The cytokine data she presented is from research performed using the same assay the clinical laboratory uses. There is variability batch to batch and machine to machine on many cytokine assays, so when using these assays and comparing across different patients from a research perspective, “we have calculated Z-scores from healthy controls to normalize the data across multiple patients,” Dr. Diorio said.
The CXCL9 level of the 18-year-old patient had a Z-score of 320, “so astronomically high levels of CXCL9,” she said. His interferon gamma level had a notably high Z-score of 100. “Not subtle changes in cytokines.”
This patient also received emapalumab and had an excellent response, with resolution of symptoms.
IEC-HS is particularly challenging, Dr. Diorio said, because all of the patients with IEC-HS who have been seen have extremely high cytokines, but the pattern is not as clearly consistent as that seen in CRS. “It’s an important area for future understanding for us.”
IEC-HS is defined as a hyperinflammatory syndrome independent from CRS and ICANS. It has features of macrophage activation and HLH (just as CRS has features of HLH) and is related to an immune effector cell-associated therapy. IEC-HS is specifically associated with cytopenias, hyperferritinemia, coagulopathy with hypofibrinogenemia, and/or transaminitis.
“The most important thing to understand about IEC-HS is it has to occur distal to the CRS,” Dr. Diorio said, “so either with an initial improvement in CRS and then worsening or far out from the occurrence of CRS, as in the case.”
Hines, et al., provide an overview of the underlying biology, delineate a framework for identifying IEC-HS, put forward a grading schema, and discuss potential treatment approaches (Hines MR, et al. Transplant Cell Ther. 2023;29[7]:438.e1–438.e16). In their article, Dr. Diorio said, “There is a description of severe CRS with HLH-like multiorgan dysfunction where patients have severe CRS but do not respond the typical way we see with CRS. I think this cohort of patients is the hardest to describe, clinically or biochemically.”
In addition to CAR T cells, many novel immunotherapy modalities are being investigated, Dr. Diorio said. “For example, NK cells are a promising therapy because they can be used also in an off-the-shelf manner without significant modifications.”
Three novel immunotherapy modalities were approved in 2024. In tumor infiltrating lymphocyte therapy, T cells are isolated from a tumor sample and expanded in the laboratory in the presence of cytokines and other growth factors, then returned to the patient, followed by IL-2 infusions.
“T-cell receptor-engineered therapy uses an endogenous T cell instead of a CAR construct to fight cancer,” Dr. Diorio said of the second such modality. And the third, interleukin-15 therapy, helps activate CD8+ T cells and NK cells in the patient to recognize and kill cancer cells in combination with a cancer-related vaccine.
“All of this is to show,” Dr. Diorio said, “that the field of cancer immunotherapy is rapidly expanding with new techniques for new indications.”
Amy Carpenter is CAP TODAY senior editor.