Altered cancer metabolism and implications for next-generation CAR T-cell therapies.

This review critically examines the evolving landscape of chimeric antigen receptor (CAR) T-cell therapy in treating solid tumors, with a particular focus on the metabolic challenges within the tumor microenvironment. CAR T-cell therapy has demonstrated remarkable success in hematologic malignancies, yet its efficacy in solid tumors remains limited. A significant barrier is the hostile milieu of the tumor microenvironment, which impairs CAR T-cell survival and function. This review delves into the metabolic adaptations of cancer cells and their impact on immune cells, highlighting the competition for nutrients and the accumulation of immunosuppressive metabolites. It also explores emerging strategies to enhance CAR T-cell metabolic fitness and persistence, including genetic engineering and metabolic reprogramming. An integrated approach, combining metabolic interventions with CAR T-cell therapy, has the potential to overcome these constraints and improve therapeutic outcomes in solid tumors.

Suppression of antitumor immune signatures and upregulation of VEGFA as IDH-mutant gliomas progress to higher grade.

OBJECTIVE: Several studies have compared the immune microenvironment of isocitrate dehydrogenase (IDH)-wildtype glioma versus IDH-mutant glioma. The authors sought to determine whether histological tumor progression in a subset of IDH-mutant glioma was associated with concomitant alterations in the intratumoral immune microenvironment. METHODS: The authors performed bulk RNA sequencing on paired and unpaired samples from patients with IDH-mutant glioma who underwent surgery for tumor progression across multiple timepoints. They compared patterns of differential gene expression, overall inflammatory signatures, and transcriptomic measures of relative immune cell proportions. RESULTS: A total of 55 unique IDH-mutant glioma samples were included in the analysis. The authors identified multiple genes associated with progression and higher grade across IDH-mutant oligodendrogliomas and astrocytomas. Compared with lower-grade paired samples, grade 4 IDH-mutant astrocytomas uniquely demonstrated upregulation of VEGFA in addition to counterproductive alterations in inflammatory score reflective of a more hostile immune microenvironment. CONCLUSIONS: Here, the authors have provided a transcriptomic analysis of a progression cohort for IDH-mutant glioma. Compared with lower-grade tumors, grade 4 astrocytomas displayed alterations that may inform the timing of antiangiogenic and immune-based therapy as these tumors progress.

County-level disparities in care for patients with glioblastoma.

OBJECTIVE: Racial and socioeconomic disparities in neuro-oncological care for patients with brain tumors remain underexplored. This study aimed to analyze county-level disparities in glioblastoma (GBM) care in the United States, focusing on access to surgery and the use of adjuvant temozolomide chemotherapy and radiation therapy. METHODS: Using repeated cross-sectional data from the Surveillance, Epidemiology, and End Results 17 database; the Area Health Resources File; and the American Community Survey, from 2010 to 2019, the authors performed multivariate regression analyses to understand the associations between county-level racial and socioeconomic characteristics, as well as the rates of surgery performed, delays in surgery, and use of adjuvant chemotherapy and radiation therapy for newly diagnosed GBM. RESULTS: In total, 29,609 GBM patients from 602 different US counties over a decade were included in this study. Counties with lower rates of surgery for GBM were associated with a higher percentage of Black residents (coefficient [CE] -0.001, 95% CI -0.002 to 0; p < 0.05) and being located in the Midwest (CE -0.132, 95% CI -0.195 to -0.069; p < 0.001) or West (CE -0.127, 95% CI -0.189 to -0.065; p < 0.001) relative to the Northeast. Counties with delayed surgical treatment were more likely to lack neurosurgeons (adjusted OR [aOR] 2.52, 95% CI 1.77-3.60; p < 0.001), have a higher percentage of Black residents (aOR 1.011, 95% CI 1.00-1.02; p < 0.05), and be located in the Midwest (aOR 3.042, 95% CI 1.12-8.24; p < 0.05) or West (aOR 3.175, 95% CI 1.12-8.97 p < 0.05). Counties with high rates of adjuvant radiation therapy were less likely to have higher percentages of Black residents (aOR 0.987, 95% CI 0.980-0.995; p < 0.01) and uninsured individuals (aOR 0.962, 95% CI 0.937-0.987; p < 0.01). CONCLUSIONS: Counties without neurosurgeons and those with a higher percentage of Black patients have delays in surgical care and demonstrate lower overall rates of surgery and adjuvant therapy for GBM. This study underscores the need for targeted interventions and policies that address structural barriers in healthcare access, improve equitable distribution of the neurosurgery workforce, and ensure timely and comprehensive GBM care to all populations.

