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Yang, M.; Oh, I.Y.; Mahanty, A.; Jin, W.; Yoo, J.S. Immunotherapy for Glioblastoma. Encyclopedia. Available online: (accessed on 14 June 2024).
Yang M, Oh IY, Mahanty A, Jin W, Yoo JS. Immunotherapy for Glioblastoma. Encyclopedia. Available at: Accessed June 14, 2024.
Yang, Minfeng, In Young Oh, Arpan Mahanty, Wei-Lin Jin, Jung Sun Yoo. "Immunotherapy for Glioblastoma" Encyclopedia, (accessed June 14, 2024).
Yang, M., Oh, I.Y., Mahanty, A., Jin, W., & Yoo, J.S. (2020, August 20). Immunotherapy for Glioblastoma. In Encyclopedia.
Yang, Minfeng, et al. "Immunotherapy for Glioblastoma." Encyclopedia. Web. 20 August, 2020.
Immunotherapy for Glioblastoma

       Glioblastoma (GBM) is the deadliest and most aggressive neuroepithelial cancer of the central nervous system (CNS) with an abysmal median survival of 14.6-month despite the multiple forms of intervention. In the United States, the total annual incidence rate of glioma has been ~6 cases per 100,000 individuals, of which GBM accounts for about 50% of the cases, with a higher predominance in males. Clinical studies have indicated that most of the GBM patients present an intact blood–brain barrier (BBB) for certain brain regions, capable of blocking the delivery of agents to cancer sites. The BBB is considered to prevent diffusion of 98% of small-molecule and 100% of large-molecule agents into the brain from blood circulation. Given the aggressive and heterogeneous nature of GBM and the blocking capability of BBB, a very limited number of medications for patients with GBM is available in clinics. In addition, due to the existence of other cellular and extracellular barriers, as well as the development of drug resistance over the treatment course, the efficacy of many current therapeutic approaches has been compromised.

       Currently available standards of care for GBM include maximal tumor resection followed by radiotherapy, chemotherapy, and corticosteroids, all of which have immune suppressive characteristics. Unfortunately, complete surgical removal of the whole tumor is almost impossible due to their diffusive characteristics into normal brain tissue. Some reports indicated that ~65% of the post-surgery cases still showed residual tumor cells, which eventually contributed to a high relapse rate of GBM . Therefore, GBM patients may undergo repeated surgical resection, radiotherapy, chemotherapy, or additional bevacizumab treatment. Eventually, most of the patients suffering from GBM will relapse despite an ample set of interventional approaches. According to the data from Surveillance and Epidemiology, the median overall survival (OS) of GBM patients was normally less than 2 years from the time of first progression or relapse. An international phase III randomized trial, conducted by the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada (EORTC/NCIC), has shown that the median OS of GBM patients who received radiotherapy and Temozolomide therapy remains poor (14.6 months). Moreover, Grossman and colleagues found that the utilization of systemic chemotherapy and hyperfractionated radiation therapy with corticosteroids is likely to disable immune activity. Immune-suppressive characteristics, high toxicity, and lower OS of traditional care made a considerable number of GBM patients (~50%) not accept any second-line of anti-tumor treatment. In addition, there is no evidence that traditional intervention can significantly impact the OS rate under a recurrence setting. Accordingly, given the poor prognosis and limited therapy regimens for patients affected by GBM, there is an urgent need to develop novel therapeutic approaches.

glioblastoa immune-checkpoint inhibitors tumor microenvironment tumor-associated macrophages and microglia immune-related adverse events

