Immunotherapy For Glioblastoma Research Articles

A Conceptual Framework for Inducing T Cell-Mediated Immunity Against Glioblastoma.

Glioblastoma is a highly aggressive brain tumor with limited treatment options. Several major challenges have limited the development of novel therapeutics, including the extensive heterogeneity of tumor cell states within each glioblastoma and the ability of glioma cells to diffusely infiltrate into neighboring healthy brain tissue, including the contralateral hemisphere. A T cell-mediated immune response could deal with these challenges based on the ability of polyclonal T cell populations to recognize diverse tumor antigens and perform surveillance throughout tissues. Here we will discuss the major pathways that inhibit T cell-mediated immunity against glioblastoma, with an emphasis on receptor-ligand systems by which glioma cells and recruited myeloid cells inhibit T cell function. A related challenge is that glioblastomas tend to be poorly infiltrated by T cells, which is not only caused by inhibitory molecular pathways but also currently utilized drugs, in particular high-dose corticosteroids that kill activated, proliferating T cells. We will discuss innovative approaches to induce glioblastoma-directed T cell responses, including neoantigen-based vaccines and sophisticated CAR T cell approaches that can target heterogeneous glioblastoma cell populations. Finally, we will propose a conceptual framework for the future development of T cell-based immunotherapies for glioblastoma.

Immune-checkpoint inhibitors for glioblastoma: what have we learned?

Glioblastoma, the most common malignant primary brain tumor, remains a lethal disease with few therapeutic options. Immunotherapies, particularly immune checkpoint inhibitors (ICPi), have revolutionized cancer treatment, but their role in glioblastoma is uncertain. To review the state of immunotherapies in glioblastoma, with an emphasis on recently published ICPi clinical trials. In this editorial/opinion article, we critically review results of the first generation of trials of ipilimumab, nivolumab and pembrolizumab in glioblastoma, as well as future directions. Expression of PD-L1 is frequent in glioblastoma, ranging from 60-70% of patients. Phase 1 studies of nivolumab with and without ipilimumab, as well as pembrolizumab, showed no new safety concerns in brain tumors, and no neurotoxicity. However, randomized phase 3 trials of nivolumab showed no survival improvements over bevacizumab in recurrent glioblastoma; no role in newly diagnosed disease as a replacement for temozolomide in unmethylated MGMT promoter tumors; and no benefit as an addition to temozolomide in methylated MGMT tumors. However, studies examining post treatment tumor samples have shown signs of increased immunologic response, and occasional long lasting radiographic responses have been seen. A small study of pembrolizumab suggested a potential role as a "neoadjuvant" treatment in resectable recurrent glioblastoma, while other studies are investigating selection of patients with higher mutational burden and novel agents and combinatorial strategies. Despite initial negative trials, immunotherapy remains of high interest in glioblastoma, and many trials are still ongoing. Improving our mechanistic understanding of the immunosuppression and T cell dysfunction induced by both tumor and the CNS microenvironment remains however crucial for the development of successful immunotherapeutic approaches in this disease.

Glioblastoma Embryonic-like Stem Cells Exhibit Immune-Evasive Phenotype.

