Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy
- Yongxian Hu†1,
- Jie Sun†1,
- Zhao Wu†2,
- Jian Yu1,
- Qu Cui3,
- Chengfei Pu2,
- Bin Liang4,
- Yi Luo1,
- Jimin Shi1,
- Aiyun Jin1,
- Lei Xiao†2 and
- He Huang†1Email author
© The Author(s). 2016
Received: 28 June 2016
Accepted: 5 August 2016
Published: 15 August 2016
Chimeric antigen receptor-modified (CAR) T cells targeting CD19 (CART19) have shown therapeutical activities in CD19+ malignancies. However, the etiological nature of neurologic complications remains a conundrum. In our study, the evidence of blood-brain barrier (BBB)-penetrating CAR T cells as a culprit was revealed. A patient with acute lymphocytic leukemia developed sustained pyrexia with tremors about 6 h after CART19 infusion, followed by a grade 2 cytokine release syndrome (CRS) and neurological symptoms in the next 3 days. Contrast-enhanced magnetic resonance showed signs of intracranial edema. Lumbar puncture on day 5 showed an over 400-mmH2O cerebrospinal pressure. The cerebrospinal fluid (CSF) contained 20 WBCs/μL with predominant CD3+ T cells. qPCR analysis for CAR constructs showed 3,032,265 copies/μg DNA in CSF and 988,747 copies/μg DNA in blood. Cytokine levels including IFN-γ and IL-6 in CSF were extremely higher than those in the serum. Methyprednisone was administrated and the symptoms relieved gradually. The predominance of CART19 in CSF and the huge discrepancies in cytokine distributions indicated the development of a cerebral CRS, presumably featured as CSF cytokines largely in situ produced by BBB-penetrating CAR T cells. For the first time, we reported the development of cerebral CRS triggered by BBB-penetrating CAR T cells.
Trial registration: ChiCTR-OCC-15007008.
KeywordsChimeric antigen receptor-modified T cells CD19 Acute lymphocytic leukemia Cytokine release syndrome Blood-brain barrier
Chimeric antigen receptor-modified (CAR) T cells targeting CD19 (CART19) have shown therapeutical activities in refractory/relapsed acute lymphocytic leukemia (ALL) [1–4]. Neurologic complications were reported in several trials [5–8]; however, the etiological nature still remains a conundrum. In our recent CART19 clinical trial (ChiCTR-OCC-15007008), the evidence of blood-brain barrier (BBB)-penetrating CAR T cells as a culprit was revealed.
In the current study, the patient had experienced recurrent CNSL before CART19 infusion. Since CNS tissues lack CD19 expression , the CNS complications might less probably result from direct interactions between CD19+ cells and CART19. The predominance of CART19 in CSF and the huge discrepancies in inflammatory cytokine distributions strongly indicated the development of a cerebral CRS, presumably featured as CSF cytokines largely in situ produced by BBB-penetrating CAR T cells. Although no evidence of WBCs in CSF was observed before CART19 infusion, potent minimal residual CD19+ leukemia cells less than detection limits might enter CNS  and dramatically trigger activation of CAR T cells. Notably, this patient complicated severe cerebral CRS rather than systemic compromisations, suggesting that systemic and cerebral CRS were independent processes.
We have to acknowledge the comprehensive roles of CRS in CAR T cell therapy. Theoretically, cerebral CRS might facilitate elimination of CNSL and also cause severe CNS complications. Therefore, the timing and strategy to terminate CRS should be deliberately evaluated in clinical practice. Previous reports showed neurologic toxicities were not prevented by cytokine blockade via tocilizumab [6–8] due to its incapability of crossing the BBB. Our experience of using glucocorticoid as a salvage option could be instructive for a quick control of the severe CRS.
In all, we reported for the first time the development and control of cerebral CRS triggered by BBB-penetrating CAR T cells. This study provided insights into the etiology, diagnosis, and treatment of CRS after CAR T cell therapy.
ALL, acute lymphocytic leukemia; BBB, blood-brain barrier; BM, bone marrow; CAR T cell, chimeric antigen receptor-modified T cell; CART19, CD19-directed CAR T cell; CNSL, central nervous system leukemia; CR, complete remission; CRS, cytokine release syndrome; CSF, cerebrospinal fluid; MRD, minimal residual disease; PB, peripheral blood; WBCs, white blood cells
This work was supported by the grants from the 973 Program (2015CB964900); Zhejiang Provincial Natural Science Foundation of China (LY14H080002, LY12H08002); the National Natural Science Foundation of China (81470341); Zhejiang Medical Technology and Education (2014KYA064, 2014KYA066); Key Project of Science and Technology Department of Zhejiang Province (2015C03G2010091); the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (CQ2014); and Beijing Municipal Administration of Hospitals’ Youth Programme (QML20150106, QML20150506). All funding sponsors had no influence in the design of the study and collection, analysis, and interpretation of the data and in writing the manuscript.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and additional files.
HH, LX, and YH designed the study. HH, LX, YH, and QC performed the research and wrote the manuscript. JS, ZW, JY, CP, YL, JS, BL, and AJ performed the research. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
The authors have obtained consent to publish from the participant to report individual patient data.
Ethics approval and consent to participate
The protocol of the clinical trial ChiCTR-OCC-15007008 was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital, School of Medicine, Zhejiang University (A2015008). All the enrolled patients provided written informed consent.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507–17.View ArticlePubMedPubMed CentralGoogle Scholar
- Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016.Google Scholar
- Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 2015;385:517–28.View ArticlePubMedGoogle Scholar
- Han EQ, Li XL, Wang CR, Li TF, Han SY. Chimeric antigen receptor-engineered T cells for cancer immunotherapy: progress and challenges. J Hematol Oncol. 2013;6:47. doi:https://doi.org/10.1186/1756-8722-6-47.View ArticlePubMedPubMed CentralGoogle Scholar
- Maus MV, Grupp SA, Porter DL, June CH. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood. 2014;123:2625–35.View ArticlePubMedPubMed CentralGoogle Scholar
- Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol. 2015;33:540–9.View ArticlePubMedGoogle Scholar
- Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.View ArticlePubMedGoogle Scholar
- Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra25.View ArticlePubMedPubMed CentralGoogle Scholar
- Uckun FM, Jaszcz W, Ambrus JL, Fauci AS, Gajl-Peczalska K, Song CW, et al. Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood. 1988;71:13–29.PubMedGoogle Scholar
- Del Principe MI, Maurillo L, Buccisano F, Sconocchia G, Cefalo M, De Santis G, et al. Central nervous system involvement in adult acute lymphoblastic leukemia: diagnostic tools, prophylaxis, and therapy. Mediterr J Hematol Infect Dis. 2014;6:e2014075.View ArticlePubMedPubMed CentralGoogle Scholar