Chimeric Antigen Receptor T-cells –⁠ Gene Therapy of the Future for Malignant Diseases?

Czech version

Authors: M. Šmída
Authors‘ workplace: CEITEC – Středoevropský technologický institut, MU, Brno
Published in: Klin Onkol 2015; 28(Supplementum 4): 44-47
Category: Generals
doi: https://doi.org/10.14735/amko20154S44

Overview

Chimeric antigen receptors are synthetic, genetically modified receptors of T-cells. The introduction of chimeric antigen receptors into autologous patient T-cells can redirect the lymphocytes to specific antigen targets on the surface of malignant cells. This has recently emerged as an intriguing therapy approach in both hematologic malignancies and later also in solid tumors. Various chimeric antigen receptor designs and manufacturing processes were developed and seem to have a strong impact on the activity of chimeric antigen receptor T-lymphocytes and thereby the therapy success. The individual variables are currently being tested in numerous clinical trials. In this review, I will briefly describe the principle, basic structure and construction of chimeric antigen receptor T-lymphocytes.

Key words:
chimeric antigen receptor –⁠ CAR‑T-cells –⁠ gene therapy –⁠ immunotherapy –⁠ neoplasms

The author declares he has no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
1. 9. 2015

Accepted:
16. 9. 2015

Sources

1. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin‑T ‑⁠ cell receptor chimeric molecules as functional receptors with antibody‑type specificity. Proc Natl Acad Sci U S A 1989; 86(24): 10024 –⁠ 10028.

2. Irving BA, Weiss A. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor‑associated signal transduction pathways. Cell 1991; 64(5): 891 –⁠ 901.

3. Cartellieri M, Bachmann M, Feldmann A et al. Chimeric antigen receptor ‑⁠ engineered T cells for immunotherapy of cancer. J Biomed Biotechnol 2010; 2010 : 956304. doi: 10.1155/ 2010/ 956304.

4. Maus MV, Grupp SA, Porter DL et al. Antibody ‑⁠ modified T cells: CARs take the front seat for hematologic malignancies. Blood 2014; 123(17): 2625 –⁠ 2635. doi: 10.1182/ blood ‑⁠ 2013 ‑⁠ 11 ‑⁠ 492231.

5. Eshhar Z, Waks T, Bendavid A et al. Functional expression of chimeric receptor genes in human T cells. J Immunol Methods 2001; 248(1 –⁠ 2): 67 –⁠ 76.

6. Rossig C, Brenner MK. Genetic modification of T lymphocytes for adoptive immunotherapy. Mol Ther 2004; 10(1): 5 –⁠ 18.

7. Milone MC, Fish JD, Carpenito C et al. 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 –⁠ 1464. doi: 10.1038/ mt.2009.83.

8. 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 U S A 2009; 106(9): 3360 –⁠ 3365. doi: 10.1073/ pnas.0813101106.

9. Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov 2013; 3(4): 388 –⁠ 398. doi: 10.1158/ 2159 ‑⁠ 8290.CD ‑⁠ 12 ‑⁠ 0548.

10. Haso W, Lee DW, Shah NN et al. Anti‑CD22-chimeric antigen receptors targeting B ‑⁠ cell precursor acute lymphoblastic leukemia. Blood 2013; 121(7): 1165 –⁠ 1174. doi: 10.1182/ blood ‑⁠ 2012 ‑⁠ 06 ‑⁠ 438002.

11. Hudecek M, Lupo ‑⁠ Stanghellini MT, Kosasih PL et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1 -⁠ specific chimeric antigen receptor T cells. Clin Cancer Res 2013; 19(12): 3153 –⁠ 3164. doi: 10.1158/1078 ‑⁠ 0432.CCR‑13 ‑⁠ 0330.

12. Hombach A, Hombach AA, Abken H. Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‚spacer‘ domain in the extracellular moiety of chimeric antigen receptors avoids ‚off ‑⁠ target‘ activation and unintended initiation of an innate immune response. Gene Ther 2010; 17(10): 1206 –⁠ 1213. doi: 10.1038/ gt.2010.91.

13. Hombach A, Heuser C, Gerken M et al. T cell activation by recombinant FcepsilonRI gamma‑chain immune receptors: an extracellular spacer domain impairs antigen ‑⁠ dependent T cell activation but not antigen recognition. Gene Ther 2000; 7(12): 1067 –⁠ 1075.

14. Kalos M, June CH. Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 2013; 39(1): 49 –⁠ 60. doi: 10.1016/ j.immuni.2013.07.002.

15. Dupuy AJ, Akagi K, Largaespada DA et al. Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 2005; 436(7048): 221 –⁠ 226.

16. Huang X, Wilber AC, Bao L et al. Stable gene transfer and expression in human primary T cells by the Sleeping Beauty transposon system. Blood 2006; 107(2): 483 –⁠ 491.

17. Maiti SN, Huls H, Singh H et al. Sleeping beauty system to redirect T ‑⁠ cell specificity for human applications. J Immunother 2013; 36(2): 112 –⁠ 123. doi: 10.1097/ CJI.0b013e3182811ce9.

18. Singh H, Manuri PR, Olivares S et al. Redirecting specificity of T ‑⁠ cell populations for CD19 using the Sleeping Beauty system. Cancer Res 2008; 68(8): 2961 –⁠ 2971. doi: 10.1158/ 0008 ‑⁠ 5472.CAN ‑⁠ 07 ‑⁠ 5600.

19. Scholler J, Brady TL, Binder ‑⁠ Scholl G et al. Decade ‑⁠ long safety and function of retroviral ‑⁠ modified chimeric antigen receptor T cells. Sci Transl Med 2012; 4(132): 132ra53. doi: 10.1126/ scitranslmed.3003761.

20. Biffi A, Bartolomae CC, Cesana D et al. Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood 2011; 117(20): 5332 –⁠ 5339. doi: 10.1182/ blood ‑⁠ 2010 ‑⁠ 09 ‑⁠ 306761.

21. Maus MV, Thomas AK, Leonard DG et al. Ex vivo expansion of polyclonal and antigen ‑⁠ specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T ‑⁠ cell receptor, CD28 and 4-1BB. Nat Biotechnol 2002; 20(2): 143 –⁠ 148.

22. Kaneko S, Mastaglio S, Bondanza A et al. IL‑7 and IL‑15 allow the generation of suicide gene ‑⁠ modified alloreactive self ‑⁠ renewing central memory human T lymphocytes. Blood 2009; 113(5): 1006 –⁠ 1015. doi: 10.1182/ blood ‑⁠ 2008 ‑⁠ 05 ‑⁠ 156059.