Research News in the Sixth Two Months of 2024

Punctual as always, this is the twenty-ninth article of the project that aims to periodically collect (every two months) the research news on possible treatments for glioblastoma multiforme. Below I list the news that we considered most significant that emerged in the last two months. As with the previous articles in the series, each news item will be preceded by the original title with a link to the source and followed by a brief comment. The criterion with which the news items are chosen is always to generally include only news related to research in the clinical phase, unless the potential of research for the treatment of glioblastoma is truly remarkable.

UNC Lineberger brings investigative cancer treatment for glioblastoma patients in Southeastern US
UNC Lineberger Cancer Center is offering an expanded access program for an investigational therapy for patients with relapsed glioblastoma who have not responded to standard treatments. This therapy uses gallium maltolate, a drug administered orally once daily for at least three months. The program has been approved by the FDA and is available at three sites across the United States, with UNC Lineberger being the only participant in the Southeast. Interested patients can contact Camisha Johnson at 919-445-4847 or via email at camisha_johnson@med.unc.edu.

NuvOx Announces Two New Publications
NuvOx Pharma has announced the publication of two new scientific papers that delve deeper into how their drug candidate, NanO2™, works. The first article, published in Artificial Cells, Nanomedicine, and Biotechnology, titled “Dodecafluoropentane emulsion as an oxygen therapeutic,” explains the mechanism of action of NanO2™ in oxygen transport. The second article, published in the British Journal of Cancer Research, titled “A Phase 2 Double-Blind, Randomized, Prospective, Placebo Controlled Study of NanO2™ Combined with Radiation and Temozolomide in Patients with Newly-diagnosed Glioblastoma Multiforme; RESTORE,” describes the design of the Phase IIb clinical trial using NanO2™ to treat glioblastoma multiforme, an extremely aggressive form of brain cancer.

Phase 1 Trial of Personalized Neoantigen Vaccines in Combination with Standard of Care To Treat Glioblastoma
A Phase 1 clinical trial evaluated the use of genetically engineered autologous γδT cells in patients with newly diagnosed glioblastoma multiforme (GBM) during maintenance chemotherapy with temozolomide (TMZ). The γδT cells were engineered to express methylguanine-DNA methyltransferase (MGMT), making them resistant to TMZ and allowing them to attack tumor cells expressing NKG2D ligands during chemotherapy. As of January 31, 2024, 19 participants were enrolled after completing radiation therapy. Sixteen patients with at least 6 months of follow-up were included in the analysis. The median age was 32 years (range 18-68) and the median follow-up was 22.7 months (range 6.0-38.3). The disease control rate (DCR) was 100% at the end of radiotherapy and remained at 100% three months after radiotherapy (2 with partial response, 14 with stable disease). These preliminary results suggest that intracranial infusion of genetically modified γδ T cells can be considered safe and shows signs of clinical efficacy in patients with newly diagnosed GBM during treatment with TMZ.

Alpheus Medical Announces Positive Phase 1/2 Trial Results for the Treatment of Recurrent High-Grade Gliomas
Alpheus Medical, a privately held clinical-stage oncology company, announced positive results from its Phase 1/2 clinical trial for the treatment of recurrent or refractory high-grade gliomas. The proprietary therapy demonstrated a robust safety profile and extended median overall survival (OS) and progression-free survival (PFS) compared to historical data. Alpheus Medical’s noninvasive therapy, called sonodynamic therapy (SDT), combines low-intensity diffuse ultrasound (LIDU™) with oral 5-aminolevulinic acid (5-ALA) to target and destroy tumor cells in the brain while preserving surrounding healthy tissue. Key study results include: OS 15.7 months, compared to approximately 6-8 months historically; PFS 5.5 months, compared to 1.8 months historically; no treatment-related deaths, serious adverse events (SAEs) or life-limiting toxicities (DuLTs) reported.

Vorasidenib update at SNO
Vorasidenib, an oral inhibitor of IDH1 and IDH2 mutations, has shown consistent efficacy and a manageable safety profile in patients with IDH1/2-mutated diffuse glioma. Updated study results or Phase 3 INDIGO studies showed that vorasidenib resulted in a significant reduction in tumor size and improved seizure control compared to placebo. In addition, the drug demonstrated effective brain penetration, reducing tumor 2-hydroxyglutarate (2-HG) concentrations by more than 90% in non-enhancing grade 2 or 3 diffuse gliomas. These data suggest that vorasidenib could represent a promising therapeutic option for patients with IDH1/2-mutated diffuse glioma, offering a targeted treatment with an acceptable safety profile.

