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Managing the Most Prevalent Clinical Side Effects of CAR-T Therapy

June 02, 2019

A Friday session at the 2019 ASCO Annual Meeting (May 31, 2019; Chicago, IL) discussed the most common adverse effects of chimeric antigen receptor (CAR) T-cell therapy, including cytokine release syndrome (CRS) and neurologic toxicity. Elizabeth J Shpall, MD, The University of Texas MD Anderson Cancer Center, chaired the session and began with an overview of the assessment and management of CRS.

Several CAR T-cell trials have shown impressive remission rates in patients with relapsed/refractory hematologic cancers. Even real-world studies are showing that this is safe and not as complicated as some assumed. Although the clinical responses of these agents in hematologic malignancies have been very encouraging, they have also produced substantial morbidity and occasionally mortality resulting from toxicity.

The most prevalent adverse effect following infusion of CAR T-cells is the onset of immune activation, known as CRS. The hallmark of CRS is immune activation resulting in elevated inflammatory cytokines. Clinical features include: high fever, malaise, fatigue, myalgia, nausea, anorexia, tachycardia/hypotension, capillary leak, cardiac dysfunction, renal impairment, hepatic failure, and disseminated intravascular coagulation. Hematopoietic toxicity is also a less-discussed problem in severe CRS, Dr Shpall noted.

Independent predictors of CRS include: high marrow tumor burden; lymphodepletion using cyclophosphamide and fludarabine; higher CAR T-cell dose; and thrombocytopenia before lymphodepletion. Dr Shpall said we can ameliorate CRS by identifying these predictive biomarkers as well as by prompt (correct) use of anti-IL6 and steroid therapy, extensive education on grading systems and management algorithms, and modification of CAR constructs, eg, “safety switches.”

She provided an overview of the MD Anderson CARTOX Program designed to enhance diagnosis and management of CAR T-cell toxicity. Program activities include comprehensive training of inpatient and outpatient clinic nurses, APPs, pharmacists, nocturnal team, and physicians managing CAR-T and other gene-modified cellular therapy patients. They have had weekly meetings with these team members since March of 2016. A total of 1680 faculty and staff have received ARTOX training to date. Algorithms for diagnosis and management of toxicities are generated, reviewed, and revised as needed. They use a 3-step approach for immune effector cell (IEC)-associated toxicity assessment and management: (1) determine if the patient has CRS and/or IEC-associated neurotoxicity syndrome (ICANS); (2) determine the grade of CRS and/or ICANS; and (3) manage CRS and/or ICANS according to grade.

Following diagnosis of CRS, a challenge has been choosing appropriate therapy to mitigate the physiological symptoms of uncontrolled inflammation without dampening the antitumor efficacy of the engineered cells, she noted.

She highlighted how effective tocilizumab has proven to be in studies, with symptoms being dramatically reduced within a few hours even after a single dose. In addition, tocilizumab/steroid use did not impact responses but was associated with higher CAR T-cell levels in studies.

As her presentation came to a close, she commented that we did not have great animal models for CRS until 2018. She noted one study of anakinra-IL-1R antagonist, which she thinks will become very important in the coming years in treating CRS. Tocilizumab and anakinra prevented CRS without affecting CAR-T expansion or leukemia clearance in animal models.

In summation, Dr Shpall said that CAR T-cell therapies for hematologic cancers are exploding, with solid tumor strategies soon to follow. Clinical efficacy does come at the cost of unique and serious toxicities. Clinical expertise and infrastructure are needed to deliver immune effector cells safely effectively, and to regulatory agency standards.—Amanda Del Signore

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