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Biomarkers may help ID patients at increased risk of neurotoxicity from CD19 CAR T-cell therapy

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Bottom Line: New potential biomarkers and a novel algorithm could help identify patients at increased risk of suffering from severe neurotoxicity after receiving CD19 CAR T-cell therapy. The study extensively characterized common and occasionally fatal side effects of this immunotherapy.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Authors: Cameron J. Turtle, MBBS, PhD, associate member at Fred Hutchinson Cancer Research Center, associate professor at the University of Washington, and attending physician on the Immunotherapy Service at Fred Hutch.

Background: On August 30, 2017, the FDA approved the first CD19 CAR T-cell therapy, tisagenlecleucel (Kymriah), for the treatment of acute lymphoblastic leukemia (ALL) in certain pediatric and young adult patients. Different CD19 CAR T-cell therapies are being developed and tested, and reports show that a small number of patients who received certain forms of this therapy in clinical trials have died from severe neurotoxicity.

Turtle and colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from CD19 CAR T-cell therapy.

How the Study Was Conducted: The researchers used data from a clinical trial in which 133 adult patients with relapsed and/or refractory CD19 B-cell ALL, non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated with lymphodepletion chemotherapy followed by infusion of JCAR014, a type of CD19 CAR T-cell therapy developed at Fred Hutchinson Cancer Research Center.

Within 28 days of treatment, 53 patients (40 percent) developed grade 1 or higher neurologic adverse events and of these 28 (21 percent) had grade 3 or higher neurotoxicity; alterations in neurologic status completely resolved in a majority of cases. Four of the 133 patients (3 percent) developed fatal neurotoxicity.

Results: Turtle and colleagues found that patients with an early onset of CRS were at increased risk of subsequently developing severe neurotoxicity. While tocilizumab (Actemra), an IL-6R antagonist approved by the FDA to treat CRS, was effective in ameliorating CRS-related fever and hypotension in most patients, the team found that its role in preventing or treating neurotoxicity is less clear.

Patients who experienced neurotoxicity were mostly younger and had B-cell ALL, higher tumor burden, and more CD19-positive cells in the bone marrow, compared with those who did not develop this side effect. Data also revealed that those with severe neurotoxicity had endothelial activation, which could contribute to manifestations such as capillary leak, blood coagulation abnormalities, and disruption of the blood-brain barrier that were observed in patients with severe CRS and neurotoxicity.

Turtle and colleagues developed a predictive classification tree algorithm based on the 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. Patients at increased risk for this adverse event may benefit from early intervention, Turtle noted; however, he pointed out that additional studies are required.

Authors' Comments: "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 one form of this therapy by the U.S. Food and Drug Administration [FDA]," said Turtle.

"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," he said. "It is important to understand the side effects, such as cytokine release syndrome [CRS] and neurological toxicity."

Enormous improvements have been made in the last few years in strategies to minimize the risk of toxicity, Turtle noted. "Because CAR T-cell therapy is so new, we are still learning how to improve the delivery and reduce the side effects," he added.

Limitations: Limitations of the study include that the characterization of side effects was only from patients who received JCAR014 and not other forms of CD19 CAR T-cell therapies, Turtle said.

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Funding & Disclosures: This research was funded by the National Cancer Institute, Juno Therapeutics Inc., Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and institutional funds from Bloodworks Northwest. Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

Fred Hutch, where Turtle and other co-authors are employed, has a financial interest in Juno, and receives licensing and other payments from the company.

To interview Cameron Turtle, contact Julia Gunther at [email protected] or 215-446-6896.

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Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 37,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 108 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with nearly 19,500 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org.

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