Recent Developments in Glioblastoma Therapies

INTRODUCTION

According to the National Cancer Institute website, glioblastoma is a fast-growing type of central nervous system tumor that forms from glial (supportive) tissue of the brain and spinal cord. Glioblastoma usually occurs in adults and affects the brain more often than the spinal cord. Glioblastomas are also sometimes called Glioblastoma Multiforme (GBM) or grade IV astrocytoma.¹ GBMs are the most aggressive and deadly type of tumor of the central nervous system and account for 60% to 70% of all gliomas.²

GBM is notoriously difficult to treat. It frequently proves resistant to treatment, recurs often, and almost always comes with a poor prognosis. It can result in death in six months or less if untreated and even with standard of care treatment, patients living two years after diagnosis are considered long-term survivors. Treatment of GBM is challenging due to many factors including localization of tumors in the brain, resistance to therapy, migration of malignant cells into nearby brain tissue, and the disrupted tumor blood supply, which reduces successful drug delivery.³ New treatments often fail to cross the blood-brain barrier, making therapies that could otherwise be effective unable to reach the cancer cells.⁴

Given the difficulty of treatment and the poor prognosis for GBM, the need for new approaches for treatment is clearly urgent. Researchers and biopharma companies continue to search for and test new developments to address the difficulties in the hopes of improving prognoses.

ADVANCES IN PRODUCTION AND DELIVERY

One promising approach for research and development of new therapies for GBM in recent years has been immunotherapy. Many techniques have been studied, including immune checkpoint inhibitors, T cell transfer, vaccination, and viral approaches. Unfortunately, the efficacy of these techniques has been reduced due to several factors such as the physical blood-brain barrier, the immunosuppressive nature of GBM, and tumor heterogeneity.⁵ These difficulties have led to more new approaches such as those outlined below.

• Combination Therapies: Researchers at the Dana Farber Cancer Institute and the University of Cincinnati Medical Center are conducting a Phase 1b study to investigate a combination immunotherapy approach with an anti-TIGIT monoclonal antibody and Cemiplimab (NCT04826393), which belongs to a class of drugs that binds to the programmed death receptor-1, blocking the PD-1/PD-L1 pathway. Researchers hope this two-pronged approach will be more successful than past trials with a single treatment.⁶Another combinatory approach being investigated in preclinical models is immunotherapy paired with a new technology of microbubble-enhanced focused ultrasound (MB-FUS). MB-FUS may offer the transitory permeabilization needed to deliver immuno-therapeutics while bypassing the blood-brain barrier and directly focusing on the tumor microenvironment.⁷
• Dual-Target CAR T-Cell Therapy: Researchers at Penn Medicine are studying a new type of Chimeric Antigen Receptor cellular therapy (CAR) that may help address the inherent heterogeneity of GBM (meaning not all cells within a GBM tumor are the same or have the same antigen that a CAR T cell is engineered to attack). The newer CAR targets both the antigens EGFRvII and IL-13Rα2 with the hope that it will get more cell coverage by adding a molecule to the CAR T cells expressing both binding domains to attack more cells.⁸
• Vaccines and Viruses: Another area of interest in the field of immunotherapy for GBM is the use of tumor vaccines, especially peptide vaccines and cell-based vaccines such as dendritic cell vaccines and tumor cell vaccines.⁹ While vaccines targeted to GBM have not met primary endpoints in Phase III clinical trials, there is optimism for combining vaccines with other treatments such as immune checkpoint inhibitors.¹⁰Engineered viruses that kill tumor cells via direct oncolysis and stimulation of antitumor immune responses are another possible way to address GBM’s immunosuppressive microenvironment, although most clinical trials are at an early stage.¹¹ One recent preclinical trial of an oncolytic Zika virus showed antitumor immune response in the GBM microenvironment and overcame resistance to PD-L1 blockade in mouse GBM models.¹²

OTHER ADVANCES IN TREATMENT

In addition to immunotherapy treatment advances in GBM, new targeted therapies and a metabolite-based therapy are being studied.

• Targeted Therapies: Selinexor, previously approved by the FDA for treatment of multiple myeloma and large B-cell lymphoma, is now being studied for GBM. Selinexor inhibits exportin-1 (XPO-1), a major exporter of proteins from the nucleus to the cytoplasm that is overexpressed in many cancers, including GBM. A phase 2 trial of the treatment in GBM showed a reduction in tumor size for 28% of patients.¹³Another approach being studied is the inhibition of mutant IDH1 and IDH2 enzymes. While two mIDH targeted inhibitors have been approved by the FDA for treatment of Acute Myeloid Leukemia, they both show limited brain drug exposure. Studies are being undertaken to find a dual inhibitor for low grade gliomas.¹⁴ A Phase II clinical study is planned to examine AB-218 (NCT05303519), in participants with recurrent or progressive histologically confirmed IDH1 mutant WHO Grade 2/3 glioma. AB-218 is a brain-penetrant mIDH1 inhibitor planned for multiple solid tumors with IDH1 mutations.¹⁵
• Metabolic Approach Researchers at the University of Michigan Rogel Cancer Center are studying a way to make radiation therapy more effective in treating GBM by targeting the metabolic pathway that makes purines, a building block of DNA. Early studies suggest that high purine levels are associated with treatment resistance and may even cause resistance. The program looks at the FDA-approved purine blocker mycophenolate mofetil, used to prevent organ rejection in transplant patients, in combination with radiation treatment.¹⁶

RESPONSE ASSESSMENT IN NEURO-ONCOLOGY

Just as new developments in treatments are continually under study, the endpoints and response assessments for use in neuro-oncology clinical trials have been evolving over time. Response and progression are key radiographic endpoints for assessing new GBM treatments. Angiogenesis, or the formation of new blood vessels, is important for the growth of malignant brain tumors. Imaging techniques such as contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are used to diagnose and manage GBM because of they identify abnormal vascularity and permeability in gliomas. This is often associated with aggressivity and proliferation in gliomas.¹⁷

The first radiographic response assessment specific to brain tumors was introduced by Macdonald et al. in 1990 and formed the basis for the development of the formal Response Assessment in Neuro-Oncology (RANO) criteria in 2010. RANO criteria recommends bidimensional measurements of contrast enhancing measurable lesions, qualitative assessment of non-measurable enhancing lesions, corticosteroid dose change data, and clinical status to determine the progression or response. Additionally, RANO incorporates the assessment of non-enhancing lesions using T2/FLAIR sequence. It also aids with defining true radiographic versus pseudo progression, which has become more prominent in the era of anti-angiogenic and other treatments such as chemoradiotherapy which disturb vascular permeability.¹⁸

Since the introduction of RANO, many variations have been developed including Modified RANO (mRANO), Immunotherapy RANO (iRANO), and RANO-Low Grade Glioma (RANO-LGG). iRANO was developed to establish guidelines for response in patients treated with immunotherapy. Like efforts in solid tumor oncology, iRANO aims to discover and define criteria to reduce early declaration of progression, as true radiographic response is often preceded by transitory worsening.¹⁹ As new potential treatments for GBM are developed, the importance of standard and reliable criteria for objective assessment of treatment response are of great importance.

SUMMARY

In conclusion, effective treatments for GBM remain a large unmet need in oncology. Developing an effective treatment is difficult due to many factors, including localization of tumors in the brain, resistance to therapy, migration of malignant cells into nearby brain tissue, and the blood-brain barrier. New treatments continue to be developed to overcome these difficulties, however, offering hope to patients diagnosed with GBM.