The Role of Antibody-Based Therapies in Neuro-Oncology.

This review explores the evolving landscape of antibody-based therapies in neuro-oncology, in particular, immune checkpoint inhibitors and immunomodulatory antibodies. We discuss their mechanisms of action, blood-brain barrier (BBB) penetration, and experience in neuro-oncological conditions. Evidence from recent trials indicates that while these therapies can modulate the tumor immune microenvironment, their clinical benefits remain uncertain, largely due to challenges with BBB penetration and tumor-derived immunosuppression. This review also examines emerging targets such as TIGIT and LAG3, the potential of antibodies in modulating the myeloid compartment, and tumor-specific targets for monoclonal antibody therapy. We further delve into advanced strategies such as antibody-drug conjugates and bispecific T cell engagers. Lastly, we explore innovative techniques being investigated to enhance antibody delivery, including CAR T cell therapy. Despite current limitations, these therapies hold significant therapeutic potential for neuro-oncology. Future research should focus on optimizing antibody delivery to the CNS, identifying novel biological targets, and discovering combination therapies to address the hostile tumor microenvironment.

Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients.

PURPOSE: We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916). PATIENTS AND METHODS: Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6). Bavituximab was given weekly, starting week 1 of chemoradiotherapy, for at least 18 weeks. The primary endpoint was proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥72%. Relative cerebral blood flow (rCBF) and vascular permeability (Ktrans) were calculated from perfusion MRIs. Peripheral blood mononuclear cells and tumor tissue were analyzed pre-treatment and at disease progression using RNA transcriptomics and multispectral immunofluorescence for myeloid-derived suppressor cells (MDSC) and macrophages. RESULTS: The study met its primary endpoint with an OS-12 of 73% (95% confidence interval, 59%-90%). Decreased pre-C1 rCBF (HR, 4.63; P = 0.029) and increased pre-C1 Ktrans were associated with improved overall survival (HR, 0.09; P = 0.005). Pre-treatment overexpression of myeloid-related genes in tumor tissue was associated with longer survival. Post-treatment tumor specimens contained fewer immunosuppressive MDSCs (P = 0.01). CONCLUSIONS: Bavituximab has activity in newly diagnosed GBM and resulted in on-target depletion of intratumoral immunosuppressive MDSCs. Elevated pre-treatment expression of myeloid-related transcripts in GBM may predict response to bavituximab.

Tandem chimeric antigen receptor (CAR) T cells targeting EGFRvIII and IL-13Rα2 are effective against heterogeneous glioblastoma.

Background: Chimeric antigen receptor (CAR) T cells have achieved remarkable responses in patients with hematological malignancies; however, the potential of this therapeutic platform for solid tumors like glioblastoma (GBM) has been limited, due in large part to the targeting of single antigens in a heterogeneous disease. Strategies that allow CAR T cells to engage multiple antigens concomitantly may broaden therapeutic responses and mitigate the effects of immune escape. Methods: Here we have developed a novel, dual-specific, tandem CAR T (TanCART) cell with the ability to simultaneously target both EGFRvIII and IL-13Rα2, two well-characterized tumor antigens that are frequently found on the surface of GBM cells but completely absent from normal brain tissues. We employed both standard immunological assays and multiple orthotopic preclinical models including patient-derived xenograft to demonstrate efficacy of this approach against heterogeneous tumors. Results: Tandem CAR T cells displayed enhanced cytotoxicity in vitro against heterogeneous GBM populations, including patient-derived brain tumor cultures (P < .05). Compared to CAR T cells targeting single antigens, dual antigen engagement through the tandem construct was necessary to achieve long-term, complete, and durable responses in orthotopic murine models of heterogeneous GBM, including patient-derived xenografts (P < .05). Conclusions: We demonstrate that TanCART is effective against heterogeneous tumors in the brain. These data lend further credence to the development of multi-specific CAR T cells in the treatment of GBM and other cancers.