1. Immune Microenvironment of Glioblastoma

       It has been regarded that the CNS lacks dedicated lymphatic channels for a long time. The CNS was considered as an immune privileged system, devoid of any immune cells. This overstated historical notion was mainly based on the experimental data reported by Peter Medawar, where foreign grafts transplanted into the brains of rodents did not induce any immune response and the same foreign grafts transplanted into other tissues or organs were rejected [1][2][3][4]. However, this perception has been challenged recently since several studies showed vigorous immunosurveillance and meaningful immune response in the CNS [5][6]. For example, the discovery of a novel route of lymphatic-based channels, reported by Louveau and colleagues [5] in 2015 and the findings of robust immune responses in multiple inflammatory conditions [6] have both demonstrated the CNS as a region for active immunosurveillance. Such findings prompted an increase in studies for the feasibility of cancer immunotherapy towards brain tumors. Although immunotherapy holds great potential for treatment of malignant GBM, unique GBM-associated immune suppression and immune escape still provide challenges to generate efficient anti-tumor responses [4][7]. GBM can form a highly immunosuppressive milieu, mediated by distinct immune or tumor cells (Figure 1). Tumor cells normally express plenty of immunosuppressive factors, such as programmed cell death 1 ligand 1 (PD-L1) and indolamine 2,3-dioxygenase (IDO), while reducing antigen presentation by diminishing major histocompatibility complex (MHC) expression [4]. Notably, gliomas produce IDO, whose function relates to the recruitment of regulatory T (Treg) cells and the inhibition of effector T cells through tryptophan depletion [4][8]. In the context of microglial cells, these often secrete transforming growth factor β (TGFβ) and/or interleukin 10 (IL-10) to decrease the amount of myeloid and lymphoid immune cells to boost systemic immunosuppression [4][9][10] (Figure 1). The lymphoid compartment also mediates immunosuppressive effects with Treg cells through upregulation of different soluble factors and some immune-checkpoint molecules [4]. These immunosuppressive factors may ultimately block T-cell proliferation and activation. One unique factor of GBM is its relatively low tumor mutational burden (TMB) which reduces the responding T cell clones resulting in poor adaptive immunity [11][12][13]. High TMB often suggested as a reliable biomarker for ICIs [11][12][13]. Other variables, including chemotherapy, corticosteroids, and patient age-related factors may also lead to immunosuppression in GBM patients [10]. Overall, GBM is considered as a highly immunosuppressive CNS-related tumor.

Figure 1. Immunity-related microenvironment of glioblastoma. (1) The immune microenvironment involving glioblastoma (GBM) is characterized by large amounts of CD8+ and CD4+ T cells, M1 and M2 polarized macrophages, microglia, and regulatory T (Treg) cells in addition to a limited number of natural killer (NK) cells. Tumor-associated macrophages and microglia (TAMs) have considerable plasticity toward anti-tumor M1 (inflammatory TAMs) and pro-tumor M2 (anti-inflammatory TAMs) phenotypes. Pharmacological strategies to re-educate tumorigenic M2 TAMs to tumoricidal M1 TAMs may help to relieve immune suppression in the tumor microenvironment (TME), as well as enhance the related anti-tumor activity. (2) GBM normally expressed high levels of immunosuppressive factors, such as programmed cell death 1 ligand 1 (PD-L1) and indolamine 2,3-dioxygenase (IDO), while limiting the presentation of antigens by decreasing major histocompatibility complex (MHC) presentation. The application of IDO inhibitors has effects on Treg cell accumulation. (3) CD47 is highly expressed in various types of tumors. Signal regulatory protein α (SIRPα) is an inhibitory receptor expressed on macrophages and other myeloid immune cells. Upon CD47 binding to SIRPα, src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) and SHP-2 phosphatases are activated to further abrogate phagocytosis via downstream mediators. Disruption of the CD47/SIRPα axis using anti-CD47 antibody (CD47 Ab) can interrupt the inhibitory signaling mediated by SIRPα, thereby promoting phagocytosis of tumor cells. (4) T-cell immunoglobulin and mucin domain-containing protein-3 (TIM3) is a strong negative regulator of lymphocyte function and survival, acting as a marker of CD4+ and CD8+ T-cell exhaustion similarly to programmed cell death 1 (PD-1). It has been verified that the co-expression of PD-1 and TIM3 in lymphocytes is positively correlated with the tumor grade, but it is negatively correlated with progression-free survival (PFS) in different types of tumors including GBM. (5) In the context of microglial cells, these often secrete transforming growth factor β (TGFβ) and/or interleukin 10 (IL-10) to decrease the amount of myeloid and/or lymphoid immune cells, resulting in a systemic immunosuppression and immune evasion of GBM cells. Th, helper T cell; ADCC, antibody-dependent-cell-mediated cytotoxicity; Treg, regulatory T cell; CTL, cytotoxic T lymphocyte; CAR T, chimeric antigen receptor T cell; DC, dendritic cell.

