November 02, 2017
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Researchers identify biomarkers for CAR T-cell therapy neurotoxicity

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Cameron Turtle

Serum biomarkers and early fever formed the basis of an algorithm that identified patients at increased risk for cytokine release syndrome and neurotoxicity following treatment with CD19 chimeric antigen receptor T-cell therapy, according to data published in Cancer Discovery.

As HemOnc Today previously reported, the FDA has approved two chimeric antigen receptor (CAR) T-cell therapies:

Tisagenlecleucel-T suspension (Kymriah, Novartis) — the first CAR T-cell therapy approved in the United States — for the treatment of children and young adults with B-cell acute lymphoblastic leukemia; and

axicabtagene ciloleucel (Yescarta; Kite, Gilead) as the first CAR T-cell therapy to treat adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.

“CD19 CAR T-cell therapy is a highly effective, novel treatment modality that has rapidly expanded in the cancer research and treatment field over the past few years, including recent approval of ... this therapy by the FDA,” Cameron Turtle, MBBS, PhD, FRACP, FRCPA, associate member of the clinical research division at Fred Hutchinson Cancer Research Center, said in a press release.

However, most patients develop cytokine release syndrome within the first 2 weeks after infusion, and neurological adverse events frequently occur with or following cytokine release syndrome. Some patients who received certain forms of CAR T-cell therapies in trials died of severe neurotoxicity.

“There is understandably anxiety about some of the side effects of CD19 CAR T-cell therapy, but these treatments have been very effective for a subgroup of patients with resistant disease,” Turtle said. “It is important to understand the side effects, such as cytokine release syndrome and neurological toxicity.”

Turtle and colleagues evaluated follow-up data from a clinical trial of JCAR014 (Juno Therapeutics) to provide clinical, radiological and pathological characterization of neurotoxicity associated with CD19 CAR T-cell therapy.

Researchers designed the trial to evaluate 133 patients with relapsed and/or refractory CD19 B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma or chronic lymphocytic leukemia who were treated with lymphodepletion chemotherapy followed by infusion of JCAR014.

Within 28 days of CD19 CAR T-cell therapy (median, 4 days), 53 patients (40%) experienced at least one grade 1 or higher neurologic adverse event.

Among these patients, 48 with any neurologic adverse event also presented with cytokine release syndrome.

Fever occurred earlier after CAR T-cell infusion among patients who subsequently developed grade 3 or higher neurotoxicity than among those who developed grade 1 to grade 2 neurotoxicity (P = .0007). However, the time from infusion to the onset of neurotoxicity and the time to maximum grade of neurotoxicity did not differ.

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“These data show that an early onset of cytokine release syndrome after CAR T-cell infusion is associated with a higher risk [for] subsequent developing severe neurotoxicity,” the researchers wrote.

Tocilizumab (Actemra, Genentech) — an IL-6R antagonist FDA approved for treatment of cytokine release syndrome — appeared effective in resolving cytokine release syndrome-related fever and hypotension. However, established neurotoxicity is less responsive than cytokine release syndrome to interventions that suppress IL-6 activity or CAR T-cell function.

Researchers then analyzed baseline patient characteristics to identify factors associated with risk for neurotoxicity. Univariate analyses showed neurotoxicity occurred more frequently among younger patients; those with B-cell ALL; those with a high tumor burden and CD19-positive cells in bone marrow; following a high CAR T-cell dose (P < .0001); and among patients with the presence of any pre-existing neurologic comorbidity.

Patients who developed grade 3 or higher neurotoxicity had more severe cytokine release syndrome (P < .0001), as well as:

earlier and higher CD4-positive and CD8-positive CAR T-cell peak counts in blood;

earlier and higher fever;

more severe hemodynamic instability and tachypnea; and

more severe hypoproteinemia, hypoalbuminemia and weight gain, consistent with loss of vascular integrity and systemic capillary leak.

Turtle and colleagues also found that those with severe neurotoxicity had endothelial activation, which could contribute to manifestations — including capillary leak, blood coagulation abnormalities and disruption of the blood-brain barrier — observed among patients with severe cytokine release syndrome and neurotoxicity.

As a result of these findings, Turtle and colleagues developed a predictive classification tree algorithm based on side effects — including fever, and high serum IL-6 and MCP-1 — to identify patients within the first 36 hours after CAR T-cell infusion who are at increased risk for severe neurotoxicity.

“Early identification of patients at risk [for] developing the most severe neurotoxicity might allow intervention with tocilizumab and/or corticosteroids, enabling reduction in serum cytokine concentrations that could mitigate or prevent subsequent toxicity,” the researchers wrote.

However, Turtle acknowledged additional studies of this algorithm are required.

“Enormous improvements have been made in the last few years in strategies to minimize the risk [for] toxicity,” he noted. “Because CAR T-cell therapy is so new, we are still learning how to improve the delivery and reduce the side effects.” – by Kristie L. Kahl

 

Disclosures: NCI, Juno Therapeutics, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program and institutional funds from Bloodworks Northwest funded this study. Turtle reports research funding from Juno Therapeutics, patents licensed by Juno, and pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno. Please see the full study for a list of all other authors’ relevant financial disclosures.