Immunotherapy for glioblastoma: current state, challenges, and future perspectives
As we know, glioblastoma (GBM) is an aggressive and lethal brain tumor in adults. Despite standard treatments, the majority of patients experience tumor recurrence. In recent years, significant progress has been made in the development of innovative immunotherapies to overcome resistance in many advanced tumors. However, the efficacy of these immune treatments in GBM is limited due to the unique characteristics of the brain immune system, tumor cell heterogeneity, and an immunosuppressive tumor microenvironment. This article provides a detailed overview of current immunotherapy strategies, discusses the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM, and proposes strategies to overcome this resistance, highlighting the importance of combination therapies. The article proposes several strategies to overcome these challenges such as: exploiting nanoparticles to improve drug delivery across the blood-brain barrier; combining immune checkpoint inhibitors with radiotherapy, chemotherapy, or targeted therapies to improve efficacy; integrating CAR-T therapies with treatments that modulate the tumor microenvironment; identifying novel GBM-specific targets, such as proteins selectively expressed by tumor cells; and using technologies such as CRISPR gene editing to improve the efficacy of CAR-T cells.

Shuttle Pharma doses three subjects in Phase II glioblastoma treatment trial
Shuttle Pharmaceuticals has administered Ropidoxuridine, its lead radiation sensitizer, to the first three participants in a Phase II clinical trial aimed at treating glioblastoma. The study will initially enroll 40 patients with isocitrate dehydrogenase (IDH) wild-type and methylation-negative glioblastoma. They will be divided into two groups to receive daily doses of Ropidoxuridine of 1,200 mg or 960 mg to determine the optimal dosage. An additional 14 patients will then receive the identified optimal dose. The primary objective of the study is to evaluate the survival of patients treated with Ropidoxuridine compared to historical data. Shuttle Pharma has partnered with six centers to enroll patients, including Georgetown University Medical Center and UNC Medical Center in the United States. The study is expected to last 18 to 24 months.

TTFields Plus Temozolomide/Pembrolizumab Controls Tumors in Glioblastoma
A clinical study showed that the addition of alternating electric fields (TTFields) to treatment with temozolomide and pembrolizumab in patients with newly diagnosed glioblastoma improved survival. Patients treated with TTFields, temozolomide and pembrolizumab had a median progression-free survival (PFS) of 27.2 months compared to 9.6 months for patients who underwent maximal resection. The median overall survival (OS) was 31.6 months compared to 18.8 months. These results suggest that the addition of TTFields with temozolomide and pembrolizumab could provide a significant benefit in tumor control in patients with glioblastoma.

AI tool for predicting MGMT methylation in glioblastoma for clinical decision support in resource limited settings
A study published in Scientific Reports developed an artificial intelligence (AI) model to predict the methylation status of the MGMT gene promoter in patients with glioblastoma, using magnetic resonance imaging (MRI). MGMT promoter methylation is a crucial biomarker for determining response to temozolomide chemotherapy in patients with glioblastoma. The AI ​​model was trained on an MRI image dataset and achieved high accuracy in predicting MGMT methylation status. This noninvasive approach could help clinicians personalize therapies for patients with glioblastoma, improving treatment allocation and potentially improving clinical outcomes.

Brain tumors exploit body’s daily rhythms to fuel growth
A recent study found that brain tumors, such as glioblastoma, can exploit the circadian rhythms of the human body to promote their growth. Circadian rhythms are 24-hour biological cycles that regulate various physiological functions, including sleep and metabolism. Researchers have observed that brain tumor cells modulate their activity based on these rhythms, increasing cell proliferation at certain times of the day. This discovery suggests that therapies aimed at interrupting the interaction between circadian rhythms and tumor cells could represent a new strategy to combat brain tumors. In addition, it could be useful to consider the timing of administration of cancer treatments to maximize their effectiveness, adapting them to the patient’s circadian rhythms.

Thanks to those who have helped us and continue to help us keep the volunteer organization alive and to develop our projects always focused on supporting patients and their caregivers. That’s all for this issue on research news. In the next posts we will start with the disclosure of the Charter of Rights of Patients with Brain Tumor that is not always and not everywhere fully respected, even in Italy, with a summary of what emerged from the annual conference of the neuro-oncology society and with the list of things that I would do myself if I were diagnosed with a brain tumor today.

A heartfelt good luck and a Happy 2025, full of hope, to all those who are fighting against glioblastoma and their loved ones!