       One distinctive aspect of the brain’s microenvironment is related to the bulk of myeloid cell population, which is capable of manipulating the immune microenvironment and GBM progression by producing immunosuppressive and anti-inflammatory cytokines and growth factors, as well as promoting T-cell apoptosis, thus suggesting a new strategy for immunotherapy [14][15]. A considerable population of brain myeloid cells are microglia, which are equivalent to macrophages from other tissues [16]. In the absence of any inflammatory stimulation, the microglia normally arise from the yolk sac and are maintained by continuous replication during our whole life [17]. Upon pro-inflammatory stimulation in the GBM tissue, microglial cells may undergo significant phenotypic changes, while extensive additional macrophages can also be recruited from peripheral monocytes into the tumor site [18][19][20]. Notably, the GBM microenvironment has a surprisingly high composition of tumor-associated macrophages and microglia (TAMs), ranging between 30 and 50% [21] of tumor mass. Such a percentage of TAMs is much higher than the ones observed in other major malignancies such as melanoma [22]. One notable feature of TAMs is that they have considerable plasticity toward anti-tumor M1 (inflammatory TAMs) and pro-tumor M2 (anti-inflammatory TAMs) phenotypes (Figure 1). Redirecting TAMs from immunoinhibitory M2 to immunostimulatory M1 phenotype is a promising approach to elicit an immune response and to inhibit GBM progression since this can reduce immunosuppressive restrains and thus boost immunity driven by cytotoxic T lymphocytes (CTLs) [23]. More recently, research evidence has indicated that pharmacological inhibition provided by certain soluble factors, such as colony-stimulating factor-1 receptor, can dramatically decrease M2 polarization and significantly improve OS [23]. Moreover, several reports have confirmed a strong association between the survival of high-grade glioma patients and M1 or M2 polarization. For instance, M1 polarization has been positively correlated with improved patient survival [24]. In contrast, M2 polarization (assessed by F11R marker) has been negatively correlated with patient survival [25]. Therefore, strategies to target TAMs have emerged as alternate routes for GBM therapy [26]. In this sense, a number of studies have pursued ways to (i) inhibit monocyte recruitment into the CNS, (ii) deplete M2 TAMs, and (iii) reprogram tumorigenic M2 to M1 phenotype [27]. One recent report has also demonstrated TAM-mediated resistance of programmed cell death 1 (PD-1) immunotherapy, thus providing a strong rationale towards TAM targeting as a reliable approach to enhance PD-1-inhibitor treatment response [28]. Of note, TAM-targeted immunotherapy has received particular attention in recent years although investigations related to this promising therapeutic area are still in progress.

