Single measurement of cytokines is rarely useful, “and certainly in the setting of CAR T we send them serially,” Dr. Diorio said, starting with a baseline and following the patient over time.
The 15-year-old patient started with an elevation in interferon gamma (11.3 pg/mL, ref range: 0.0–6.5 pg/mL), “which is unusual,” Dr. Diorio said, and an elevated IL-8 (42.6 pg/mL, ref range: 0.0–10.0 pg/mL). Several days after his CAR T infusion, the patient developed hypotension. At CHOP, hypotension requiring intervention with three crystalloid boluses is the trigger to treat with tocilizumab, Dr. Diorio noted, so the patient received the drug and was transferred to the pediatric ICU. At the time of the PICU transfer, the patient’s IL-6 and IL-8 levels were very high (>7,250 pg/mL and 2,780 pg/mL, respectively), his IL-10 level was exceptionally high (2,610 pg/mL), and his interferon gamma level was above what the CHOP laboratory could measure.
“You have to have a very wide dynamic range on these assays, and certainly in these patients with severe CRS, they are very, very high,” Dr. Diorio said.
The patient continued to require multiple pressors to maintain his blood pressure and was started on steroids and anakinra.
“Once we’ve given tocilizumab,” she said, “we also lose our ability to measure IL-6 because tocilizumab increases the IL-6.”
From Dr. Diorio’s standpoint, IL-10 is a useful measure in these situations. “It’s sort of a surrogate for your degree of T-cell activation because you have an increase of IL-10 as a compensatory measure for the amount of proinflammatory cytokines that are being produced.”
There was an improvement transiently with the addition of steroids and anakinra, but the patient had ongoing severe inflammation. The results of a subsequent cytokine panel showed that the patient’s IL-10 level had become immeasurably high (> 3,250 pg/mL, ref range: 0.0–2.0 pg/mL) and his TNF-α level was very high (97.2 pg/mL, ref range: 0.0–3.5 pg/mL). The patient was continuing to require multiple inotropes and was in renal failure.
The patient was given emapalumab, an interferon gamma-blocking antibody that is FDA approved for primary hemophagocytic lymphohistiocytosis. “It’s one of the few drugs that has a specific pediatric indication [for primary HLH],” Dr. Diorio said.
The patient had a remarkable turnaround. His interferon gamma level became undetectable, his IL-6 and IL-8 levels dropped, and all other inflammatory markers on the panel decreased markedly, coinciding with his clinical improvement.
Dr. Diorio’s group and others have reported on the similarities between CRS and HLH (Diorio C, et al. Clin Cancer Res. 2022;28[17]:3804–3813). CAR T-associated HLH, or IEC-HS, and CRS have overlapping areas with the fundamental pathophysiology of primary HLH, she said, including excessive elevation of interferon gamma and other proteins.
“We took a signature developed by our colleagues at Cincinnati Children’s using a similar technology, although an aptamer-based one, where they developed an HLH-associated signature. We applied their signature to our CRS patients, and we found that signature sorted patients between minimal and severe CRS with almost complete accuracy,” Dr. Diorio said.
“It speaks to the fundamental similarities between the biology, and this is our rationale,” she said, “for using interferon gamma blockade in some of these patients.”
In the same study, she and coauthors identified IL-18 as a novel targetable biomarker for the treatment and prevention of ICANS.