Patients with glioblastoma, a devastating and lethal form of brain cancer, receive treatment that frequently leads to the unfortunate side effect of low white blood cell counts that lasts six months to a year. The low numbers of white blood cells are associated with shorter survival — but the specific reason for the prolonged drop in white blood cells and the link with shorter survival has vexed scientists.

A new study led by Washington University School of Medicine in St. Louis and supported, in part, by Washington University’s Department of Radiation Oncology; Alvin J. Siteman Cancer Center; Barnes-Jewish Hospital; the Barnard Cancer Institute; and the Washington University Institute of Clinical and Translational Sciences, which is, in part, supported by the National Institutes of Health (NIH), reveals at least one cause of low white blood cell counts in patients treated for glioblastoma and demonstrates a potential treatment strategy that improves survival in mice.

The study is published in the January 25th edition of the journal Science Translational Medicine.[1]

Low lymphocyte counts
Typically, the average life expectancy of patients after a diagnosis of glioblastoma is 14 to 16 months. Less than. 1% of patients will live to reach 10 years after diagnosis.

The standard treatment is radiation and chemotherapy, after which many patients develop severely low numbers of lymphocytes — a type of white blood cell — in the bloodstream. The cause of these low lymphocyte counts has been something of a mystery because the therapy does not target the bone marrow, where these cells originate, and not all patients experience the problem.

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Jiayi Huang, MD, is Associate Professor of Radiation Oncology; Chief, CNS/Gamma Knife Service and Co-director, Brain Tumor Center at Siteman Cancer Center. – In a recently published study, Huang and his team reveals at least one cause of low white blood cell counts in patients treated for glioblastoma and demonstrates a potential treatment strategy that improves survival in mice.

“We know patients who develop low lymphocyte counts do worse than average,” said co-corresponding author Jiayi Huang, MD, an associate professor of radiation oncology and co-clinical director of the Brain Tumor Center at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

“To improve their outcomes and extend their lives, we needed to understand what is causing these low levels of white blood cells and how it contributes to worse survival.”

Huang and his colleagues at Siteman led a study that collected and analyzed blood samples from glioblastoma patients. About half of the patients developed low white blood cell counts following treatment.

Myeloid-derived suppressor cells
The researchers found a significant increase in what are called myeloid-derived suppressor cells — a type of cell known for suppressing the immune system — in those that developed low white blood cell levels. In mouse studies, the scientists then established a causal relationship between the increased myeloid-derived suppressor cells induced by irradiation of the tumor and the suppression of white blood cells.

“We wanted to find out if we could block these myeloid-derived suppressor cells using an inhibitor to improve treatment response to radiation,” noted senior corresponding author Dinesh Thotala, Ph.D., who conducted this work at Washington University and is now with the University of Oklahoma Health Sciences Center.

“We ended up testing two inhibitors separately with radiation and found a significant improvement in survival in multiple mouse models of this cancer,” Thotala added.

The researchers, including first author Subhajit Ghosh, PhD, a postdoctoral fellow who conducted this work in Thotala’s lab, first at Washington University and now at the University of Oklahoma, found that, on average, all of the mice with glioblastoma that received radiation alone died by day 40. Of the mice that received either inhibitor plus radiation, 50% to 60% were still alive at day 120, when the experiment ended.

Arginase-1 and phosphodiesterase-5 inhibitors
One inhibitor, called CB1158, is in a class of drugs called arginase-1 inhibitors and is being investigated in a clinical trial for the treatment of solid tumors, including colorectal, lung and bladder cancers.

The second drug is a phosphodiesterase-5 inhibitor called tadalafil (Cialis®/Adcirca®; Eli Lilly and Company) is used to treat erectile dysfunction (ED, , which is approved by the U.S. Food and Drug Administration (FDA) to treat other conditions, including erectile dysfunction(ED), benign prostatic hyperplasia (BPH), and pulmonary arterial hypertension.

“The myeloid-derived suppressor cells have normal functions in the body,” said Huang, who develops clinical trials for glioblastoma patients.

“During pregnancy, the body makes these cells to suppress the immune cells so it doesn’t attack the embryo or fetus. But glioblastoma takes this normal process and exploits it for its own purpose. Furthermore, radiating the tumor triggers the body to create massive quantities of these cells, leading to low white blood cell counts in our patients, sometimes for many months. Our work suggests that targeting those cells in combination with radiation may be a new, exciting strategy to improve the treatment of glioblastoma,” Huang concluded.

Ongoing research
To further confirm their findings, the researchers have conducted a small clinical trial that combined tadalafil with standard radiation for patients with glioblastoma. According to the researchers, they are finding encouraging results, with some patients responding well to the investigational treatment. This work is currently under review in another scientific journal. The researchers also are working toward developing new therapies with even more potential than these two inhibitors to block myeloid-derived suppressor cells.

Clinical trial
Tadalafil to Overcome Immunosuppression During Chemoradiotherapy for IDH-wildtype Grade III-IV Astrocytoma – NCT04757662

Highlights of prescribing information
Tadalafil (Adcirca®; Eli Lilly and Company)[Prescribing Information]
Tadalafil (Cialis®; Eli Lilly and Company) [Prescribing Information]

Reference
[1] Ghosh S, Huang J, Inkman M, Zhang J, Thotala S, Tikhonova E, Miheecheva N, Frenkel F, Ataullakhanov R, Wang X, DeNardo D, Hallahan D, Thotala D. Radiation-induced circulating myeloid-derived suppressor cells induce systemic lymphopenia after chemoradiotherapy in patients with glioblastoma. Sci Transl Med. 2023 Jan 25;15(680):eabn6758. doi: 10.1126/scitranslmed.abn6758. Epub 2023 Jan 25. PMID: 36696484.

Featured image Brain/MRI.  Photo courtesy: © 2016 – 2023 Fotolia/Adobe. Used with permission.

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