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NEW YORK, NY (February 15, 2019) – Columbia researchers have learned why some glioblastomas – the most common type of brain cancer – respond to immunotherapy. The findings could help identify patients most likely to benefit from treatment with immunotherapy drugs and lead to the development of more effective treatments.
The study, led by Raul Rabadan, PhD, Professor of Systems Biology and Biomedical Informatics at the College of Physicians and Surgeons Vagelos of Columbia University, was published online in the journal Nature Medicine.
Fewer than one in 10 patients with glioblastoma respond to immunotherapy, which has demonstrated remarkable success in recent years in the treatment of various aggressive cancers. But there was no way of knowing in advance which patients with glioblastoma would react.
Patients with glioblastoma are usually treated with surgery to remove as much of the tumor as possible, followed by radiation therapy and chemotherapy. Even with aggressive therapy, the prognosis is often bleak, with a median survival of about 14 months.
Like many other cancers, glioblastomas can prevent the immune system from attacking cancer cells. Cancers sometimes slow down the immune system by acting on a protein called PD-1. Immunotherapy medications called PD-1 inhibitors are designed to release these brakes, thereby releasing the immune system. Given the success of PD-1 inhibitors in other cancers, doctors hoped that immunotherapy drugs would help glioblastoma patients.
To understand why only a few of these tumors respond to immunotherapy drugs, the Rabadan team thoroughly examined the microenvironment of the tumor – including the tumor itself and all the cells that support it. – in 66 patients with glioblastoma before and after treatment. with PD-1 inhibitors (nivolumab or pembrolizumab). (Of these, 17 had a response to medications of 6 months or more.)
Nonsusceptible tumors showed more mutations in a gene called PTEN, which resulted in increased levels of macrophages – immune cells that usually help the body fight bacteria and other invaders. But in glioblastoma, macrophages release a number of growth factors that promote the survival and spread of cancer cells.
Cancer cells in tumors with PTEN mutations have also been tightly grouped, which can prevent immune cells from entering the tumor and its microenvironment.
Reactive tumors, on the other hand, had more mutations in a signaling pathway called MAPK, which helps regulate essential cellular functions.
"These mutations occurred before patients were treated with PD-1 inhibitors, so screening for these mutations could be a reliable way to predict which patients are likely to respond to immunotherapy," says the neuro. -computer Fabio M. Iwamoto, badistant professor of neurology at the College of Physicians and Surgeons Vagelos of Columbia University and co-author of the study.
The study also suggests that glioblastoma patients with MAPK mutations could benefit more from immunotherapy if PD-1 inhibitors were combined with targeted MAPK therapy, although the combination requires clinical trials. . MAPK-targeted therapies have been approved for metastatic melanoma and are currently being tested to treat other cancers.
"We are still in the early stages of understanding cancer immunotherapy, especially glioblastoma," said Rabadan. "But our study shows that we may be able to predict which glioblastoma patients might benefit from this treatment." We also identified new treatment targets that could improve immunotherapy for all glioblastoma patients. . "
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Raul Rabadan, PhD, and Fabio Iwamoto, MD, are also part of the Herbert Irving Comprehensive Cancer Center at the New York-Presbyterian / Columbia Irving Medical Center.
The study entitled "Immune and genomic correlates of the immune response to tobanti-PD-1 in glioblastoma". The other contributors are: Junfei Zhao (CUIMC), Andrew X. Chen (CUIMC), Robyn D. Gartrell (CUIMC), Andrew M. Silverman (CUIMC), Luis Aparicio (CUIMC), Tim Chu (CUIMC), Darius Bordbar ( CUIMC), David Shan (CUIMC), Jorge Samanamud (CUIMC), Aayushi Mahajan (CUIMC), Ioan Filip (CUIMC), Rose Orenbuch (CUIMC), Morgan Goetz (University of North Carolina at Chapel Hill, Chapel Hill, NC) , Jonathan T. Yamaguchi (Feinberg School of Medicine, Northwestern University, Chicago, Illinois), Michael Cloney (Northwestern), Craig Horbinski (Northwestern), Rimas V. Lukas (Northwestern), Jeffrey Raizer (Northwestern), Ali I Rae ( Oregon Health & Sciences University, Portland, OR), Jinzhou Yuan (CUIMC), Peter Canoll (CUIMC), Jeffrey N. Bruce (CUIMC), Yvonne M. Saenger (CUIMC), Peter Sims (CUIMC), Fabio M. Iwamoto ( CUIMC), and Adam M. Sonabend (Northwest).
The study was funded by grants from the National Institutes of Health (R01 CA185486, R01 CA179044, U54 CA193313, U54 209997 and R01 NS103473), from the National Science Foundation / Multidisciplinary Team of Ideas Laboratory, the V-Foundation and Ideas Foundation. , SPORE for translational approaches to brain cancer and the Robert H. Lurie Cancer Center at NCI.
The authors do not declare any conflict of financial or other interests.
The Irving Medical Center at Columbia University provides international leadership in the areas of basic, preclinical and clinical research; teaching of medical and health sciences; and patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists and nurses from the College of Physicians and Surgeons Vagelos, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and related research centers and institutions.
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