Immunotherapy against Gliomas

Immunotherapy has been demonstrably effective against various cancers, particularly those in the hematopoietic system and those with a high tumor-specific antigenic burden. Unfortunately, the development of immunotherapeutic strategies has proven more challenging against central nervous system (CNS) malignancies due to several unique characteristics of brain tumors that pose extraordinary barriers. To date, there is a lack of phase III trials demonstrating improved progression-free survival (PFS) and/or overall survival (OS) using immunotherapies in brain cancers. However, a better mechanistic understanding of current resistance to immunotherapies along with data from novel innovative techniques to overcome these barriers has been encouraging. This chapter gives an overview of current immunotherapies in the development of brain cancers. We will evaluate the present studies available in the clinical setting and any of their potential findings. The chapter will also discuss pertinent preclinical strategies whose translation for human use would potentially prove efficacious or provide invaluable scientific discovery.

Characterization and Prognosis of Temozolomide-Induced Aplastic Anemia

Introduction: Temozolomide-induced aplastic anemia (TIAA) is a very rare and highly challenging complication of temozolomide (TMZ) chemotherapy. TMZ is a mainstay of therapy in patients with central nervous system (CNS) malignancies. Single-patient case reports and small case series have described variable morbidity and mortality associated with TIAA. However, quantitative evidence describing prognosis, clinical characteristics, and treatment of this entity is absent or very limited. Methods: We performed a 5-center, 22-year observational cohort study of patients with CNS malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. We compared patients who achieved meaningful hematologic recovery [partial hematologic recovery (PHR) or complete hematologic recovery (CHR)] to those who did not recover [refractory disease (RD)]. We used descriptive statistics, T-tests, and chi-square tests to evaluate patient characteristics, outcomes, and laboratory values. Overall time to hematologic recovery and overall survival of patients with PHR, CHR, and RD were estimated using the Kaplan-Meier method and compared using the log-rank test, and a multivariable logistic model evaluated potential predictors of achieving CHR. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery (TABLE 1). Results: Study Population and TIAA Prevalence. Of 3,821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA (FIGURE 1). Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle (TABLE 2). Complications and Outcomes of Hematologic Recovery. 23 patients (67.6%) ultimately achieved a hematologic recovery and the remaining 11 patients (32.4%) had refractory disease. Figure 2A illustrates the time from TIAA diagnosis to PHR and CHR for the cohort. In Kaplan-Meier survival analysis, the median time from TIAA diagnosis to PHR was 84 days and the median time to CHR was 134 days. Patients without recovery were more likely to develop serious complications (TABLE 3), including febrile neutropenia (72.7% vs. 30.4%, P=0.03), major infection (45.5% vs. 8.7%, P=0.02), hospitalization (81.8% vs. 43.5%, P=0.04), and death (100.0% vs. 60.9%, P=0.02). This increased risk of complications in patients not achieving hematologic recovery was observed despite a similar median time from TMZ initiation to TIAA diagnosis in the two groups (45 days vs. 40 days). Figure 2B illustrates the overall survival in the entire cohort and by each hematologic recovery subgroup. In Kaplan-Meier survival analysis, median overall survival from the time of TIAA diagnosis was as follows: entire cohort, 355 days; achieved PHR, 752 days; achieved CHR, 1414 days; refractory disease, 28 days (P<0.0001 for comparison of PHR, CHR, and refractory disease). In a multivariable logistic model, none of the evaluated covariates (age, sex, TMZ dose, body surface area, and use of hematopoietic growth factors) were significantly associated with achieving CHR. Treatment of TIAA and Outcomes of Therapy. 29 patients (85.3%) received hematopoietic growth factors (TABLE 3); no patients were treated with immunosuppression or hematopoietic stem cell transplant. Hematologic recovery rates were numerically higher in patients receiving thrombopoietin receptor agonists vs. those who did not (81.8% vs. 54.2%, P=0.15), but were not higher in patients receiving granulocyte colony stimulating factors vs. those who did not (68.0% vs. 66.7%, P=0.99). Conclusions: TIAA occurs in less than 1% of patients receiving temozolomide for CNS malignancies, occurring rapidly after TMZ initiation, but is highly morbid and often fatal when it occurs, precluding further use of cytotoxic therapy in the vast majority of patients. In the one-third who do not recover, risks of febrile neutropenia, infection, and hospitalization are increased, and overall survival greatly diminished. Hematologic recovery is potentially aided by the use of thrombopoietin receptor agonists, as has been demonstrated in classical autoimmune aplastic anemia. Further study of TIAA treatment is needed for this serious complication of TMZ therapy. Figure 1 Figure 1. Disclosures Forst: Eli Lilly: Current holder of individual stocks in a privately-held company. Al-Samkari: Rigel: Consultancy; Argenx: Consultancy; Moderna: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

Pediatric Brain Tumors: From Modern Classification System to Current Principles of Management

Central nervous system (CNS) malignancies contribute significantly to the global burden of cancer. Brain tumors constitute the most common solid organ tumors in children and the second most common malignancies of childhood overall. Accounting for nearly 20% of all pediatric malignancies, these are the foremost cause of cancer-related deaths in children 0–14 years of age. This book chapter provides a state-of-the-art overview of pediatric brain tumors. It discusses their morbidity and mortality and introduces the WHO 2021 classification of CNS tumors, which is critical to therapeutic decision-making. It then describes the modern understanding of tumor grading and its clinical implications, followed by the general principles of diagnosis and management. The chapter then discusses, in detail, those brain tumors which have the highest disease burden in children, including medulloblastoma, astrocytoma, ependymoma, schwannoma, meningioma, amongst others. The landscape of treatment of pediatric brain tumors has been rapidly evolving, with several effective therapies on the horizon.

