Engineered T Cells for the Adoptive Therapy of B-cell Chronic Lymphocytic Leukaemia

Overview

Journal Adv Hematol

Publisher Wiley

Specialty Hematology

Date 2011 Aug 13

PMID 21837241

Citations 7

Authors

Philipp Koehler

Patrick Schmidt

Andreas A Hombach

Michael Hallek

Hinrich Abken

Affiliations

Soon will be listed here.

Abstract

B-cell chronic lymphocytic leukaemia (B-CLL) remains an incurable disease due to the high risk of relapse, even after complete remission, raising the need to control and eliminate residual tumor cells in long term. Adoptive T cell therapy with genetically engineered specificity is thought to fulfil expectations, and clinical trials for the treatment of CLL are initiated. Cytolytic T cells from patients are redirected towards CLL cells by ex vivo engineering with a chimeric antigen receptor (CAR) which binds to CD19 on CLL cells through an antibody-derived domain and triggers T cell activation through CD3ζ upon tumor cell engagement. Redirected T cells thereby target CLL cells in an MHC-unrestricted fashion, secret proinflammatory cytokines, and eliminate CD19(+) leukaemia cells with high efficiency. Cytolysis of autologous CLL cells by patient's engineered T cells is effective, however, accompanied by lasting elimination of healthy CD19(+) B-cells. In this paper we discuss the potential of the strategy in the treatment of CLL, the currently ongoing trials, and the future challenges in the adoptive therapy with CAR-engineered T cells.

Citing Articles

A CD19-Anti-ErbB2 scFv Engager Protein Enables CD19-Specific CAR T Cells to Eradicate ErbB2 Solid Cancer.

Hombach A, Ambrose C, Lobb R, Rennert P, Abken H Cells. 2023; 12(2).

PMID: 36672182 PMC: 9856536. DOI: 10.3390/cells12020248.

Building on Synthetic Immunology and T Cell Engineering: A Brief Journey Through the History of Chimeric Antigen Receptors.

Abken H Hum Gene Ther. 2021; 32(19-20):1011-1028.

PMID: 34405686 PMC: 10112879. DOI: 10.1089/hum.2021.165.

T Cells in Chronic Lymphocytic Leukemia: A Two-Edged Sword.

Vlachonikola E, Stamatopoulos K, Chatzidimitriou A Front Immunol. 2021; 11:612244.

PMID: 33552073 PMC: 7857025. DOI: 10.3389/fimmu.2020.612244.

Cellular Immune Responses and Immune Escape Mechanisms in Breast Cancer: Determinants of Immunotherapy.

Domschke C, Schneeweiss A, Stefanovic S, Wallwiener M, Heil J, Rom J Breast Care (Basel). 2016; 11(2):102-7.

PMID: 27239171 PMC: 4881254. DOI: 10.1159/000446061.

Role of allogeneic transplantation in patients with chronic lymphocytic leukemia in the era of novel therapies: a review.

Mewawalla P, Nathan S Ther Adv Hematol. 2014; 5(5):139-52.

PMID: 25324955 PMC: 4199093. DOI: 10.1177/2040620714550773.

References

Nishida T, Hudecek M, Kostic A, Bleakley M, Warren E, Maloney D . Development of tumor-reactive T cells after nonmyeloablative allogeneic hematopoietic stem cell transplant for chronic lymphocytic leukemia. Clin Cancer Res. 2009; 15(14):4759-68. PMC: 2785487. DOI: 10.1158/1078-0432.CCR-09-0199. View

Zhao Y, Wang Q, Yang S, Kochenderfer J, Zheng Z, Zhong X . A herceptin-based chimeric antigen receptor with modified signaling domains leads to enhanced survival of transduced T lymphocytes and antitumor activity. J Immunol. 2009; 183(9):5563-74. PMC: 6292203. DOI: 10.4049/jimmunol.0900447. View

