Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor. Approximately 16% of all primary brain and central nervous system neoplasms are diagnosed as glioblastoma. The mean age of diagnosis of the disease, which has a higher incidence in non-Hispanic white men, is 64 years of age and the average age-adjusted incidence rate is 3.2 per 100,000 population. [1][2]

A majority of glioblastomas are primary, and these patients tend to be older-aged and have a poorer prognosis than patients with secondary glioblastoma. In addition, the current standard of care, which requires a multidisciplinary approach and includes maximal safe surgical resection (which is difficult because these tumors are frequently invasive and often involves areas of the brain that control speech, motor function, and the senses), followed by concurrent radiation with temozolomide (TMZ) (Temodar®; Merck & Co) an oral alkylating chemotherapy agent, and then adjuvant chemotherapy with temozolomide, is not curative, and, over time, patients may experience tumor progression after treatment.[3]

Furthermore, the differential benefit from concurrent versus adjuvant temozolomide in patients with anaplastic glioma continues to be unclear.

Beyond disease stage
Glioblastoma is generally noted for a rapid neurological and clinical demise.  This, in turn, results in disproportionate disability for patients, hampering the overall health-related Quality of Life (hrQoL). It also makes caring for patients diagnosed with the disease complex, intense and multidisciplinary in nature. The required treatment for glioblastoma and other brain tumors is often expensive. Because patients are generally unable to return to the workforce, which is generally linked to their employer-based health insurance, patients often have to cope with financial toxicity following treatment.

Because there is no cure for glioblastoma, there is an urgent unmet medical need for patients diagnosed with the disease. Hence, researchers are looking for more effective therapies.

Advertisement #3

Novel treatment approaches
Over the last decades, the number of approved therapeutic agents for the treatment of different forms of cancer has skyrocketed. However, in contrast to treatments for breast and lung cancer or hematological malignancies, since 2005 only 3 new treatments, including temozolomide, bevacizumab (Avastin®; Genentech/Roche), and tumor-treating fields (TTFields; NovoTTF System, Novocure), have been approved for the treatment of glioblastomas.[4]

Recent clinical studies have demonstrated the feasibility and safety of chimeric antigen receptors (CAR) T-cell therapy for the treatment of glioblastoma. Despite formidable barriers to T-cell localization and effector function in glioblastoma, researchers have observed signs of efficacy in a select number of patients.[4]

Christine E. Brown, Ph.D., Deputy Director, T Cell Therapeutics Research Laboratory; Professor, Departments of Hematology & Hematopoietic Cell Transplantation and Immuno-Oncology and a team of researchers at Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, together with Michael C. Jensen, M.D., Vice President, Seattle Children’s Therapeutics, and Chief Therapeutics Officer; Janet and Jim Sinegal Endowed Chair in Pediatric Solid Tumor Research in honor of Korey Rose at the Center for Immunity and Immunotherapies, Seattle Children’s Research Institute, Seattle, WA, are developing T-cell therapies for malignant glioma targeting IL-13 receptor α2 (IL13Rα2), a cell surface receptor that is over-expressed by a subset of high-grade gliomas, but not expressed at significant levels by the normal, healthy, brain.

The team of researchers developed an IL13Rα2-targeting immunotherapy platform for high-grade glioma by genetically modifying cytolytic T cells (CTLs) to express an IL13Rα2-specific chimeric antigen receptor termed IL13-zetakine. This CAR recognizes IL13Rα2 via a membrane-tethered IL13 ligand, and initiates cytolytic killing via an intracellular CD3-zeta domain.

The researchers found that their CAR T-cell therapies demonstrated in vitro efficacy against glioma stem cells, and as a result, they believe that adoptive T cell therapy using IL13Rα2-specific cytolytic T cells may be a promising approach that can enhance therapeutic options for patient populations having the poorest prognoses.

Noninvasive treatment options
In addition to the development of novel immunotherapeutic approaches, researchers are also investigating other treatment options.

For example, SonALAsense, a clinical-stage company, is developing ALA sonodynamic therapy (SDT) as a potential first-in-class, non-invasive drug-device combination for the treatment of recurrent glioblastoma. The company platform technology uses MRI-guided focused ultrasound in combination with aminolevulinic acid to selectively target and kill tumor cells.

Strategic collaboration
The company has entered into a Collaboration and License Agreement with Insightec to develop and commercialize its focused ultrasound technology in oncology for use in ALA SDT.

In addition, the company also entered into an agreement with the Ivy Brain Tumor Center at Barrow Neurological Institute to conduct a first-in-human clinical trial in recurrent glioblastoma using their innovative Phase 0 approach to rapidly assess the safety and biological and clinical efficacy of ALA SDT.