Isolated High-Grade Malignancy of the Spinal Cord Presenting as Longitudinally Extensive Transverse Myelitis

This article characterizes 2 cases of longitudinally extensive transverse myelitis (LETM) that did not respond to immunotherapy and were diagnosed by biopsy as primary central nervous system (CNS) malignancies. Diffuse H3 K27M-mutant glioma is a recently described entity with very few cases of isolated spinal disease described in adults. Primitive neuroectodermal tumor is similarly uncommon in the spinal cord. Malignancies should be considered in patients who fail to improve with immunomodulatory therapy. We believe the experiences of our center will raise awareness about that point, broaden the existing understanding of the diagnostic approach to LETM, and highlight the need for additional studies.

Histone-mutant glioma presenting as diffuse leptomeningeal disease

Glioblastoma multiforme is the most common malignant primary brain tumor in adults. Histone H3 mutations have been identified in pediatric and adult gliomas, with H3K27M mutations typically associated with a posterior fossa midline tumor location and poor prognosis. Leptomeningeal disease is a known complication of histone-mutant glioma, but uncommon at the time of initial diagnosis. We describe a case of glioblastoma with H3K27M mutation that initially presented with progressive vision loss due to diffuse leptomeningeal disease in the absence of a mass lesion other than a small cerebellar area of enhancement and with cerebrospinal fluid cytology negative for malignant cells on two occasions, highlighting the importance of including primary CNS malignancies in the differential of diffuse radiographic leptomeningeal enhancement.

Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance

According to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.

IMMU-03. CHARACTERIZING THE IMMUNE MICROENVIRONMENT OF PEDIATRIC BRAIN TUMORS

Therapy for pediatric central nervous system (CNS) malignancies can be toxic, and outcomes are suboptimal. Immunotherapy holds promise as a therapeutic avenue, but one of the challenges in its application is the poorly understood microenvironment of pediatric CNS tumors. The Children’s Brain Tumor Network released the Pediatric Brain Tumor Atlas, containing the expression profile of nearly 700 primary CNS tumors. To study the immune microenvironment, a classification from The Cancer Genome Atlas project is applied. High-grade lesions are predominantly lymphocyte deplete (C4, 80%) or immunologically quiet (C5, 7.6%). Low-grade lesions are more mixed with 43% C4, 26% C5, and a higher proportion of inflammatory subtype (C3, 28%). For survival parameters, immune subtype and tumor grade are associated. Using a multivariate cox regression model, the hazard ratio is 2.2 (0.86 – 5.4, p = 0.102) and 3.6 (1.2 – 10.9, p = 0.02) for C4 and C5, respectively. Deconvolution of immune cell gene signatures provides insight into the phenotype of lymphocyte infiltrate, which averages 8.6% (IQR 5.4% – 9.8%) across all samples. For high-grade samples, greater than median expression of T cell-, monocyte-, macrophage-, and B cell-gene signatures are each associated with decreased survival (p < 0.05). Microglia gene signatures have decreased relative expression in high-grade samples compared to low-grade samples (p < 0.001). It is hypothesized that the expression of inhibitory immunomodulators contributes to a pro-tumorigenic microenvironment and represent potential therapeutic targets. In the absence of normal samples in the data set, differential gene expression experiments between disease states can reveal upregulated immunomodulators. Focusing on diffuse midline glioma, immunologic pathways are downregulated. Furthermore, 9 inhibitory immunomodulators, including KDM1A, EZH2, CD276, and VTCN1, are significantly expressed relative to midline low-grade glioma with equivalent immune subtype. Overall, our analysis contributes to the understanding of the immune microenvironment and mechanisms of immune escape for pediatric CNS malignancies.

EPCT-24 THE REMIND TRIAL: MULTI-ANTIGEN TARGETED T CELLS FOR PEDIATRIC CNS TUMORS

Background Patients with relapsed CNS malignancies or DIPG face terrible prognoses. We hypothesized that T cells specific for 3 tumor-associated antigens (TAA), WT1, PRAME and survivin, would be safe and elicit anti-tumor immunity. Methods Patients (n=18) received autologous tumor antigen-associated T cells (TAAT) (up to 8x107/m2) for newly diagnosed DIPG (Group A) or recurrent CNS malignancies (Group B) on a Phase I dose-escalation study (NCT03652545) and were monitored for safety and response. Results/Discussion 16/18 patients who received TAAT completed the 45-day safety monitoring phase with no dose-limiting toxicities. Adverse events were minimal despite multiple pretreatments in Group B. Infused cells were predominantly CD3+ T cells (median 96%; range: 87–99%), with CD4+ and CD8+ comprising 16% (range: 5–87%) and 40% (range: 4–67%) respectively. Specificity for 1–3 TAAs was demonstrated in 11/18 TAAT by a-IFN-γ ELISPOT. Dose escalation is complete, and clinical and immunologic response assessments are ongoing. Plasma cytokine and proteomic analyses demonstrated dynamic post-infusion immune cytokine and protein responses. Consistent with an infusion-mediated immune response all patients in Grp A showed increased T cell effector, inflammatory and immune-stimulatory cytokines IFN-γ, TNF-α, IL-2, IL-5, IL-7, IL-1β, IL-6, IL-8, IL-12p70, IL-17A and GM-CSF at Weeks 1 and 2 post-infusion (n = 6). Of 9 patients who have been tested, 29/92 plasma proteins showed significant differences between dose levels 1 and 2, including increased IL-7 (p <0.0004) and CD40L (p <0.046) and reduced IL-4 (p <0.0004). T cell receptor sequencing showed expansion and persistence of clones detected in infusion products. In summary, TAAT have thus far been safe and elicit immune responses in vivo. Clinical and immunologic response assessments are ongoing.