) is present in approximately one-third of [[glioblastoma]] (Glioblastoma) patients. It is never found in normal tissues; therefore, it represents a candidate target for [[glioblastoma immunotherapy]]. PEPvIII, a peptide sequence from EGFRvIII, was designed to represent a target of glioma and is presented by MHC I/II complexes. [[Dendritic cell]]s (DCs) have great potential to sensitize CD4+ T and CD8+ T cells to precisely target and eradicate Glioblastoma. Li et al. show that PEPvIII could be loaded by DCs and presented to T lymphocytes, especially PEPvIII-specific CTLs, to precisely kill U87-EGFRvIII cells. In addition to inhibiting proliferation and inducing the apoptosis of U87-EGFRvIII cells, miR-326 also reduced the expression of TGF-β1 in the tumour environment, resulting in improved efficacy of T cell activation and killing via suppressing the SMO/Gli2 axis, which at least partially reversed the immunosuppressive environment. Furthermore, combining the EGFRvIII-DC vaccine with miR-326 was more effective in killing U87-EGFRvIII cells compared with the administration of either one alone. This finding suggested that a DC-based vaccine combined with miR-326 may induce more powerful anti-tumour immunity against Glioblastoma cells that express a relevant antigen, which provides a promising approach for Glioblastoma immunotherapy ((Li J, Wang F, Wang G, Sun Y, Cai J, Liu X, Zhang J, Lu X, Li Y, Chen M, Chen L, Jiang C. Combination epidermal growth factor receptor variant III peptide-pulsed dendritic cell vaccine with miR-326 results in enhanced killing on EGFRvIII-positive cells. Oncotarget. 2017 Feb 17. doi: 10.18632/oncotarget.15445. [Epub ahead of print] PubMed PMID: 28412740. )). ===== Reviews ===== Yuan et al. provided an overview of the basic knowledge underlying [[immune targeting]] and promising immunotherapeutic strategies including CAR T cells, oncolytic viruses, cancer vaccines, and checkpoint blockade inhibitors that have been recently investigated in glioblastoma. Current clinical trials and previous clinical trial findings are discussed, shedding light on novel strategies to overcome various limitations and challenges ((Yuan B, Wang G, Tang X, Tong A, Zhou L. Immunotherapy of glioblastoma: recent advances and future prospects. Hum Vaccin Immunother. 2022 Mar 28:1-16. doi: 10.1080/21645515.2022.2055417. Epub ahead of print. PMID: 35344682.)). ---- Rui Y, Green JJ. Overcoming delivery barriers in immunotherapy for glioblastoma. Drug Deliv Transl Res. 2021 May 30. doi: 10.1007/s13346-021-01008-2. Epub ahead of print. PMID: 34053034. ===== Glioblastoma Immune Checkpoint Inhibitor Therapy ===== [[Glioblastoma Immune Checkpoint Inhibitor Therapy]] ===== Glioblastoma CAR-T cell therapy ===== [[Glioblastoma CAR-T cell therapy]]