Simple SummaryMost glioblastoma (GBM) patients relapse after an initial response to treatment. These aggressive traits are often associated with the presence of glioma stem cells (GSCs) within the tumor bulk, which are thought to participate in GBM therapy resistance. Given GBM cellular heterogeneity, we hypothesized that GSCs might also display cellular hierarchies associated with different degrees of stemness. Based on single-cell RNAseq data from GBM patients, we identified a subpopulation of GSCs, named core-GSCs (c-GSCs), with a similar profile to embryonic stem cells and downregulation of immune-associated pathways. In addition, we developed an in vitro induced c-GSC (ic-GSC) model resembling their tumor counterpart. The characterization of immune-privileged c-GSCs provides a valuable resource to study immune evasion mechanisms in GBM and to identify potential unexplored targets to improve immunotherapy treatments.Background: Glioma stem cells (GSCs) have self-renewal and tumor-initiating capacities involved in drug resistance and immune evasion mechanisms in glioblastoma (GBM). Methods: Core-GSCs (c-GSCs) were identified by selecting cells co-expressing high levels of embryonic stem cell (ESC) markers from a single-cell RNA-seq patient-derived GBM dataset (n = 28). Induced c-GSCs (ic-GSCs) were generated by reprogramming GBM-derived cells (GBM-DCs) using induced pluripotent stem cell (iPSC) technology. The characterization of ic-GSCs and GBM-DCs was conducted by immunostaining, transcriptomic, and DNA methylation (DNAm) analysis. Results: We identified a GSC population (4.22% ± 0.59) exhibiting concurrent high expression of ESC markers and downregulation of immune-associated pathways, named c-GSCs. In vitro ic-GSCs presented high expression of ESC markers and downregulation of antigen presentation HLA proteins. Transcriptomic analysis revealed a strong agreement of enriched biological pathways between tumor c-GSCs and in vitro ic-GSCs (κ = 0.71). Integration of our epigenomic profiling with 833 functional ENCODE epigenetic maps identifies increased DNA methylation on HLA genes’ regulatory regions associated with polycomb repressive marks in a stem-like phenotype. Conclusions: This study unravels glioblastoma immune-evasive mechanisms involving a c-GSC population. In addition, it provides a cellular model with paired gene expression, and DNA methylation maps to explore potential therapeutic complements for GBM immunotherapy.

Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma.

Tumor Treating Fields (TTFields), an approved therapy for glioblastoma (GBM) and malignant mesothelioma, employ noninvasive application of low-intensity, intermediate-frequency, alternating electric fields to disrupt the mitotic spindle, leading to chromosome missegregation and apoptosis. Emerging evidence suggests that TTFields may also induce inflammation. However, the mechanism underlying this property and whether it can be harnessed therapeutically are unclear. Here, we report that TTFields induced focal disruption of the nuclear envelope, leading to cytosolic release of large micronuclei clusters that intensely recruited and activated 2 major DNA sensors — cyclic GMP-AMP synthase (cGAS) and absent in melanoma 2 (AIM2) — and their cognate cGAS/stimulator of interferon genes (STING) and AIM2/caspase 1 inflammasomes to produce proinflammatory cytokines, type 1 interferons (T1IFNs), and T1IFN-responsive genes. In syngeneic murine GBM models, TTFields-treated GBM cells induced antitumor memory immunity and a cure rate of 42% to 66% in a STING- and AIM2-dependent manner. Using single-cell and bulk RNA sequencing of peripheral blood mononuclear cells, we detected robust post-TTFields activation of adaptive immunity in patients with GBM via a T1IFN-based trajectory and identified a gene panel signature of TTFields effects on T cell activation and clonal expansion. Collectively, these studies defined a therapeutic strategy using TTFields as cancer immunotherapy in GBM and potentially other solid tumors.

Emerging Biomarkers for Immunotherapy in Glioblastoma.

Simple SummaryImmunotherapy has shown clinical benefits in several solid cancers; still, glioblastoma remains very challenging to treat. Glioblastoma is the most frequent brain cancer and displays great heterogeneity. The standard of care has remained the same for over fifteen years, and to overcome the therapeutic limitations, emerging immune correlates of therapy responses and improved prognosis should be further developed for a more personalized therapy approach and increased clinical responses.Immunotherapy has shown clinical benefits in several solid malignancies—in particular, melanoma and non-small cell lung cancer. However, in other solid tumours such as glioblastoma (GBM), the response to immunotherapy has been more variable, and except for anti-PD-1 for patients with microsatellite instable (MSI)+ cancers, no immunotherapy is currently approved for GBM patients. GBM is the most common and most aggressive brain cancer with a very poor prognosis and a median overall survival of 15 months. A few prognostic biomarkers have been identified and are used to some extent, but apart from MSI, no biomarkers are used for patient stratification for treatments other than the standard of care, which was established 15 years ago. Around 25% of new treatments investigated in GBM are immunotherapies. Recent studies indicate that the use of integrated and validated immune correlates predicting the response and guiding treatments could improve the efficacy of immunotherapy in GBM. In this review, we will give an overview of the current status of immunotherapy and biomarkers in use in GBM with the main challenges of treatment in this disease. We will also discuss emerging biomarkers that could be used in future immunotherapy strategies for patient stratification and potentially improved treatment efficacy.

Characterising Distinct Migratory Profiles of Infiltrating T-Cell Subsets in Human Glioblastoma.

