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| A WashU Medicine-led clinical trial conducted at Siteman Cancer Center has found that a personalized vaccine to treat glioblastoma is safe and could potentially improve outcomes. Trial participant Kim Garland (left) reviews a scan with the study’s primary investigator, Tanner Johanns, MD, PhD, a WashU Medicine oncologist. Photo Credit: Courtesy of Scott Garland |
Scientific Frontline: Extended "At a Glance" Summary: Personalized DNA Vaccine for Glioblastoma (GNOS-PV01)
The Core Concept: A personalized therapeutic DNA vaccine engineered to target unique neoantigens on a patient's tumor, stimulating the immune system to recognize and eliminate aggressive glioblastoma cells.
Key Distinction/Mechanism: Unlike conventional treatments, this DNA-based platform can target up to 40 unique tumor-specific proteins simultaneously. It successfully transforms immunologically "cold" tumors—which typically evade immune detection—into "hot" tumors vulnerable to targeted immune-mediated eradication.
Major Frameworks/Components:
- Neoantigen Identification: Utilizes computational algorithms to accurately identify and select cancer-specific proteins from various regions of an individual's tumor.
- Synthetic DNA Encoding: Custom-manufactures specialized DNA molecules that encode the unique information for each patient's tumor neoantigens.
- Adjuvant Immunotherapy Intervention: Administered post-operatively during a patient's recovery and radiation treatment to systematically boost immune-cell activity against remaining cancer cells.
Branch of Science: Oncology, Immunology, Molecular Biology, Computational Biology.
Future Application: The platform is slated for larger efficacy trials and expansion to treat all types of glioblastomas, with active investigations into combination therapies that leverage this personalized DNA framework for other intractable solid tumors.
Why It Matters: Glioblastoma is an aggressively fast-growing and typically incurable brain cancer with high recurrence rates. This targeted approach has demonstrated the ability to significantly prolong overall survival and increase recurrence-free intervals without causing severe side effects, doubling the historical two-year survival rate in its early-stage trial cohort.
A personalized vaccine to treat glioblastoma—a fast-growing and incurable brain cancer that affects 4 in 100,000 people in the United States—is safe, elicits robust and broad immune responses, and appears to increase recurrence-free survival in a subset of patients after surgery, according to an early-stage clinical trial co-led by researchers at Washington University School of Medicine in St. Louis.
In patients with an especially aggressive form of glioblastoma, the vaccine caused no serious side effects and prolonged patients’ overall survival compared to historical outcomes after standard-of-care surgery and chemoradiotherapy. One long-term survivor remains recurrence-free nearly five years later.
The results of the phase 1 trial, conducted at Siteman Cancer Center (based at Barnes-Jewish Hospital and WashU Medicine), were published May 12 in Nature Cancer. The study was led jointly by Mass General Brigham and Geneos Therapeutics, a Philadelphia-based biotechnology company.
“We are extremely encouraged by these results,” said Tanner M. Johanns, MD, PhD, lead author of the study and an assistant professor in the Division of Oncology in the John T. Milliken Department of Medicine at WashU Medicine. “This kind of vaccine is a first for glioblastoma, and it is exciting to think how we can leverage this individualized therapeutic DNA cancer vaccine platform to make a positive impact on the lives of patients who are fighting this disease. Additionally, combination therapies leveraging this personalized platform are currently being investigated at WashU to test if outcomes may be improved further.”
The novel treatment uses engineered DNA molecules designed to stimulate the patient’s immune system against the cancer. Each patient’s tumor has unique proteins specific to that tumor, and this vaccine activates the patient’s immune system to recognize those proteins and eliminate the tumor cells.
Johanns said that although some immunotherapies targeting glioblastoma have shown promise in previous studies, they ultimately are ineffective in significantly delaying or preventing recurrence. That is likely because glioblastoma can evolve and escape immune attack, but Johanns’s vaccine was designed to help the immune system recognize many different targets on cancer cells. So even if the tumor loses several of these targets, the vaccine is still able to generate responses to many others.