Pinthus J, Waks T, Malina V, Kaufman-Francis K, Harmelin A, Aizenberg I . Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes. J Clin Invest. 2004; 114(12):1774-81. PMC: 535069. DOI: 10.1172/JCI22284. View

Hombach A, Abken H . Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signalling. Int J Cancer. 2011; 129(12):2935-44. DOI: 10.1002/ijc.25960. View

Wierda W, OBrien S, Wen S, Faderl S, Garcia-Manero G, Thomas D . Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005; 23(18):4070-8. DOI: 10.1200/JCO.2005.12.516. View

Zhao Y, Moon E, Carpenito C, Paulos C, Liu X, Brennan A . Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 2010; 70(22):9053-61. PMC: 2982929. DOI: 10.1158/0008-5472.CAN-10-2880. View

Klebanoff C, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones A, Finkelstein S . Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci U S A. 2005; 102(27):9571-6. PMC: 1172264. DOI: 10.1073/pnas.0503726102. View

Huarte E, Fisher J, Turk M, Mellinger D, Foster C, Wolf B . Ex vivo expansion of tumor specific lymphocytes with IL-15 and IL-21 for adoptive immunotherapy in melanoma. Cancer Lett. 2009; 285(1):80-8. PMC: 3772508. DOI: 10.1016/j.canlet.2009.05.003. View

Gattinoni L, Finkelstein S, Klebanoff C, Antony P, Palmer D, Spiess P . Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005; 202(7):907-12. PMC: 1397916. DOI: 10.1084/jem.20050732. View

10.

Kochenderfer J, Feldman S, Zhao Y, Xu H, Black M, Morgan R . Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 2009; 32(7):689-702. PMC: 2747302. DOI: 10.1097/CJI.0b013e3181ac6138. View

11.

Kowolik C, Topp M, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N . CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006; 66(22):10995-1004. DOI: 10.1158/0008-5472.CAN-06-0160. View

12.

Kruschinski A, Moosmann A, Poschke I, Norell H, Chmielewski M, Seliger B . Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. Proc Natl Acad Sci U S A. 2008; 105(45):17481-6. PMC: 2582261. DOI: 10.1073/pnas.0804788105. View

13.

Hudecek M, Schmitt T, Baskar S, Lupo-Stanghellini M, Nishida T, Yamamoto T . The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. Blood. 2010; 116(22):4532-41. PMC: 2996114. DOI: 10.1182/blood-2010-05-283309. View

14.

Kochenderfer J, Yu Z, Frasheri D, Restifo N, Rosenberg S . Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. 2010; 116(19):3875-86. PMC: 2981541. DOI: 10.1182/blood-2010-01-265041. View

15.

Pule M, Savoldo B, Myers G, Rossig C, Russell H, Dotti G . Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008; 14(11):1264-70. PMC: 2749734. DOI: 10.1038/nm.1882. View

16.

Milone M, Fish J, Carpenito C, Carroll R, Binder G, Teachey D . Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009; 17(8):1453-64. PMC: 2805264. DOI: 10.1038/mt.2009.83. View

17.

Hallek M, Langenmayer I, Nerl C, Knauf W, Dietzfelbinger H, Adorf D . Elevated serum thymidine kinase levels identify a subgroup at high risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood. 1999; 93(5):1732-7. View

18.

Ritgen M, Stilgenbauer S, von Neuhoff N, Humpe A, Bruggemann M, Pott C . Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood. 2004; 104(8):2600-2. DOI: 10.1182/blood-2003-12-4321. View

19.

Brentjens R, Latouche J, Santos E, Marti F, Gong M, Lyddane C . Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med. 2003; 9(3):279-86. DOI: 10.1038/nm827. View

20.

Kaneko S, Mastaglio S, Bondanza A, Ponzoni M, Sanvito F, Aldrighetti L . IL-7 and IL-15 allow the generation of suicide gene-modified alloreactive self-renewing central memory human T lymphocytes. Blood. 2008; 113(5):1006-15. DOI: 10.1182/blood-2008-05-156059. View