image: An MSK researcher works in the lab.
Credit: Memorial Sloan Kettering Cancer Center
New research from Memorial Sloan Kettering Cancer Center (MSK) uncovers new details of the immune response against leptomeningeal metastasis; develops a grading system to assess the risk of developing thrombocytopenia after CAR T cell therapy; outlines a method for scientists to estimate metabolic characteristics from challenging clinical samples; and probes CRISPR’s anti-viral capabilities.
Surprising findings about the immune response to leptomeningeal metastasis
An MSK research team led by investigator Adrienne Boire, MD, PhD, discovered that a signaling molecule called interferon-gamma plays a key — and surprising — role in the body’s immune response against leptomeningeal metastasis (LM), which occurs when cancer cells spread to the fluid around the brain and spinal cord. By increasing interferon-gamma levels in the spinal fluid, the researchers were able to slow cancer growth and improve survival in mouse models.
Surprisingly, interferon-gamma did not rely on the adaptive immune system to exert its anti-tumor effects. Instead, the signaling molecule drove maturation of dendritic cells. These dendritic cells generated cytokines (proteins key to immune cell regulation) to support natural killer cells and promote tumor killing. Interferon-gamma orchestrates the entire complex process.
“The mechanism that underlies interferon-gamma’s anti-tumor effects was surprising,” Dr. Boire says. “We did not expect to find that this effect was independent of adaptive immunity. Unraveling this unusual mechanism step-by-step was exciting; we truly did not know what we might find! We have not solved the entire puzzle of anti-tumor immunity in the leptomeningeal space, but we have uncovered key players and principles.”
Read more in Nature.
MSK researchers develop a new grading system to assess the risk of developing a common CAR T cell therapy side effect
Thrombocytopenia, or low platelet count, is a common side effect of chimeric antigen receptor (CAR) T cell therapy, which is used to treat many types of blood cancer. Because platelets help blood clot, patients with thrombocytopenia are at increased risk of bleeding complications. While significant progress has been made in managing CAR T–related side effects, no previous studies have determined the incidence of low platelet count after CAR T cell therapy, or how it affects patients’ recovery and long-term health.
A recent study led by research fellow Kai Rejeski, MD, visiting investigator Jaime Sanz, MD, and bone marrow transplant specialists Miguel-Angel Perales, MD, and Roni Shouval, MD, PhD, introduced a new grading system called T-ICAHT to evaluate low platelet counts in patients undergoing CAR T cell therapy for B cell non-Hodgkin lymphoma. Analyzing data from 744 patients, researchers found that nearly half experienced early thrombocytopenia within the first month post-treatment, with a significant portion developing severe cases. This condition was associated with a greater need for blood transfusions, a higher risk of bleeding, and reduced overall survival. The grading system was validated in additional patient groups, suggesting its broad applicability. By incorporating T-ICAHT into existing frameworks, healthcare providers can more accurately predict and manage the side effects of CAR T cell therapy. T-ICAHT will be included in the upcoming “Consensus Grading for Toxicities After Immune Effector Cells,” published by the American Society of Transplantation and Cellular Therapy. Read more in Blood.
New method allows scientists to estimate metabolic characteristics from challenging clinical samples
Measuring changes in the body’s chemical reactions — the metabolites it produces as it processes nutrients — are important for understanding a variety of diseases, including cancer. Directly measuring these changes in clinical samples at scale is challenging, however, because individual samples have to be specially preserved to prevent tissue damage and changes to the metabolites, not to mention other analytical complexities.
To overcome these barriers, a team of researchers from MSK have developed a statistical method called UnitedMet to estimate levels of metabolites using more readily available data about which gene programs are active across samples (transcriptomics).
The team — which included graduate student Amy Xie, and computational oncologists Wesley Tansey, PhD, and Ed Reznik, PhD — demonstrated how UnitedMet could be used by looking at the metabolic characteristics of kidney cancer. They found that certain mutations in genes were associated with specific metabolic patterns in the cancer cells. They also observed that advanced kidney cancers have different metabolic features compared to early-stage disease, and that the presence of these features is associated with poorer outcomes in response to combination therapy.
“UnitedMet provides a way to study metabolism when direct measurements of metabolites are not possible,” Xie says. The team is continuing to refine and validate the model. Read more in Nature Cancer.
Researchers probe anti-viral CRISPR capabilities
Bacteria have evolved savvy strategies against viruses — the most well-known being CRISPR-Cas9, which has been adapted into a gene-editing tool.
Now researchers at MSK and The Rockefeller University are shedding new light on immune components of some CRISPR systems, called CARF effectors. A new study examines a newly discovered CARF effector, which they dubbed Cat1. Thanks to an unusually complex molecular structure, this protein can deplete a metabolite essential for cellular function, leaving the invading virus short on the fuel it needs, according to findings overseen by senior authors Dinshaw Patel, PhD, at MSK and Luciano Marraffini, PhD, at Rockefeller.
“The collective work of our labs is revealing just how effective — and different — these CARF effectors are,” the researchers note in a press release. “The range of their molecular activities is quite amazing.” Read more in Science.