Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Experimental Hematology & Oncology
Published in: Experimental Hematology & Oncology 1/2017

Open Access 01-12-2017 | Review

Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia

Authors: Guoqing Wei, Lijuan Ding, Jiasheng Wang, Yongxian Hu, He Huang

Published in: Experimental Hematology & Oncology | Issue 1/2017

Login to get access

Abstract

Refractory/relapsed B-cell acute lymphoblastic leukemia remains to be a significant cause of cancer-associated morbidity and mortality for children and adults. Developing novel and effective molecular-targeted approaches is thus a major priority. Chimeric antigen receptor-modified T cell (CAR-T) therapy, as one of the most promising targeted immunotherapies, has drawn extensive attention and resulted in multiple applications. According to published studies, CD19-directed CAR-T cells (CD19 CAR-T) can reach a complete remission rate of 94% in both children and adults with refractory/relapsed ALL, much higher than that of chemotherapy. However, the encouraging outcomes are often associated with complications such as cytokine release syndrome (CRS), serious neurotoxicity, and on-target off-tumor effect, which seriously impeded further clinical application of CAR-T cells. Moreover, CAR-T therapy is typically associated with high relapse rate. This article briefly reviews the manufacture technologies, the conditioning regimens, the cell infusion doses, as well as the prevention and treatment strategies of complications for CAR-T cell therapy.
Literature
1.
Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a children’s oncology group study. Leukemia. 2008;22(12):2142–50.CrossRefPubMedPubMedCentral
2.
Dinner S, Lee D, Liedtke M. Current therapy and novel agents for relapsed or refractory acute lymphoblastic leukemia. Leuk Lymphoma. 2013;55(8):1715–24.CrossRef
3.
Davila ML, Sadelain M. Biology and clinical application of CAR T cells for B cell malignancies. Int J Hematol. 2016;104(1):6–17.CrossRefPubMed
4.
Carpenito C, Milone MC, Hassan R, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proc Natl Acad Sci USA. 2009;106(9):3360–5.CrossRefPubMedPubMedCentral
5.
Wang J, Jensen M, Lin Y, et al. Optimizing adoptive polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Hum Gene Ther. 2007;18(8):712–25.CrossRefPubMed
6.
Hombach AA, Rappl G, Abken H. Arming cytokine-induced killer cells with chimeric antigen receptors: CD28 outperforms combined CD28-OX40 “super-stimulation”. Mol Ther. 2013;21(12):2268–77.CrossRefPubMedPubMedCentral
7.
Pegram HJ, Lee JC, Hayman EG, et al. Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning. Blood. 2012;119(18):4133–41.CrossRefPubMedPubMedCentral
8.
9.
Wang X, Olszewska M, Qu J, et al. Large-scale clinical-grade retroviral vector production in a fixed-bed bioreactor. J Immunother. 2015;38(3):127–35.CrossRefPubMedPubMedCentral
10.
Jin C, Fotaki G, Ramachandran M, et al. Safe engineering of CAR T cells for adoptive cell therapy of cancer using long-term episomal gene transfer. Embo Mol Med. 2016;8(7):702–11.CrossRefPubMedPubMedCentral
11.
Naldini L, Blömer U, Gallay P, et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science. 1996;272(5259):263–7.CrossRefPubMed
12.
Jensen MC, Popplewell L, Cooper LJ, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant. 2010;16(9):1245–56.CrossRefPubMedPubMedCentral
13.
Ivics Z, Hackett PB, Plasterk RH, et al. Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell. 1997;91(4):501–10.CrossRefPubMed
14.
Narayanavari SA, Chilkunda SS, Ivics Z, et al. Sleeping Beauty transposition: from biology to applications. Crit Rev Biochem Mol Biol. 2017;52(1):18–44.CrossRefPubMed
15.
Huang X, Guo H, Kang J, et al. Sleeping Beauty transposon-mediated engineering of human primary T cells for therapy of CD19+ lymphoid malignancies. Mol Ther. 2008;16(3):580–9.CrossRefPubMedPubMedCentral
16.
17.
18.
Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Investig. 2016;126(6):2123–38.CrossRefPubMedPubMedCentral