Additionally, glioblastoma is termed a “cold” tumor, meaning the tumor environment is able to hide from the immune system. The cancer vaccine used in this trial, developed by Geneos Therapeutics, transforms cold tumors into “hot” tumors that are then susceptible to immune-mediated eradication. The vaccine is thus able to improve the patient’s immune response by targeting proteins on the cancer cell and by making the environment within the tumor more favorable to immune activation.
“We chose a DNA-based platform because it would allow us an opportunity to target more cancer proteins than any vaccine had targeted before,” said Johanns, who treats patients at Siteman and is a research member there. “Our thinking was that if we could generate a broader range of immune responses against those proteins, it might lead to a more potent vaccine compared to other vaccine platforms with more limited protein targets.”
This DNA-based vaccine platform was able to activate each patient’s immune system to seek out as many as 40 cancer proteins specific to each patient’s tumor—twice as many as had been targeted by any cancer vaccine therapy to date.
More Targets, More Chances for Success
The vaccine in the study, called GNOS-PV01, targets so-called neoantigens—proteins unique to an individual patient’s cancer cells that their immune cells can recognize. The neoantigens were identified and selected using an algorithm developed at WashU Medicine by computational biologists and coauthors Obi Griffith, PhD, a professor of medicine, and Malachi Griffith, PhD, an associate professor of medicine, both in the Division of Oncology and research members at Siteman. Johanns and his colleagues selected neoantigens from different regions of a patient’s tumor, a method they incorporated to further increase the number of cancer cell proteins targeted by the vaccine.
A vaccine platform using a different DNA-based technology developed for breast cancer by coauthor William Gillanders, MD, the Mary Culver Distinguished Professor of Surgery at WashU Medicine who treats patients at Siteman, inspired the idea to bring Geneos’s GNOS-PV01 vaccine to WashU Medicine for use against glioblastoma, Johanns said.
The trial enrolled nine adult patients who had been recently diagnosed with glioblastoma. All patients were treated at Siteman Cancer Center. The team prepared a synthetic DNA molecule encoding the unique information for each patient’s tumor neoantigens. The vaccine was manufactured at the Biologic Therapy Core Facility at Siteman during the patient’s postoperative recovery and subsequent radiation treatment.
The vaccine injections started, on average, 10 weeks after the patient’s surgery and were administered every three weeks for a nine-week period, and then every nine weeks thereafter as long as patients were able to participate. All participants, except one who was taking an immunosuppressive steroid, showed an increase in immune-cell activity, indicating a response to the vaccine intervention.
Two-thirds of the patients had no progression of their cancer six months out from their surgeries, and two-thirds survived one year. Typically, around 40% of patients with glioblastoma reach either milestone.
One-third of the participants were still alive after two years, which is twice the historical survival rate for this patient population. One participant is still alive and recurrence-free today, almost five years after her initial diagnosis.
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A WashU Medicine-led clinical trial conducted at Siteman Cancer Center has found that a personalized vaccine to treat glioblastoma appears to increase recurrence-free survival in a subset of patients after surgery. Trial participant Kim Garland (left) has had no recurrence of her tumor in the nearly five years since her surgery, which was performed by Albert Kim, MD, PhD (right), the August A. Busch, Jr. Professor of Neurological Surgery at WashU Medicine. Kim’s husband, Scott Garland, is pictured in the middle.
Photo Credit: Courtesy of Scott Garland
An Investment in the Future
Kim Garland is a retired school nurse who lives in Kirkwood, Missouri, with Scott, her husband of 31 years. In June 2021, at age 62, Kim was volunteering at a youth camp in Ironton, Missouri, when her daughter-in-law, who was also volunteering at the same camp, noticed that Kim was struggling with confusion and forgetfulness, as well as headaches that would come and go throughout the day.
“I was forgetting things, things that should have been very obvious,” said Kim.
A scan at a local hospital’s emergency room back in St. Louis revealed a 6.5 cm mass in Kim’s brain—about the size of a small avocado. Within the week, Albert Kim, MD, PhD, the August A. Busch Jr. Professor of Neurological Surgery at WashU Medicine, director of the Brain Tumor Center at Siteman, and coauthor of the study, performed the initial surgery to remove her tumor. The grim diagnosis of grade 4 glioblastoma came after the tumor was removed.