2. Overview of Current Immunotherapy Modalities for Glioblastoma

       As a paradigm shift in cancer treatment, immunotherapy has recently gained enormous attention and also achieved a rapid expansion in the context of GBM. Immunotherapy approaches for GBM have been focused on ICIs, oncolytic viruses, chimeric T-cell receptors, and dendritic cell (DC) vaccines [4][9]Figure 2 outlines four distinct immunotherapy modalities available for GBM. We can notice that a successful vaccine for GBM treatment depends on DC-mediated presentation of GBM-related antigens as well as peptides for T-cell activation in the adaptive immune system. Among the pathways involved in these processes, one is related to the combination of T-cell receptors and MHC, while another pathway involves the interaction between CD80/CD86 and CD28. Cytotoxic T lymphocytes (CTLs) can be subsequently activated to kill GBM cells having specific antigens for MHC I presentation [4][29]. In general, tumor cells avoid this disruption by upregulating PD-L1, which binds to its complementary receptor, PD-1 along the T-cell surface to further inhibit the activation of CTLs [30]. We can utilize different approaches of immune-checkpoint blockage to effectively prevent the interaction between PD-L1 and PD-1 in GBM. However, a phase III trial result to compare therapeutic efficacy of nivolumab and bevacizumab in recurrent GBM was disappointing with no improvement in OS (Clinical trial identifier: NCT02017717, Table 1). Cytotoxic T lymphocyte protein 4 (CTLA-4) is another important immune regulatory molecule that binds to CD80 or CD86 and inhibits their combination with CD28 to prevent T-cell activation [30]. Epidermal growth factor receptor variant III (EGFRvIII), IL-13 receptor subunit-α2 (IL-13R α2), and human epidemic growth factor receptor 2 (HER2) are expressed on the surface of GBM cells and may also be targeted by a genetically modified chimeric antigen receptor (CAR) T cell to promote GBM cell death [4][9][29]. Given the promising role of cancer immunotherapies towards GBM pathophysiology, a substantial number of clinical trials have been performed or planned to explore the potential roles and efficacy of targeting these three antigens [4][9][29] (Table 1). These clinical trials have demonstrated feasibility, safety, and efficacy of CAR T cell therapy for GBM. For example, treatment constituted of virus-specific T cells (VSTs) expressing HER2-specific CAR (HER2-CAR VST)in progressive GBM patients resulted in an median OS of up to 11.1 months from the first T cell infusion and 24.5 months from the first diagnosis (Clinical trial identifier: NCT01109095, Table 1).Interestingly, genetic engineering has also been applied in oncolytic viral treatment to produce viruses that may infect tumor cells, trigger tumor cell lysis, and hijack tumor cell replication, which ultimately leads to tumor cell death [4][9] (Table 1). This particular treatment has enabled the breakage of shackles from many tumors and also triggered a higher immune backlash, thus shifting GBM from cold to hot tumor types [4][9]. Promisingly, data from phase II trial have verified the high clinical response in GBM patients after intratumoral inoculation of Polio/Rhinovirus Recombinant (PVSRIPO), with an increase in OS up to 12.5 months from the time of inoculation and higher survival rate at 24 and 36 months over historical controls (Clinical trial identifier: NCT01491893, Table 1). These results show that oncolytic-based therapy has a high potential to improve OS and quality of life for patients affected by GBM [29]. Although oncolytic-based therapies may provide significant immunostimulatory effects, including the depletion of regulatory T cells, the induction of immunogenic cell death, and abscopal effects, these therapeutic approaches still carry some intrinsic limitations. For instance, pro-inflammatory responses caused by oncolytic viruses may potentially limit the application of oncolytic viruses as a single-modality immunotherapy [29]. Besides, CAR T-cell treatment for GBM relies on the identification of stably expressed and sufficient tumor-related antigens, which might eventually limit the clinical application of this therapy [9][29]. Considering the highly heterogeneous characteristics of GBM, one could postulate that targeting one antigen in GBM might not be sufficient to eradicate all the GBM cells. Overall, these obstacles have promoted the development of alternate immunotherapy modalities, which may better recapitulate tumor immunology with improved accuracy. 

Figure 2. Current immunotherapy strategies for glioblastoma. (1) Vaccines for glioblastoma (GBM) treatment have been relied on dendritic cell (DC)-mediated presentation of GBM-related antigens and peptides for T-cell activation in the adaptive immune system. (2) The immunosuppression status of cytotoxic T lymphocytes (CTLs) can be relieved by the application of immune-checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 (PD-1), anti-cytotoxic T lymphocyte protein 4 (CTLA-4) and anti-programmed cell death 1 ligand 1 (PD-L1). (3) Genetically engineered chimeric antigen receptor (CAR) T cells can generate artificial T-cell receptors with high affinity to cancer-specific antigens. (4) Genetic engineering has also been applied in oncolytic viral treatment to medicate cancer cell lysis and promote tumor necrosis. MHC, Major histocompatibility complex; TCR, T-cell receptor; EGFRvIII, Epidermal growth factor receptor variant III.

Table 1. Recent clinical studies with immune-checkpoint inhibitors and some combinational therapies targeting glioblastoma.


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