Glioblastoma is the most common and aggressive form of primary brain cancer, with no improvements in the 5-year survival rate of 4.6% over the past three decades. T-cell-based immunotherapies such as immune-checkpoint inhibitors and chimeric antigen receptor T-cell therapy have prolonged the survival of patients with other cancers and have undergone early-phase clinical evaluation in glioblastoma patients. However, a major challenge for T-cell-based immunotherapy of glioblastoma and other solid cancers is T-cell infiltration into tumours. This process is mediated by chemokine-chemokine receptor and integrin-adhesion molecule interactions, yet the specific nature of the molecules that may facilitate T-cell homing into glioblastoma are unknown. Here, we have characterised chemokine receptor and integrin expression profiles of endogenous glioblastoma-infiltrating T cells, and the chemokine expression profile of glioblastoma-associated cells, by single-cell RNA-sequencing. Subsequently, chemokine receptors and integrins were validated at the protein level to reveal enrichment of receptors CCR2, CCR5, CXCR3, CXCR4, CXCR6, CD49a, and CD49d in glioblastoma-infiltrating T-cell populations relative to T cells in matched patient peripheral blood. Complementary chemokine ligand expression was then validated in glioblastoma biopsies and glioblastoma-derived primary cell cultures. Together, enriched expression of homing receptor-ligand pairs identified in this study implicate a potential role in mediating T-cell infiltration into glioblastoma. Importantly, our data characterising the migratory receptors on endogenous tumour-infiltrating T cells could be exploited to enhance the tumour-homing properties of future T-cell immunotherapies for glioblastoma.

Biomimetic GBM-targeted drug delivery system boosting ferroptosis for immunotherapy of orthotopic drug-resistant GBM

BackgroundClinical studies have shown that the efficacy of programmed cell death receptor-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors on glioblastoma (GBM) is much lower than what is expected because of the low immunogenicity of GBM. Ferroptosis of cancer cells can induce the maturation of dendritic cells (DC cells) and increase the activity of T cell. The activated T cells release IFN-γ, which subsequently induces the ferroptosis of cancer cells. Thus, the aim of this paper is to set up a new GBM-targeted drug delivery system (Fe3O4-siPD-L1@M-BV2) to boost ferroptosis for immunotherapy of drug-resistant GBM.ResultsFe3O4-siPD-L1@M-BV2 significantly increased the accumulation of siPD-L1 and Fe2+ in orthotopic drug-resistant GBM tissue in mice. Fe3O4-siPD-L1@M-BV2 markedly decreased the protein expression of PD-L1 and increased the ratio between effector T cells and regulatory T cells in orthotopic drug-resistant GBM tissue. Moreover, Fe3O4-siPD-L1@M-BV2 induced ferroptosis of GBM cells and maturation of DC cell, and it also increased the ratio between M1-type microglia and M2-type microglia in orthotopic drug-resistant GBM tissue. Finally, the growth of orthotopic drug-resistant GBM in mice was significantly inhibited by Fe3O4-siPD-L1@M-BV2.ConclusionThe mutual cascade amplification effect between ferroptosis and immune reactivation induced by Fe3O4-siPD-L1@M-BV2 significantly inhibited the growth of orthotopic drug-resistant GBM and prolonged the survival time of orthotopic drug-resistant GBM mice.Graphical

Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers.

Simple SummaryThe poor prognosis for glioblastoma (GBM) despite the existence of a standard-of-care treatment of resection, radiotherapy, and adjuvant chemotherapy has necessitated the exploration of other therapeutic avenues. One particularly promising avenue is an immunotherapeutic approach in which the body′s immune system is artificially stimulated to directly identify and attack the tumor cells. A variety of methods including immune checkpoint inhibition, T-cell transfer, vaccination, and a viral approach are being developed for GBM. Barriers such as tumor heterogeneity, the physical blood–brain barrier, the immunosuppressive nature of GBM, and the limited number of identifiable GBM-specific targets have reduced the efficacy of the aforementioned approaches. In the following review, we document the advances in immunotherapy, the barriers to implementation, and the development of a new technology (microbubble-enhanced focused ultrasound) to overcome the physical barriers to immunotherapy.Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood–brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.