When offered the opportunity to participate in a clinical trial, Kim Garland agreed in hopes that her participation would improve future treatments. After receiving this prognosis, both Kim and Scott did not expect that she would be alive with no recurrence nearly five years after her initial diagnosis.
“We know we are fortunate to have the kind of care that Kim has been able to receive, just a 30-minute drive from our home,” Scott said. “We see many other patients who are traveling long distances for their treatments. Having this level of care and treatment so close to home has been a huge blessing.”
With the support of their team, the Garlands have gained the confidence to make longer-term plans, including a long-delayed vacation this summer and spending quality time with their children and 15 grandchildren—a big change from the week-by-week life they were living in the aftermath of Kim’s initial diagnosis.
“Cancer vaccines have a long history, and the development of personalized neoantigen-targeting therapeutic vaccines now represents a highly compelling approach in glioblastoma and in other cancers,” said co-senior author Gavin Dunn, MD, PhD, a neurosurgical oncologist at Mass General Brigham Cancer Institute. “These programs require a high degree of integrated teamwork, and we are fortunate to have collaborated with many dedicated team members in this effort.”
Kim Garland’s cancer, along with those of the other patients in the trial, was an unmethylated MGMT subtype of glioblastoma, which is particularly hard to treat because it is not responsive to available treatment options, such as chemotherapy. Johanns said the next step is to assess the vaccine’s efficacy in a larger group of patients and to expand the treatment to all types of glioblastomas. The goal of Johanns and his team is to improve the vaccine response to ensure that more patients can experience benefits like those experienced by Kim Garland.
The knowledge that their participation in the trial has potentially advanced care is a comfort to the Garlands, who still need to steel themselves before each follow-up appointment out of concern that Kim’s tumor could yet return.
“What we’re hopeful for is that through research like this, someday, when another person hears the words ‘you have glioblastoma’ as their diagnosis, it will not cause as much anxiety,” said Scott. “Maybe, they will be told, ‘This is the cancer you have, but it is very treatable.’ We are fortunate and blessed to be at the right place and at the right time, to be part of this clinical trial and have a small part in the battle against this terrible disease.”
Funding: for this study came from the Mark Foundation for Cancer Research Momentum Fellowship, National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) grants R01NS117149 and R01NS107833, the Nationwide Foundation Pediatric Innovation Fund, NIH K12CA167540, and The Alvin J. Siteman Cancer Center Investment Program, along with The Foundation for Barnes-Jewish Hospital, NIH NINDS R01NS112712, The Schnuck Family Fund, and The Knight and Christopher Davidson Family Fund.
Additional information: Additional study support for development, manufacture, and administration of the treatment and monitoring of the immune responses was provided by Geneos Therapeutics.
Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Published in journal: Nature Cancer
Authors: Elizabeth A. R. Garfinkle, Renzo Perales-Linares, Ryan C. Gimple, Alexandra J. Livingstone, Kaleigh F. Roberts, Omar H. Butt, S. Peter Goedegebuure, Michael D. McLellan, Gue Su Chang, Jasreet Hundal, Jian Yan, Jaye B. Navarro, Sophia A. Paxton, Srestha Chattopadhyay, Neil Cooch, Alfredo Perales-Puchalt, Konstantina Stavroulaki, Sarah Rochestie, Joann Peters, Beth Junker, Jian L. Campian, Milan G. Chheda, Michael R. Chicoine, Albert H. Kim, Jon T. Willie, Gregory J. Zipfel, Joshua L. Dowling, Christopher A. Miller, Obi L. Griffith, Malachi Griffith, William E. Gillanders, Katherine E. Miller, Elaine R. Mardis, Niranjan Y. Sardesai, Gavin P. Dunn, and Tanner M. Johanns
Source/Credit: Washington University in St. Louis | Mark Reynolds
Reference Number: ongy051226_01
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