Roswell Park in the Spotlight at Tandem Meetings: Experts Share Insights on Overcoming GvHD, Improving CAR T

ORLANDO, FL — Two experts from Roswell Park Comprehensive Cancer Center are delivering presentations this week at an international conference highlighting research aimed at extending and improving the lives of patients with blood-related cancers. Nataliya Buxbaum, MD, from the Department of Pediatric Oncology and Marco Davila, MD, PhD, Vice Chair for Cellular Therapies and Senior Vice President and Associate Director for Translational Research, were invited to highlight their work in podium talks at the 2023 Tandem Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and Center for International Blood and Marrow Transplant Research (CIBMTR) this week in Orlando, Florida.

A biology-based approach to GvHD

Dr. Buxbaum, a member of the Chronic GvHD National Institutes of Health (NIH) Consensus Project Biology Task Force, described recent advances in understanding the biology of chronic graft-versus-host disease (GvHD) — a potentially fatal condition that affects between 25% and 75% of patients who undergo allogeneic hematopoietic cell transplant. She also discussed her research on the immunometabolism of GvHD that may lead to  new imaging approaches and therapy for this condition.

If it’s successful, the strategy may:

• Detect GvHD non-invasively within affected internal organs without subjecting the patient to an invasive biopsy
• Make it possible to treat the disease more effectively by interrupting its metabolic pathways

“We are still uncovering the complex biological underpinnings of GvHD,” Dr. Buxbaum observes. “For four decades we treated all patients with the same systemic treatment — corticosteroids. Not only do many patients not respond, but those who do respond end up being on them a long time, and they have many side effects.”

She notes that preclinical work has opened insights into the biological pathways involved in GvHD and has led to the development of targeted therapies for this transplant barrier. At the same time, the work of the NIH Consensus Project Biology Task Force has better defined the disease, laying the groundwork for the FDA to approve three drugs for chronic GvHD and one to prevent acute GvHD in the last five years alone. “That’s groundbreaking,” she says.

However, while blood-based biomarkers are being developed for GvHD, it is still challenging to pinpoint the exact areas of the body where GvHD is developing based on blood sampling alone. Because there currently is no diagnostic imaging for detecting GvHD, a minimum of 28 days must elapse after the start of treatment before a biopsy can determine whether or not the disease has responded to treatment — “and a biopsy is challenging to do in somebody who’s sick,” Dr. Buxbaum notes. If the initial treatment hasn’t worked, a different drug is started and more time is needed before re-evaluation for response.

Locating areas of high glucose metabolism is key to detecting the presence of cancer. This is currently accomplished with a positron emission tomography (PET) scan after having the patient ingest a radioactive sugar molecule. PET is then able to map  where glucose is being absorbed by cancer cells. But high sugar metabolism can also indicate the presence of GvHD: “When you first start getting GvHD, the immune system fires up the T cells, and they start using a lot of sugar,” explains Dr. Buxbaum.

She and her team see great potential in performing metabolic imaging with magnetic resonance imaging (MRI), which uses a magnetic field and radio waves to produce images and, unlike PET, does not require radioactive sugar molecules. Within the next six to 12 months, Dr. Buxbaum and her colleagues hope to run a pilot study to gauge the effectiveness of locating GvHD with metabolic MRI, using a sugar molecule labeled with deuterium, a nonradioactive form of hydrogen.

“Targeting this metabolic pattern of high glycolysis is something we should do therapeutically,” says Dr. Buxbaum. “We’re studying it in preclinical models right now and having some success.” She says previous work with preclinical models has shown that GvHD can be detected this way in the liver and gut, “and we think the same can happen in a human being. We then use a drug that inhibits the processing of sugar to ameliorate GvHD.”

Allogeneic stem cell transplants are especially challenging. “Each time it’s a unique mismatch between the host and donor, if they’re unrelated,” says Dr. Buxbaum. “It’s a unique situation every time, so it requires personalized therapy.”

Dr. Buxbaum’s talk, “Biology of GvHD,” was presented Wednesday, Feb. 15, from 11-11:30 a.m. EST.

Identifying the cause of poor outcomes in CAR T-cell therapy for B-cell malignancies

Dr. Davila will discuss his team’s efforts to determine why some patients with B-cell malignancies do not respond well to CAR T-cell therapy targeting CD19, a surface protein expressed by most B cells. What accounts for poor outcomes in those patients?

Using patient samples, the investigators identified gene signatures and cell signatures showing that the lymphoid tissue in those patients contained high numbers of myeloid cells, which originate in the bone marrow and can develop into various types of adult blood cells, including macrophages, which are capable of killing tumor cells and other cells. They then developed assays of CD19-targeted CAR T cells, tumors and macrophages, and cultured them together — and discovered that certain types of macrophages were capable of killing CAR T cells.

While macrophages might kill up to 90% of the CAR T cells, “the remaining 10% that survive proliferate and persist,” says Dr. Davila, which means it would be possible for the surviving CAR T cells to continue attacking the cancer cells. But   how well would they function? “We compared them to other CD19-targeted T cells that had never been exposed to macrophages, and they performed worse,” he explains. “They didn’t kill as well, they didn’t secrete as much cytokine — which can stimulate the immune system— and they didn’t proliferate as well.”

Further investigation using preclinical models revealed the specific metabolic pathways that Dr. Davila and his colleagues believe are key to how macrophages trigger this dysfunction in CD19-targeted CAR T cells. “Our goal now,” he says, “is “to retrain the CAR T cells to be more resistant to this metabolic dysfunction. We hope this will result in better outcomes for patients.”

Dr. Davila will present “Mechanisms of Resistance to CD19-Targeted CAR T Cells: Lessons from Mice and Patients,” Friday, Feb. 17, from 3-3:30 p.m. EST, World Center Marriott, Cypress 3.

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Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancer’s grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@RoswellPark.org.