Phase 0 studies
Growing concerns related to slow and costly drug development led the Food and Drug Administration to introduce the Phase 0 clinical trial, a new mechanism to accelerate and streamline the drug testing and approval process. Unlike traditional Phase, I, II, and III clinical trials, Phase 0 studies are designed to bridge the gap between initial drug testing and definitive efficacy studies. The approach allows physicians to measure the effects of a treatment on a patient’s tumor within 10 days following surgery. This makes it possible for the medical team to inform patients if therapy could be working and make faster treatment decisions.

This approach also guides drug developers in quickly identifying how a drug works in patients and whether it should be fast-tracked for further development.

“The Ivy Brain Tumor Center strives to be at the forefront of best-in-class solutions so that we can identify early-stage therapies for accelerated development,” explained Nader Sanai, M.D., the director and chief scientific officer of the Ivy Brain Tumor Center and a neurosurgical oncologist who has been internationally recognized for his clinical expertise and research efforts dedicated to the treatment of brain tumors.

“We are proud to collaborate with SonALAsense to work towards the first non-invasive drug-device combination therapy for glioblastoma and other aggressive brain tumors. This novel modality has the potential to change the lives of hundreds of thousands of patients and their families, worldwide,” Sanai added.

“The Ivy Brain Tumor Center has become one of the country’s leaders in Phase 0 brain cancer clinical research and they wanted to be the first to work with SonALAsense on this trial taking an innovative, noninvasive fast-acting therapeutic approach to brain cancer treatment,” noted Stuart Marcus, MD, Ph.D., Founder, Chief Executive Officer and Chief Medical Officer of SonALAsense, who has pioneered photodynamic therapy systems for over 30 years, with multiple Food and Drug Administration (FDA) approved drug-device products.

Stuart Marcus, MD, Ph.D., Founder, Chief Executive Officer, and Chief Medical Officer of SonALAsense, has pioneered photodynamic therapy systems for over 30 years, with multiple Foor and Drug Administration (FDA) approved drug-device products. Photo courtesy: SonALAsense. Used with permission.

Stuart Marcus, MD, Ph.D., Founder, Chief Executive Officer, and Chief Medical Officer of SonALAsense, has pioneered photodynamic therapy systems for over 30 years, with multiple Foor and Drug Administration (FDA) approved drug-device products. Photo courtesy: SonALAsense. Used with permission.

The ALA SDT process works by a dual-action which quickly kills brain tumor cells and simultaneously triggers programmed tumor cell death within 48 hours in animal models. ALA is currently FDA approved as a visual aid for neurosurgeons as the selective fluorescence of its metabolite in glioblastoma cells helps guide surgical excision. Because of ALA’s unique selectivity for gliomas, as well as the precision-targeted energies of MR-guided, focused ultrasound used for SDT, researchers believe the treatment should be safe for normal brain tissue.

Light-activated drugs
“The discovery that light-activated drugs can also be activated by focused ultrasound has led to our development of sonodynamic therapy, which is the achievement of my life’s goal, to bring renewed hope to brain tumor patients without the use of invasive procedures,” explained Marcus, who has spent the past 27 years working towards this breakthrough technology that has the potential to turn recurrent glioblastoma patients into cancer survivors.

“There have been many studies and research around treating recurrent glioblastoma and other lethal brain tumors over the years, but none have been proven effective. ALA SDT has the potential to meaningfully improve the length and quality of patients’ lives,” Marcus concluded.

Highlights of Prescribing Information
Temozolomide (TMZ) (Temodar®; Merck & Co)[Prescribing Information]
Bevacizumab (Avastin®; Genentech/Roche)[Prescribing Information]

Reference
[1] Davis ME. Glioblastoma: Overview of Disease and Treatment. Clin J Oncol Nurs. 2016 Oct 1;20(5 Suppl):S2-8. doi: 10.1188/16.CJON.S1.2-8. PMID: 27668386; PMCID: PMC5123811.
[2] Thakkar JP, Dolecek TA, Horbinski C, Ostrom QT, Lightner DD, Barnholtz-Sloan JS, Villano JL. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol Biomarkers Prev. 2014 Oct;23(10):1985-96. doi: 10.1158/1055-9965.EPI-14-0275. Epub 2014 Jul 22. PMID: 25053711; PMCID: PMC4185005.
[3] Central Nervous System Cancers; NCCN Guidelines with NCCN Evidence Blocks Glioblastoma.
[4] Bagley SJ, Desai AS, Linette GP, June CH, O’Rourke DM. CAR T-cell therapy for glioblastoma: recent clinical advances and future challenges. Neuro Oncol. 2018 Oct 9;20(11):1429-1438. doi: 10.1093/neuonc/noy032. PMID: 29509936; PMCID: PMC6176794.

Advertisement #5