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BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

The efficacy and safety of anti-CD19/CD20 chimeric antigen receptor- T cells immunotherapy in relapsed or refractory B-cell malignancies:a meta-analysis

Authors: Hui Zhou, Yuling Luo, Sha Zhu, Xi Wang, Yunuo Zhao, Xuejin Ou, Tao Zhang, Xuelei Ma

Published in: BMC Cancer | Issue 1/2018

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Abstract

Background

Chimeric antigen receptor T (CAR T) cells immunotherapy is rapidly developed in treating cancers, especially relapsed or refractory B-cell malignancies.

Methods

To assess the efficacy and safety of CAR T therapy, we analyzed clinical trials from PUBMED and EMBASE.

Results

Results showed that the pooled response rate, 6-months and 1-year progression-free survival (PFS) rate were 67%, 65.62% and 44.18%, respectively. We observed that received lymphodepletion (72% vs 44%, P = 0.0405) and high peak serum IL-2 level (85% vs 31%, P = 0.04) were positively associated with patients’ response to CAR T cells. Similarly, costimulatory domains (CD28 vs CD137) in second generation CAR T was positively associated with PFS (52.69% vs 33.39%, P = 0.0489). The pooled risks of all grade adverse effects (AEs) and grade ≥ 3 AEs were 71% and 43%. Most common grade ≥ 3 AEs were fatigue (18%), night sweats (14%), hypotension (12%), injection site reaction (12%), leukopenia (10%), anemia (9%).

Conclusions

In conclusion, CAR T therapy has promising outcomes with tolerable AEs in relapsed or refractory B-cell malignancies. Further modifications of CAR structure and optimal therapy strategy in continued clinical trials are needed to obtain significant improvements.
Appendix
Available only for authorised users
Literature
1.
Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nature biotechnology. 2002;20(1):70–5.CrossRef
2.
Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 2004;18(4):676–84.CrossRef
3.
van der Stegen SJ, Hamieh M, Sadelain M. The pharmacology of second-generation chimeric antigen receptors. Nature reviews Drug discovery. 2015;14(7):499-509.CrossRef
4.
Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817–28.CrossRef
5.
Abraham RT, Weiss A. Jurkat T cells and development of the T-cell receptor signalling paradigm. Nature reviews Immunology. 2004;4(4):301–8.CrossRef
6.
Weijtens ME, Willemsen RA, Valerio D, Stam K, Bolhuis RL. Single chain Ig/gamma gene-redirected human T lymphocytes produce cytokines, specifically lyse tumor cells, and recycle lytic capacity. Journal of immunology (Baltimore, Md : 1950). 1996;157(2):836–43.
7.
Wang X, Riviere I. Manufacture of tumor- and virus-specific T lymphocytes for adoptive cell therapies. Cancer gene therapy. 2015;22(2):85–94.CrossRef
8.
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(1):13–29.PubMed
9.
Cooper LJ, Topp MS, Serrano LM, Gonzalez S, Chang WC, Naranjo A, et al. T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B-lineage leukemia effect. Blood. 2003;101(4):1637–44.CrossRef
10.
Maloney DG. Anti-CD20 antibody therapy for B-cell lymphomas. N Engl J Med. 2012;366(21):2008–16.CrossRef
11.
Jensen M, Tan G, Forman S, Wu AM, Raubitschek A. CD20 is a molecular target for scFvFc:zeta receptor redirected T cells: implications for cellular immunotherapy of CD20+ malignancy. Biol Blood Marrow Transplant. 1998;4(2):75–83.CrossRef
12.
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.CrossRef
13.
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(12):2709–20.CrossRef
14.
Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33.CrossRef
15.
Zhang T, Cao L, Xie J, Shi N, Zhang Z, Luo Z, et al. Efficiency of CD19 chimeric antigen receptor-modified T cells for treatment of B cell malignancies in phase I clinical trials: a meta-analysis. Oncotarget. 2015;6(32):33961–71.PubMedPubMedCentral
16.
Xu XJ, Zhao HZ, Tang YM. Efficacy and safety of adoptive immunotherapy using anti-CD19 chimeric antigen receptor transduced T-cells: a systematic review of phase I clinical trials. Leuk Lymphoma. 2013;54(2):255–60.CrossRef
17.
Zhu Y, Tan Y, Ou R, Zhong Q, Zheng L, Du Y, et al. Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trials. European journal of haematology. 2016;96(4):389–96.CrossRef
18.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed). 2003;327(7414):557–60.CrossRef
19.
Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121(7):1165–74.CrossRef
20.
Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Molecular therapy : the journal of the American Society of Gene Therapy. 2009;17(8):1453–64.CrossRef
21.
Song DG, Ye Q, Carpenito C, Poussin M, Wang LP, Ji C, et al. In vivo persistence, tumor localization, and antitumor activity of CAR-engineered T cells is enhanced by costimulatory signaling through CD137 (4-1BB). Cancer research. 2011;71(13):4617–27.CrossRef
22.
Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. The Journal of experimental medicine. 2005;202(7):907–12.CrossRef
23.
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346–57.CrossRef
24.
Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends in immunology. 2005;26(2):111–7.CrossRef
25.
Caserta S, Alessi P, Basso V, Mondino A. IL-7 is superior to IL-2 for ex vivo expansion of tumour-specific CD4(+) T cells. European journal of immunology. 2010;40(2):470–9.CrossRef
26.
Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.CrossRef
27.
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.CrossRef
28.
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.CrossRef
29.
Kohn DB, Dotti G, Brentjens R, Savoldo B, Jensen M, Cooper LJ, et al. CARs on track in the clinic. Molecular therapy : the journal of the American Society of Gene Therapy. 2011;19(3):432–8.CrossRef
30.
Cui Y, Zhang H, Meadors J, Poon R, Guimond M, Mackall CL. Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts. Blood. 2009;114(18):3831–40.CrossRef
31.
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.CrossRef
32.
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(6):540–9.CrossRef
33.
Gargett T, Brown MP. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Frontiers in pharmacology. 2014;5:235.CrossRef
34.
Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. 2010;16(9):1245–56.
35.
Kochenderfer JN, Dudley ME, Carpenter RO, Kassim SH, Rose JJ, Telford WG, et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. 2013;122(25):4129–39.
36.
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. 2013;5(177):177ra38.
37.
Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. 2012;119(17):3940–50.
38.
Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. 2013;122(17):2965–73.
39.
Dai H, Zhang W, Li X, Han Q, Guo Y, Zhang Y, et al. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. 2015;4(11):e1027469.
40.
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. 2014;6(224):224ra25.
41.
Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. 2014;371(16):1507–17.
42.
Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, et al. Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. 2014;155(2):160–75.
43.
Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. 2010;116(20):4099–102.
44.
Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, et al. Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. 2016;127(24):2980–90.
Metadata
Title
The efficacy and safety of anti-CD19/CD20 chimeric antigen receptor- T cells immunotherapy in relapsed or refractory B-cell malignancies:a meta-analysis
Authors
Hui Zhou
Yuling Luo
Sha Zhu
Xi Wang
Yunuo Zhao
Xuejin Ou
Tao Zhang
Xuelei Ma
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4817-4

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