Excessive activated T-cell proliferation after anti-CD19 CAR T-cell therapy

• Published in: Gene therapy 2018-06, Vol.25 (3), p.198-204
• Main Authors: Zhang, Wen-ying, Liu, Yang, Wang, Yao, Nie, Jing, Guo, Ye-lei, Wang, Chun-meng, Dai, Han-ren, Yang, Qing-ming, Wu, Zhi-qiang, Han, Wei-dong
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 38/47; 631/250/2152; 631/67/1990/291/1621/1915; Alanine; Alanine transaminase; Aspartate aminotransferase; B-cell lymphoma; Biomedical and Life Sciences; Biomedicine; Cancer; CD19 antigen; CD8 antigen; Cell Biology; Cell growth; Cell number; Cell proliferation; Chemotherapy; Chimeric antigen receptors; Cyclophosphamide; Cytokines; Fever; Fludarabine; Gene Expression; Gene Therapy; Genomes; Health aspects; Human Genetics; Kinases; L-Lactate dehydrogenase; Lactic acid; Lymphocytes B; Lymphocytes T; Nanotechnology; Next-generation sequencing; Non-Hodgkin's lymphomas; Patients; Peripheral blood; Point mutation; T cell receptors; T cells; Toxicity; Transaminase
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/s41434-017-0001-8

Excessive activated T-cell proliferation was observed in vivo in one patient after an anti-CD19-chimeric antigen receptor (CAR) T-cell infusion. The patient, who had chemotherapy refractory and CD19 + diffuse large B-cell lymphoma (DLBCL), received an anti-CD19 CAR T-cell infusion following conditioning chemotherapy (fludarabine/cyclophosphamide). The lymphocyte count in the peripheral blood (PB) increased to 77 × 10 9 /L on day 13 post infusion, and the proportion of CD8 + actived T cells was 93.06% of the lymphocytes. Then, the patient suffered from fever and hypoxaemia. Significant increases in serum cytokine, lactate dehydrogenase, aspartate aminotransferase (AST), alanine transaminase (ALT), and glutamic-oxalacetic transaminase (γ-GT) levels were observed. A high-throughput sequencing analysis for T-cell receptors (TCRs) and whole-genome sequencing were used to explore the mechanisms underlying this excessive T-cell proliferation. TCR diversity was demonstrated, but no special gene mutation was found. The patient was found to be infected with the John Cunningham polyomavirus (JCV). It cannot be ruled out the bystander activation pathway induced by JCV infections related the excessive activated T-cell proliferation. Although the clinical and laboratory data do not fully explain the reason for excessive T-cell proliferation after the anti-CD19 CAR T-cell infusion, the risk of this type of toxicity should be emphasized. This study was registered at www.clinicaltrials.gov as NCT01864889.