Chimeric antigen receptor T-cell therapy - assessment and management of toxicities

Abstract

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

Conflict of interest statement

Competing interests statement

S.S.N. has received research support from Bristol-Myers Squibb, Celgene, Cellectis, Kite Pharma, Merck, and Poseida Therapeutics. S.S.N. has also served as a consultant and/or Scientific Advisory Board member for Celgene, Kite Pharma, Merck, and Novartis. S.T. served as a Scientific Advisory Board member for Kite Pharma. F.L.L. has served as a Scientific Advisory Board member for Kite Pharma, and as a Consultant to Cellular Biomedicine Group. K.V.K. has served as a scientific advisor to and has received research funding from Juno Therapeutics and Kite Pharma. Y.L. has received research funding from Janssen. N.J. has received research support from Abbvie, ADC Therapeutics, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Pharmacyclics, Pfizer, Seattle Genetics, Servier, and Verastem. N.J. has also served on the advisory board and received honorarium from Adaptive Biotechnologies, ADC Therapeutics, Novartis, Novimmune, Pharmacyclics, Pfizer, Servier, and Verastem. N.D. has received research support from Bristol-Myers Squibb, Daichi-Sanky, Incyte, Karyopharm, Pfizer, and Sunesis. N.D. has also received served as a consultant for Incyte, Jazz, Karyopharm, Novartis, Otsuka, Pfizer, and Sunesis. J.W. has received research funding and served on the Advisory Boards for Kite Pharma and Novartis. J.F.d.G. has received research support from Astrazeneca, Deciphera Pharmaceuticals, Eli Lilly, EMD-Serono, Mundipharma, Novartis, Sanofi-Aventis. J.F.d.G. has also served as a consultant or Advisory Board member for AbbVie, Astrazeneca, Celldex, Deciphera Pharmaceuticals, FivePrime Therapeutics, Foundation Medicine, Genentech, Insys Therapeutics, Kadmon, Merck, Novartis, and Novogen. J.F.d.G. is a stock owner of Gilead and Ziopharm Oncology, and his spouse is employed by Ziopharm Oncology. S.A. served as an Advisory Board member for Kite Pharma. K.R. is on the Independent Data Monitoring Committee for Kiadis Pharma. The other authors declare no competing interests.

Figures

Figure 1 |. Clinical case study.

The findings of key clinical assessments are shown for a representative patient with cytokine-release syndrome and chimeric antigen receptor (CAR)-T-cell-related encephalopathy syndrome after anti-CD19 CAR-T-cell therapy for refractory diffuse large-B-cell lymphoma. a | The graph shows the patient’s maximum temperature (Tmax), maximum heart rate (HRmax), minimum systolic blood pressure (SBPmin), minimum oxygen saturation (O2 satmin), and serum C-reactive protein (CRP) level recorded on each day after anti-CD19 CAR-T-cell therapy. The anti-IL-6 receptor antibody tocilizumab was administered on days 1, 3, and 5 (arrows) for the treatment of hypotension, hypoxia, and encephalopathy, respectively. b | Handwriting samples and mini mental status exam (MMSE) scores obtained on days 4, 5, and 6 after CAR-T-cell therapy; note how the patient’s handwriting was markedly impaired on day 5, despite only a small decrease in their MMSE score. c | 2-[18F]fluoro-2-deoxy-d-glucose PET images showing the retroperitoneal lymph nodes and ileocolic region harbouring lymphoma at baseline (highlighted in red circle; bottom left), and loss of tracer uptake indicative of induction of disease remission at 30 days after infusion of CAR T cells (bottom right).

Figure 2 |. Three-step approach to the assessment and management of acute toxicities associated with chimeric antigen receptor (CAR)-T-cell therapy.

Step 1: the patient’s clinical and biological symptoms should be monitored to determine the nature of the CAR-T-cell-related toxicity, in order to diagnose cytokine-release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), and haemophagocytic lymphohistiocytosis/macrophage-activation syndrome (HLH/MAS; BOX 5). Step 2: the severity of CRS, CRES, and HLH/MAS should be graded using the criteria provided in TABLE 2, TABLE 4, and the Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE), respectively. Step 3: the toxicities should be treated according to the management algorithms we have provided for CRS (TABLE 3), CRES (BOX 2), and HLH/MAS (FIG. 3). CARTOX-10, CAR-T-cell-therapy-associated toxicity 10-point neurological assessment; CSF, cerebrospinal fluid; ICP, intracranial pressure.

Figure 3 |. Recommendations for the management of Chimeric antigen receptor (CAR)-T-cell-related haemophagocytic lymphohistiocytosis/macrophage-activation syndrome (HLH/MAS).

HLH/MAS should initially be managed according to the guidelines for cytokine-release syndrome (CRS; TABLE 3), with appropriate subsequent laboratory testing to monitor response to treatment. If the results of these tests reveal no improvement within 48 h, escalation of treatment should be considered.