Summary
Cytokine measurement is crucial for managing toxicities associated with CAR T-cell therapy, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic-like syndrome (IEC-HS). These toxicities are linked to elevated cytokine levels, and measuring cytokines helps identify the specific syndrome and guide treatment with cytokine-blocking agents.
Amy Carpenter
January 2026—Translating cytokine science into better cancer care was the focus of a presentation at last year’s ADLM meeting, where the toxicities associated with CAR T-cell therapy were explained with cases and the need to measure cytokines was made clear.
Cytokine measurement has evolved from research curiosity to clinical necessity, said Caroline Diorio, MD, MSTR, pediatric oncologist with the Cancer Center at Children’s Hospital of Philadelphia, where in-house, rapid cytokine panel testing for routine clinical use began in 2020.
“It serves our patients very well when we’re able to keep the membrane between the clinical lab, the patient, and the research lab as thin as possible to learn as quickly as possible what benefits our patients,” Dr. Diorio said.
Cytokines are signaling proteins that orchestrate immune responses.
Chimeric antigen receptor T cells are one way the immune system can be harnessed to fight cancer, as is the blockade of checkpoints and bispecific T-cell engagers. The latter are bispecific antibodies that bind to a target on a tumor antigen and onto a T cell itself, generally via CD3, Dr. Diorio said, noting blinatumomab is the best example in current practice. It’s a CD19-targeting bispecific T-cell engager that is now FDA approved for up-front and relapsed B-cell acute lymphoblastic leukemia. “It has been responsible for remarkable improvements in long-term survival in pediatric and adult patients,” she said.
CAR T cells are “essentially taking out the middleman. You take a T cell, engineer it in the lab to target a specific target, ideally unique to the tumor, and reinfuse it into the patient,” said Dr. Diorio, who is also assistant professor of pediatrics (oncology), Department of Pediatrics, University of Pennsylvania Perelman School of Medicine. They’re approved for the treatment of pediatric B-ALL, adult non-Hodgkin lymphomas, and adult multiple myeloma. “Currently, all FDA-approved products are autologous CAR T products,” she said, “although many allogeneic CAR T products are in the pipeline.”
The three main post-CAR T-cell therapy toxicities are cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and the newest one, immune effector cell-associated hemophagocytic-like syndrome (IEC-HS), previously known as CAR T-associated hemophagocytic lymphohistiocytosis.
CRS tends to occur as early as day three after CAR T-cell infusion, usually peaks around days seven to 10, and almost universally resolves by day 14. ICANS has a more variable course of onset and can occur anytime before day 28 post-infusion. IEC-HS tends to be a later phenomenon.
CRS was originally thought to be associated with the increase in CAR T-cell numbers, Dr. Diorio said, “and that’s true to some extent, but not as clearly as it was initially thought to be.” All three toxicities are associated with the rise of many different cytokines that can be measured in the peripheral blood.
Many specific cytokine-blocking agents are available, which is one reason to measure cytokines. Tocilizumab and siltuximab block interleukin-6 (IL-6), emapalumab can block interferon gamma (IFN-γ), anakinra can block IL-1, JAK-inhibitors can block several cytokines, and IL-18 blockade medications are in clinical development. “With so many tools available in our toolbox, it’s important to know what exactly it is we’re blocking,” she said.