19.
Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):638–43.CrossRef
20.
21.
Lee DW, Kochenderfer JN, 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.CrossRefPubMed
22.
Hu Y, Wu Z, Luo Y, 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. 2016. doi:10.​1158/​1078-0432.PubMedCentral
23.
Kenderian SS, Porter DL, Gill S. Chimeric antigen receptor T cells and hematopoietic cell transplantation: how not to put the CART before the horse. Biol Blood Marrow Transplant. 2017;23(2):235–46.CrossRefPubMed
24.
25.
Zhao Z, Condomines M, Sj VDS, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T Cells. Cancer Cell. 2015;28(4):415–28.CrossRefPubMedPubMedCentral
26.
27.
Morgan RA, Yang JC, Kitano M, et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther J Am Soc Gene Ther. 2010;18(4):843–51.CrossRef
28.
Chatenoud L, Ferran C, Legendre C, et al. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation. 1990;49(4):697–702.CrossRefPubMed
29.
Xu XJ, Tang YM, Liao C, et al. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med. 2013;39(2):319–26.CrossRefPubMed
30.
Brisse E, Wouters CH, Matthys P. Hemophagocytic lymphohistiocytosis (HLH): a heterogeneous spectrum of cytokine-driven immune disorders. Cytokine Growth Factor Rev. 2015;26(3):263–80.CrossRefPubMed
31.
Sato A, Nishida C, Sato-Kusubata K, et al. Inhibition of plasmin attenuates murine acute graft-versus-host disease mortality by suppressing the matrix metalloproteinase-9-dependent inflammatory cytokine storm and effector cell trafficking. Leukemia. 2015;29(1):145–56.CrossRefPubMed
32.
Kochenderfer JN, Dudley ME, Feldman SA, 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.CrossRefPubMedPubMedCentral
33.
Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6(6):664–79.CrossRefPubMed
34.
35.
36.
Davila ML, Riviere I, Wang X, 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):268–76.CrossRef
37.
Hu Y. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol. 2016;9(1):70.CrossRefPubMedPubMedCentral
38.
Porter DL, Hwang WT, Frey NV, 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.CrossRefPubMed
39.
40.
Ruella M, Barrett DM, Kenderian SS, et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J Clin Investig. 2016;126(10):3814–26.CrossRefPubMedPubMedCentral
41.
Sotillo E, Barrett DM, Black KL, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282–95.CrossRefPubMedPubMedCentral
42.
43.
44.
45.
De Oliveira SN, Ryan C, Giannoni F, et al. Modification of hematopoietic stem/progenitor cells with CD19-specific chimeric antigen receptors as a novel approach for cancer immunotherapy. Hum Gene Ther. 2013;24(10):824–39.CrossRefPubMedPubMedCentral
46.
Otáhal P, Průková D, Král V, et al. Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells. Oncoimmunology. 2016;5(4):e1115940.CrossRefPubMed
Metadata
Title
Advances of CD19-directed chimeric antigen receptor-modified T cells in refractory/relapsed acute lymphoblastic leukemia
Authors
Guoqing Wei
Lijuan Ding
Jiasheng Wang
Yongxian Hu
He Huang
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Experimental Hematology & Oncology / Issue 1/2017
Electronic ISSN: 2162-3619
DOI
https://doi.org/10.1186/s40164-017-0070-9

Other articles of this Issue 1/2017

Experimental Hematology & Oncology 1/2017 Go to the issue

Research

Low-dose methotrexate in sickle-cell disease: a pilot study with rationale borrowed from rheumatoid arthritis

Review

Incorporation of functional elements enhances the antitumor capacity of CAR T cells

Research

Pharmacokinetics of carfilzomib in patients with advanced malignancies and varying degrees of hepatic impairment: an open-label, single-arm, phase 1 study

Case report

Atypical hemolytic uremic syndrome in first trimester pregnancy successfully treated with eculizumab

Short report

Microfluidic device for primary tumor spheroid isolation

Research

Post-transplant lymphoproliferative disorder (PTLD): single institutional experience of 141 patients
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits