Detailed study of cytokine release syndrome and neurologic toxicities could help make emerging cancer immunotherapies safer.

Two new papers from teams at Fred Hutchinson Cancer Research Center provide the most comprehensive data yet reported on side effects of the emerging cancer immunotherapy strategy known as CAR T-cell therapy.

Based on their data from 133 adult participants in one clinical trial, the researchers identified potential biomarkers associated with the development of the toxic effects, known as cytokine release syndrome and neurotoxicity. They also created algorithms aimed at identifying the rare patients whose symptoms were most likely to turn life-threatening.

The researchers anticipate that their work could eventually help doctors reduce the risk of the severe side effects and occasional deaths, which have been seen in clinical trials of various CAR T-cell products. They said that their findings will need to be tested and improved upon by further study, and they noted that their results arise from a clinical trial of one particular CAR T-cell product, which is made by and at Fred Hutch.

“It’s essential that we understand the potential side effects of CAR T therapies,” said Fred Hutch’s Dr. Cameron Turtle, who led the research. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

The product studied by the Fred Hutch team, like the product recently approved by the FDA, reprograms patients’ immune cells to kill blood cancer cells bearing a protein called CD19. The 133 participants in the Fred Hutch clinical trial — believed to be the largest sample size in any published study of CAR T-cell therapy side effects — had advanced leukemias or lymphomas that had proven resistant to standard therapies. Over the last two years, Fred Hutch researchers reported results from different groups of patients treated with the optimal regimen of chemotherapy and CAR T cells: 93 percent of participants with B-cell acute lymphoblastic leukemia went into complete remission; 64 percent with non-Hodgkin lymphoma experienced complete remission; and 86 percent of a subset of patients with high-risk chronic lymphocytic leukemia cleared disease from their bone marrow.

“These patients had highly resistant, refractory disease,” Turtle said. “For many of them, it was their last option.”

The two latest papers provide detailed descriptions of the clinical courses of cytokine release syndrome and of neurotoxicity in study participants, including the types of symptoms present, the timing of their occurrence and the course they ran to resolution. The neurotoxicity paper also includes detailed data from imaging and pathological studies. The team’s paper on neurotoxicity was published online in Cancer Discovery journal October 12. Their paper on cytokine release syndrome, or CRS, was published online in the journal Blood September 18. The findings show that in the vast majority of patients (about 95 percent of participants) harms were either reversible or did not occur; however, as previously reported, complications of CRS, neurotoxicity or both were fatal for some participants.

One of the studies’ novel findings is that severe cases of both types of toxicities were associated with signs that endothelial cells — those lining blood vessels — were ramping up activity in response to injury. For example, the team found that the normally tight barrier between the blood and the brain had broken down in some patients with severe neurotoxicity, and cytokines and CAR T cells from the blood had entered the fluid bathing the brain. The researchers say that biomarkers for endothelial activation could help identify which patients are at greatest risk of CRS and neurotoxicity.

“It appears that cytokine release syndrome is probably necessary