Measles Virus as a Vector Platform for Glioblastoma Immunotherapy (Review)

Introduction. Oncolytic virotherapy is one of the approaches in immunotherapy of solid brain tumors. Measles virus vaccine strains are prospective agents for the therapy of cancers such as neuroblastoma, mesothelioma, and glioblastoma multiforme. The hyperexpression of the CD46 and other receptors on the surface of malignant cells allows the measles virus to infect and lyse the tumor, thus inducing an immune response. However, widespread immunization of the population and the resistance of neoplasms to oncolysis present difficulties in clinical practice.Text. This review covers approaches to modifying the measles virus genome in order to increase specificity of virotherapy, overcome existing immunity, and enhance the oncolytic effect. It was shown that expression of proinflammatory cytokines on viral particles leads to tumor regression in mice and triggers a T-cell response. Several approaches have been used to overcome virus-neutralizing antibodies: shielding viral particles, using host cells, and altering the epitope of the protein that enables entry of the virus into the cell. Furthermore, the insertion of reporter genes allows the infection of target cells to be monitored in vivo. A combination with the latest immunotherapies, such as immune checkpoint inhibitors, demonstrates synergistic effects, which suggests the successful use of combined approaches in the therapy of refractory tumors.Conclusion. Measles virus attenuated strains appear to be an easy-to-modify and reliable platform for the therapy of solid brain tumors.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Synergy between glutamate modulation and anti-programmed cell death protein 1 immunotherapy for glioblastoma.

Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM. C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry. The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05). In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Oncolytic Zika virus promotes intratumoral T cell infiltration and improves immunotherapy efficacy in glioblastoma

Glioblastoma (GBM) is the deadliest primary brain tumor and is generally resistant to immunotherapy because of severe dysfunction of T cells. Novel treatment options are critically needed to overcome the immunotherapy resistance of GBM. Here we demonstrate that Zika virus (ZIKV) treatment improves the efficacy of anti-PD ligand 1 (PD-L1) immunotherapy in GBM. We found that ZIKV induces a strong pro-inflammatory response and increases CD4+ and CD8+ T cell intratumoral infiltration and activation in GBM mouse models. ZIKV treatment of mice bearing GBM tumors inhibits tumor growth and prolongs survival. These therapeutic effects of ZIKV on GBM tumors are negated in mice depleted of T cells. Moreover, ZIKV dramatically promotes activation of the type I interferon signaling pathway in GBM cells. ZIKV treatment potently sensitizes GBM to PD-L1 blockade and provides significant and durable survival benefits. Our findings reveal that ZIKV overcomes the resistance of GBM to immune checkpoint blockade, which may lead to therapeutic applications of ZIKV in individuals with GBM receiving immunotherapy.

Dose-dependent thresholds of dexamethasone destabilize CAR T-cell treatment efficacy.

Chimeric antigen receptor (CAR) T-cell therapy is potentially an effective targeted immunotherapy for glioblastoma, yet there is presently little known about the efficacy of CAR T-cell treatment when combined with the widely used anti-inflammatory and immunosuppressant glucocorticoid, dexamethasone. Here we present a mathematical model-based analysis of three patient-derived glioblastoma cell lines treated in vitro with CAR T-cells and dexamethasone. Advanced in vitro experimental cell killing assay technologies allow for highly resolved temporal dynamics of tumor cells treated with CAR T-cells and dexamethasone, making this a valuable model system for studying the rich dynamics of nonlinear biological processes with translational applications. We model the system as a nonautonomous, two-species predator-prey interaction of tumor cells and CAR T-cells, with explicit time-dependence in the clearance rate of dexamethasone. Using time as a bifurcation parameter, we show that (1) dexamethasone destabilizes coexistence equilibria between CAR T-cells and tumor cells in a dose-dependent manner and (2) as dexamethasone is cleared from the system, a stable coexistence equilibrium returns in the form of a Hopf bifurcation. With the model fit to experimental data, we demonstrate that high concentrations of dexamethasone antagonizes CAR T-cell efficacy by exhausting, or reducing the activity of CAR T-cells, and by promoting tumor cell growth. Finally, we identify a critical threshold in the ratio of CAR T-cell death to CAR T-cell proliferation rates that predicts eventual treatment success or failure that may be used to guide the dose and timing of CAR T-cell therapy in the presence of dexamethasone in patients.

Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside.

Glioblastoma multiforme (GBM) is an aggressive and dismal disease with a median overall survival of around 15 months and a 5-year survival rate of 7.2%. Owing to genetic mutations, drug resistance, disruption to the blood–brain barrier (BBB)/blood–brain tumor barrier (BBTB), and the complexity of the immunosuppressive environment, the therapeutic approaches to GBM represent still major challenges. Conventional therapies, including surgery, radiotherapy, and standard chemotherapy with temozolomide, have not resulted in satisfactory improvements in the overall survival of GBM patients. Among cancer immunotherapeutic approaches, we propose that adjuvant NKT immunotherapy with invariant NKT (iNKT) and cytokine-induced killer (CIK) cells may improve the clinical scenario of this devastating disease. Considering this, herein, we discuss the current strategies of NKT therapy for GBM based primarily on in vitro/in vivo experiments, clinical trials, and the combinatorial approaches with future therapeutic potential.

Prolonged response of recurrent IDH-wild-type glioblastoma to laser interstitial thermal therapy with pembrolizumab.

Despite the improved understanding of the molecular and genetic heterogeneity of glioblastoma, there is still an unmet need for better therapeutics, as treatment approaches have remained unchanged in recent years. Research into the role of the immune microenvironment has generated enthusiasm for testing immunotherapy (specifically, immune checkpoint inhibitors). However, to date, trials of immunotherapy in glioblastoma have not demonstrated a survival advantage. Combination approaches aimed at optimally inducing response to immune checkpoint inhibitors with radiotherapy are currently being investigated. Herein, the authors describe their experience of the potential benefit and clinical outcomes of using combination pembrolizumab (an immune checkpoint inhibitor) and laser interstitial thermal therapy in a case series of patients with recurrent IDH-wild-type glioblastoma.

Interactions Between Anti-Angiogenic Therapy and Immunotherapy in Glioblastoma.

Glioblastoma is the most aggressive brain tumor with a median survival ranging from 6.2 to 16.7 months. The complex interactions between the tumor and the cells of tumor microenvironment leads to tumor evolution which ultimately results in treatment failure. Immunotherapy has shown great potential in the treatment of solid tumors but has been less effective in treating glioblastoma. Failure of immunotherapy in glioblastoma has been attributed to low T-cell infiltration in glioblastoma and dysfunction of the T-cells that are present in the glioblastoma microenvironment. Recent advances in single-cell sequencing have increased our understanding of the transcriptional changes in the tumor microenvironment pre and post-treatment. Another treatment modality targeting the tumor microenvironment that has failed in glioblastoma has been anti-angiogenic therapy such as the VEGF neutralizing antibody bevacizumab, which did not improve survival in randomized clinical trials. Interestingly, the immunosuppressed microenvironment and abnormal vasculature of glioblastoma interact in ways that suggest the potential for synergy between these two therapeutic modalities that have failed individually. Abnormal tumor vasculature has been associated with immune evasion and the creation of an immunosuppressive microenvironment, suggesting that inhibiting pro-angiogenic factors like VEGF can increase infiltration of effector immune cells into the tumor microenvironment. Remodeling of the tumor vasculature by inhibiting VEGFR2 has also been shown to improve the efficacy of PDL1 cancer immunotherapy in mouse models of different cancers. In this review, we discuss the recent developments in our understanding of the glioblastoma tumor microenvironment specially the tumor vasculature and its interactions with the immune cells, and opportunities to target these interactions therapeutically. Combining anti-angiogenic and immunotherapy in glioblastoma has the potential to unlock these therapeutic modalities and impact the survival of patients with this devastating cancer.

