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Open Access 01-12-2020 | Acute Lymphoblastic Leukemia | Research

Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia

Authors: Runxia Gu, Fang Liu, Dehui Zou, Yingxi Xu, Yang Lu, Bingcheng Liu, Wei Liu, Xiaojuan Chen, Kaiqi Liu, Ye Guo, Xiaoyuan Gong, Rui Lv, Xia Chen, Chunlin Zhou, Mengjun Zhong, Huijun Wang, Hui Wei, Yingchang Mi, Lugui Qiu, Lulu Lv, Min Wang, Ying Wang, Xiaofan Zhu, Jianxiang Wang

Published in: Journal of Hematology & Oncology | Issue 1/2020

Abstract

Background

Recent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary.

Methods

We generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL).

Results

Data from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49–24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74–18.08 months) and 6.93 months (95% CI, 3.13–10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8⁺ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017–0.601).

Conclusions

The results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8⁺ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy.

Trial registration

ClinicalTrials.gov: NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687

Available only for authorised users

Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.PubMedPubMedCentral

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(9967):517–28.PubMed

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(16):1507–17.PubMedPubMedCentral

Brudno JN, Somerville RPT, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. 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;34(10):1112–21.PubMedPubMedCentral

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(224):224ra225.

Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest. 2011;121(5):1822–6.PubMedPubMedCentral

Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500.PubMed

Ying Z, Huang XF, Xiang X, Liu Y, Kang X, Song Y, et al. A safe and potent anti-CD19 CAR T cell therapy. Nat Med. 2019;25(6):947–53.PubMed

Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282–95.PubMedPubMedCentral

10.

Fischer J, Paret C, El Malki K, Alt F, Wingerter A, Neu MA, et al. CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in B-ALL patients at initial diagnosis. J Immunother. 2017;40(5):187–95.PubMedPubMedCentral

11.

An N, Tao Z, Li S, Xing H, Tang K, Tian Z, et al. Construction of a new anti-CD19 chimeric antigen receptor and the anti-leukemia function study of the transduced T cells. Oncotarget. 2016;7(9):10638–49.PubMedPubMedCentral

12.

Park JH, Riviere I, Gonen M, Wang X, Senechal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449–59.PubMedPubMedCentral

13.

Hinrichs CS, Borman ZA, Gattinoni L, Yu ZY, Burns WR, Huang JP, et al. Human effector CD8(+) T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy. Blood. 2011;117(3):808–14.PubMedPubMedCentral

14.

Xu Y, Zhang M, Ramos CA, Durett A, Liu E, Dakhova O, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123(24):3750–9.PubMedPubMedCentral

15.

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(95):95ra73.PubMedPubMedCentral

16.

Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunother. 2012;35(9):651–60.PubMedPubMedCentral

17.

Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V, Hocker JD, et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood. 2016;128(4):519–28.PubMedPubMedCentral

18.

Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011;118(23):6050–6.PubMedPubMedCentral

19.

Busch DH, Frassle SP, Sommermeyer D, Buchholz VR, Riddell SR. Role of memory T cell subsets for adoptive immunotherapy. Semin Immunol. 2016;28(1):28–34.PubMedPubMedCentral

20.

Wu F, Zhang W, Shao H, Bo H, Shen H, Li J, et al. Human effector T cells derived from central memory cells rather than CD8(+)T cells modified by tumor-specific TCR gene transfer possess superior traits for adoptive immunotherapy. Cancer Lett. 2013;339(2):195–207.PubMed

21.

Hoffmann JM, Schubert ML, Wang L, Huckelhoven A, Sellner L, Stock S, et al. Differences in expansion potential of naive chimeric antigen receptor T cells from healthy donors and untreated chronic lymphocytic leukemia patients. Front Immunol. 2018;8.

22.

