Chimeric antigen receptor (CAR) T-cell therapy has displayed potent anti-leukemia activity in acute lymphocytic leukemia (ALL), acting as a new ray of hope to refractory/relapsed patients. However, the influence of CAR-T therapy on host immune system has not been well elucidated. Thus, We applied high-throughput T cell receptor β chain sequencing to track the dynamic change of T-cell repertoire induced by CAR-T therapy in B-cell ALL patients. Six Chinese patients achieving complete remission were under observation, whose blood samples, bone marrow samples and infused CAR-T samples were collected at serial time points before and after CAR-T therapy. We observed decreased TCR diversity and increased clonality of T-cell repertoire in both peripheral blood and bone marrow after CAR-T administration. The persistent T cell clones in blood and bone marrow expanded following leukemic cell destruction and were barely detected in CAR T-cell pool. For the first time, our results demonstrated CAR-T therapy could stimulate the clonal proliferation of CAR-negative T cells in patients. Considering other groups’ animal results indicating that CAR-T therapy could facilitate the proliferation of tumor antigen-specific T cells and that the emergence of these T cell clones followed the destruction of leukemic cells, they are most likely tumor antigen-specific.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–8.
Sadelain M, RiviSre I, Riddell S. Therapeutic T cell engineering. Nature. 2017;545:423–31.
Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science 2015;350:aab4077.
Brentjens RJ, Davila ML, Riviere I, Park J, Wang XY, Cowell LG, et al. CD19-Targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38.
Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YZK, 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.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. New Engl J Med. 2014;371:1507–17.
Davila ML, Riviere I, Wang XY, 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.
Hu YX, Wu Z, Luo Y, Shi JM, Yu J, Pu CF, et al. Potent anti-leukemia activities of chimeric antigen receptor-modified T cells against CD19 in chinese patients with relapsed/refractory acute lymphocytic leukemia. Clin Cancer Res. 2017;23:3297–306.
Barber A, Sentman CL. Chimeric NKG2D T cells require both T cell- and host-derived cytokine secretion and perforin expression to increase tumor antigen presentation and systemic immunity. J Immunol. 2009;183:2365–72.
Barber A, Rynda A, Sentman CL. Chimeric NKG2D Expressing T cells eliminate immunosuppression and activate immunity within the ovarian tumor microenvironment. J Immunol. 2009;183:6939–47.
Spear P, Barber A, Sentman CL. Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors. Oncoimmunology. 2013;2:e23564.
Nikolich-Zugich J, Slifka MK, Messaoudi I. The many important facets of T-cell repertoire diversity. Nat Rev Immunol. 2004;4:123–32.
Tamura K, Hazama S, Yamaguchi R, Imoto S, Takenouchi H, Inoue Y, et al. Characterization of the T cell repertoire by deep T cell receptor sequencing in tissues and blood from patients with advanced colorectal cancer. Oncol Lett. 2016;11:3643–9.
Morris GP, Allen PM. How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat Immunol. 2012;13:121–8.
Arstila TP, Casrouge A, Baron V, Even J, Kanellopoulos J, Kourilsky P. A direct estimate of the human alphabeta T cell receptor diversity. Science. 1999;286:958–61.
Arstila TP, Casrouge A, Baron V, Even J, Kanellopoulos J, Kourilsky P. Diversity of human alpha beta T cell receptors. Science. 2000;288:1135.
Linnemann C, Mezzadra R, Schumacher TNM. TCR repertoires of intratumoral T-cell subsets. Immunol Rev. 2014;257:72–82.
Linnemann C, Heemskerk B, Kvistborg P, Kluin RJC, Bolotin DA, Chen XJ. et al. High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat Med. 2013;19:1534–41.
Fang H, Yamaguchi R, Liu X, Daigo Y, Yew PY, Tanikawa C, et al. Quantitative T cell repertoire analysis by deep cDNA sequencing of T cell receptor alpha and beta chains using next-generation sequencing (NGS). Oncoimmunology. 2014;3:e968467.
Liu X, Venkataraman G, Lin JY, Kiyotani K, Smith S, Montoya M, et al. Highly clonal regulatory T-cell population in follicular lymphoma—inverse correlation with the diversity of CD8(+) T cells. Oncoimmunology 2015;4:e1002728.
Kirsch I, Vignali M, Robins H. T-cell receptor profiling in cancer. Mol Oncol. 2015;9:2063–70.
Emerson RO, Sherwood AM, Rieder MJ, Guenthoer J, Williamson DW, Carlson CS, et al. High-throughput sequencing of T-cell receptors reveals a homogeneous repertoire of tumour-infiltrating lymphocytes in ovarian cancer. J Pathol. 2013;231:433–40.