Biomimetic nanoparticles directly remodel immunosuppressive microenvironment for boosting glioblastoma immunotherapy

Glioblastoma (GBM), as a very aggressive cancer of central nervous system, is very challenging to completely cure by the conventional combination of surgical resection with radiotherapy and chemotherapy. The success of emerging immunotherapy in hot tumors has attracted considerable interest for the treatment of GBM, but the unique tumor immunosuppressive microenvironment (TIME) of GBM leads to the failure of immunotherapy. Here, we show the significant improvement of the immunotherapy efficacy of GBM by modulating the TIME through novel all-in-one biomimetic nanoparticles (i.e. CS-I/J@CM NPs). The nanoparticles consist of utrasmall Cu2-xSe nanoparticles (NPs) with outstanding intrinsic properties (e.g., photo-responsive Fenton-like catalytic property for inducing immunogenic cell death (ICD) and alleviating the hypoxia of tumor), indoximod (IND, an inhibitor of indoleamine-2,3-dioxygenease in tumor), JQ1 (an inhibitor for reducing the expression of PD-L1 by tumor cells), and tumor cell membrane for improving the targeting capability and accumulation of nanoparticles in tumor. We reveal that these smart CS-I/J@CM NPs could drastically activate the immune responses through remodeling TIME of GBM by multiple functions. They could (1) increase M1-phenotype macrophages at tumor site by promoting the polarization of tumor-associated macrophages through the reactive oxygen species (ROS) and oxygen generated from the Fenton-like reaction between nanoparticles and H2O2 within tumor under NIR II irradiation; (2) decrease the infiltration of Tregs cells at tumor site through the release of IND; (3) decrease the expression of PD-L1 on tumor cells through JQ1. The notable increments of anti-tumor CD8+T cells in the tumor and memory T cells (TEM) in the spleen show excellent therapy efficacy and effectively prevent the recurrence of GBM after modulation of the TIME. This work demonstrates the modulation of TIME could be a significant strategy to improve the immunotherapy of GBM and other cold tumors.

Abstract P022: Reciprocal influence of immune response and tumor hypoxia during glioblastoma progression

Abstract Tumor hypoxia is linked to poor outcome for glioblastoma (GBM), a highly malignant brain cancer, but underlying mechanisms and instigators that initiate tumor hypoxia remain unclear. We tracked tumor hypoxia in GBM in mice using a sensitive fluorescent reporter. We revealed that tumor hypoxia functions as a critical link between immune cells and tumor cells that drives malignant potency and immunosuppression in GBM. Single-cell RNA sequencing analysis revealed that hypoxic GBM cells are quiescent, display a mesenchymal transition, are more represented in recurrent GBM and predict worse patient outcome. Interestingly, the in vivo GBM hypoxia gene signatures surprisingly showed an enrichment for immune pathways. We unveiled two potential mechanisms of hypoxia-induced immunosuppression: by sequestrating activated immune cells in hypoxia zones, thus limiting inflammatory spread and cutting off immune cell communication, and by reprograming entrapped immune cells towards an immunotolerant state. Reciprocally, entrapped TAMs release CCL8 and IL1β as hypoxic niche factors that not only reinforce immune cell retainment in hypoxic cores, but also shape the transcriptional response of hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia; attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion greatly decreased GBM hypoxia. Altogether, our study revealed a reciprocal influence of anticancer immunity and tumor hypoxia, which has significant ramifications for prognosis and immunotherapy for GBM. Citation Format: Anirudh Sattiraju, Valerie Marallano, Zhihong Chen, Sangjo Kang, Concetta Brusco, Aarthi Ramakrishnan, Li Shen, Dolores Hambardzumyan, Roland H. Friedel, Hongyan Zou. Reciprocal influence of immune response and tumor hypoxia during glioblastoma progression [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P022.

Sexual dimorphism of the immune system predicts clinical outcomes in glioblastoma immunotherapy: A systematic review and meta-analysis.

BackgroundBiological differences based on sex have been documented throughout the scientific literature. Glioblastoma (GBM), the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exists.MethodWe analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and GBM outcome following immunotherapy.ResultsWe found that in general females possess enriched immunological signatures on gene set enrichment analysis, which also stratified patient survival when delineated by sex. Female GBM patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (relative risk [RR] = 1.15; P = .0241). This effect was even more pronounced in vaccine-based immunotherapy (RR = 1.29; P = .0158).ConclusionsOur study shows a meaningful difference in the immunobiology between males and females that also influences the overall response to immunotherapy in the setting of GBM.

Systemic high-dose dexamethasone treatment may modulate the efficacy of intratumoral viral oncolytic immunotherapy in glioblastoma models

BackgroundIntratumoral viral oncolytic immunotherapy is a promising new approach for the treatment of a variety of solid cancers. CAN-2409 is a replication-deficient adenovirus that delivers herpes simplex virus thymidine kinase...