Teplyakov A, Obmolova G, Luo J, Gilliland GL. Crystal structure of B-cell co-receptor CD19 in complex with antibody B43 reveals an unexpected fold. Proteins. 2018;86(5):495–500.PubMed

23.

Li S, Tao Z, Xu Y, Liu J, An N, Wang Y, et al. CD33-specific chimeric antigen receptor T cells with different co-stimulators showed potent anti-leukemia efficacy and different phenotype. Hum Gene Ther. 2018;29(5):626–39.PubMed

24.

Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95.PubMedPubMedCentral

25.

Ghorashian S, Kramer AM, Onuoha S, Wright G, Bartram J, Richardson R, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019;25:1408–14.PubMed

26.

Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322–31.PubMedPubMedCentral

27.

Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019;20(1):31–42.PubMed

28.

Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, 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(177):177ra138.

29.

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(6):2123–38.PubMedPubMedCentral

30.

Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018;378(5):439–48.PubMedPubMedCentral

31.

Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishnaet S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24(1):20–8.PubMed

32.

Zhao Y, Liu ZF, Wang X, Wu HT, Zhang JP, Yang JF, et al. Treatment with humanized selective CD19 CAR-T cells shows efficacy in highly treated B-ALL patients who have relapsed after receiving murine-based CD19 CAR-T therapies. Clin Cancer Res. 2019;25(18):5595–607.PubMed

33.

Maus MV, Haas AR, Beatty GL, Albelda SM, Levine BL, Liu XJ, et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol Res. 2013;1(1):26–31.PubMedPubMedCentral

34.

Neelapu SS. CAR-T efficacy: is conditioning the key? Blood. 2019;133(17):1799–800.PubMed

35.

Lowe KL, Mackall CL, Norry E, Amado R, Jakobsen BK, Binder G. Fludarabine and neurotoxicity in engineered T-cell therapy. Gene Ther. 2018;25:176–91.PubMed

36.

Santomasso BD, Park JH, Salloum D, Riviere I, Flynn J, Mead E, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8(8):958–71.PubMedPubMedCentral

37.

Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404–19.PubMedPubMedCentral

38.

Yu S, Yi M, Qin S, Wu KM. Next generation chimeric antigen receptor T cells: safety strategies to overcome toxicity. Mol Cancer. 2019;18(1):125.PubMedPubMedCentral

39.

Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest. 2005;115(6):1616–26.PubMedPubMedCentral

40.

Golubovskaya V, Wu L. Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy. Cancers (Basel). 2016;8(3).

41.

McLellan AD, Ali Hosseini Rad SM. Chimeric antigen receptor T cell persistence and memory cell formation. Immunol Cell Biol. 2019;97(7):664–74.PubMed

42.

Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer. 2012;12(10):671–84.PubMedPubMedCentral

43.

Hinrichs CS, Borman ZA, Cassard L, Gattinoni L, Spolski R, Yu Z, et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc Natl Acad Sci U S A. 2009;106(41):17469–74.PubMedPubMedCentral

44.

Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest. 2008;118(1):294–305.PubMed

45.

Gargett T, Brown MP. Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy. 2015;17(4):487–95.PubMed

Title: Efficacy and safety of CD19 CAR T constructed with a new anti-CD19 chimeric antigen receptor in relapsed or refractory acute lymphoblastic leukemia
Authors: Runxia Gu
Fang Liu
Dehui Zou
Yingxi Xu
Yang Lu
Bingcheng Liu
Wei Liu
Xiaojuan Chen
Kaiqi Liu
Ye Guo
Xiaoyuan Gong
Rui Lv
Xia Chen
Chunlin Zhou
Mengjun Zhong
Huijun Wang
Hui Wei
Yingchang Mi
Lugui Qiu
Lulu Lv
Min Wang
Ying Wang
Xiaofan Zhu
Jianxiang Wang
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Acute Lymphoblastic Leukemia
CAR T-Cell Therapy
Published in: Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-020-00953-8

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Abstract

Background

Methods

Results

Conclusions

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