Hsu MS, Sedighim S, Wang TN, Antonios JP, Everson RG, Tucker AM, et al. TCR sequencing can identify and track glioma-infiltrating T cells after DC vaccination. Cancer Immunol Res. 2016;4:412–8.
Liu X, Kline J. Selection and Monitoring of Patients for Immunotherapy (PeptideVaccines). In: Nakamura Y (ed). Immunopharmacogenomics. Springer Japan: Tokyo, 2015, pp 63–84.
Zewde M, Kiyotani K, Park JH, Fang H, Yap KL, Yew PY, et al. The era of immunogenomics/immunopharmacogenomics. J Hum Genet 2018. https://doi.org/10.1038/s10038-018-0468-1
Cha E, Klinger M, Hou YF, Cummings C, Ribas A, Faham M, et al. Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci Transl Med. 2014;6:238ra70.
Sheikh N, Cham J, Zhang L, DeVries T, Letarte S, Pufnock J, et al. Clonotypic diversification of intratumoral T cells following sipuleucel-T treatment in prostate cancer subjects. Cancer Res. 2016;76:3711–8.
Robert L, Tsoi J, Wang XY, Emerson R, Homet B, Chodon T, et al. CTLA4 blockade broadens the peripheral T-cell receptor repertoire. Clin Cancer Res. 2014;20:2424–32.
Yew PY, Alachkar H, Yamaguchi R, Kiyotani K, Fang H, Yap KL, et al. Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transpl. 2015;50:1227–34.
Zhang L, Cham J, Paciorek A, Trager J, Sheikh N, Fong L. 3D: diversity, dynamics, differential testing a proposed pipeline for analysis of next-generation sequencing T cell repertoire data. Bmc Bioinformatics. 2017;18:129.
Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T Cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011;3:95ra73.
Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119:2709–20.
Yu SN, Li AP, Liu Q, Li TF, Yuan X, Han XW, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. J Hematol Oncol. 2017; 10.
Elizabeth FK, Hui-Sheng A, Brian S, Jean-Sebastien D, Kai-Xun H, Anthony DS. Do we need full donor chimerism? How alloreactive cell therapies without substantial engraftment might treat Hematologic cancers. Curr Drug Targets. 2017;18:281–95. https://doi.org/10.2174/1389450116666150304103849
Guo M, Hu KX, Liu GX, Yu CL, Qiao JH, Sun QY, et al. HLA mismatched stem-cell Microtransplantation as postremission therapy for acute myeloid leukemia: long-term follow-up. J Clin Oncol. 2012;30:4084–90.
Bachireddy P, Hainz U, Rooney M, Pozdnyakova O, Aldridge J, Zhang WD, et al. Reversal of in situ T-cell exhaustion during effective human antileukemia responses to donor lymphocyte infusion. Blood. 2014;123:1412–21.
The authors thank the patients and families for their participation in this study and the help of nurse team on patients’ care and sample collection. Finally, thank the grant supported by the National Key Basic Research Program of China (2015CB964900), National Key Nature Science Foundation of China (81730008), Key Project of Science and Technology Department of Zhejiang Province (2015C03038; 2018C030162), and National Nature Science Foundation of China (81770201).
This work was supported by the National Key Basic Research Program of China (2015CB964900), National Key Nature Science Foundation of China (81730008), Key Project of Science and Technology Department of Zhejiang Province (2015C03038; 2018C030162), and National Nature Science Foundation of China (81770201).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors shared senior authorship: He Huang, Tao Sun
About this article
Cite this article
Wang, X., Hu, Y., Liu, X. et al. Quantitative characterization of T-cell repertoire alteration in Chinese patients with B-cell acute lymphocyte leukemia after CAR-T therapy. Bone Marrow Transplant 54, 2072–2080 (2019). https://doi.org/10.1038/s41409-019-0625-y
This article is cited by
Multidisciplinary recommendations for the management of CAR-T recipients in the post-COVID-19 pandemic era
Experimental Hematology & Oncology (2023)
Level of unique T cell clonotypes is associated with clonal hematopoiesis and survival in patients with lymphoma undergoing ASCT
Bone Marrow Transplantation (2022)
BMC Infectious Diseases (2021)
Efficacy and safety of sintilimab in combination with chemotherapy in previously untreated advanced or metastatic nonsquamous or squamous NSCLC: two cohorts of an open-label, phase 1b study
Cancer Immunology, Immunotherapy (2021)