Implications of IDH mutations on immunotherapeutic strategies for malignant glioma.

Immunotherapy has emerged as a promising approach for treating aggressive solid tumors, even within the CNS. Mutation in the metabolic gene isocitrate dehydrogenase 1 (IDH1) represents not only a major glioma defining biomarker but also an attractive therapeutic neoantigen. As patients with IDH-mutant glioma enter early-phase vaccine and immune checkpoint inhibitor clinical trials, there is emerging evidence that implicates the oncometabolite, 2-hydroxyglutarate (2HG), generated by the neomorphic activity of mutant IDH, as a potential barrier to current immunotherapeutic approaches. Here, the authors review the immunomodulatory and immunosuppressive roles of 2HG within the unique IDH-mutant glioma tumor immune microenvironment and discuss promising immunotherapeutic approaches currently being investigated in preclinical models.

Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma.

Cancer-associated fibroblasts (CAFs) are activated fibroblasts constituting the major stromal components in many types of cancer. CAFs contribute to hallmarks of cancer such as proliferation, invasion and immunosuppressive tumor microenvironment, and are associated with poor prognosis of patients with cancer. However, in glioblastoma (GBM), the most common and aggressive primary malignant brain tumor, our knowledge about CAFs or CAF-like stromal cells is limited. Here, using commonly accepted CAF markers, we characterized CAF-like cell populations in clinical glioma specimens and datasets along with mouse models of GBM. We found that tumor-associated pericytes marked by co-expression of fibroblast activation protein α (FAP) and PDGFRß represent major stromal cell subsets in both human GBM and mouse GBM models, while a fraction of mesenchymal neoplastic cells also express FAP in patient tumors. Since oncolytic viruses can kill cancer cells and simultaneously modulate the tumor microenvironment by impacting non-neoplastic populations such as immune cells and tumor vasculature, we further investigated the ability of oncolytic viruses to target GBM-associated stromal cells. An oncolytic adenovirus, ICOVIR15, carrying ∆24-E1A and an RGD-fiber, infects and depletes FAP+ pericytes as well as GBM cells in murine GBM. Our study thus identifies FAP+/PDGFRß+ pericytes as a major CAF-like stromal cell population in GBM, and highlights the unique property of this oncolytic adenovirus to target both GBM cells and GBM-associated stromal FAP+ cells.

IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice.

The metabolic gene isocitrate dehydrogenase 1 (IDH1) is commonly mutated in lower grade glioma (LGG) and secondary glioblastoma (GBM). Regulatory T cells (Tregs) play a significant role in the suppression of antitumor immunity in human glioma. Given the importance of Tregs in the overall framework of designing immune-based therapies, a better understanding on their association with IDH mutational status remains of critical clinical importance. Using multispectral imaging analysis, we compared the incidence of Tregs in IDH-mutant and IDH wild-type glioma from patient tumor samples of LGG. An orthotopic IDH-mutant murine model was generated to evaluate the role of mutant IDH on Treg infiltration by immunohistochemistry. When compared to IDH wild-type controls, Tregs are disproportionally underrepresented in mutant disease, even when taken as a proportion of all infiltrating T cells. Our findings suggest that therapeutic agents targeting Tregs may be more appropriate in modulating the immune response to wild-type disease.