Linfocitos T con receptor de antígeno quimérico

Inicio>>Volumen>>Vol 25, N ° 1 enero – abril 2019>>Linfocitos T con receptor de antígeno quimérico

Linfocitos T con receptor de antígeno quimérico


Diego Molina-Leiva, Marianela Amador-Araya


A los linfocitos T con receptor de antígeno quimérico (CAR, por sus siglas en inglés) se les incorpora el fragmento variable de un anticuerpo monoclonal, cambiando la especificidad del receptor T. Al darse el reconocimiento específico, se activa la célula T colaboradora o citotóxica desarrollando una respuesta T clásica; esta propiedad puede utilizarse para combatir blancos específicos en células alteradas, entre ellas las tumorales. Han pasado casi 30 años desde su descubrimiento y en la actualidad su uso clínico como inmunoterapia comienza a extenderse ampliamente, razón por la cual es importante comprender su concepto, fabricación, acción citotóxica y toxicidad.

Palabras clave

Linfocitos T con receptor de antígeno quimérico, toxicidad, primera generación, segunda generación.


T lymphocytes with a Chimeric Antigen Receptor (CAR) express the variable region of a monoclonal antibody of known specificity permanently, changing the specificity of the T cell that expresses it becoming reactive to the desired antigenic structure. Upon specific recognition, the recombinant T cell becomes fully activated, proliferates, and then differentiates into specific CD4+ helper or CD8+ cytotoxic T cells programs which ultimately execute their immune capabilities against cells that express such specific antigen. This methodology can be used today in patients to target the patient’s own T cells towards specific relevant molecular clues express by altered cells, e.g. tumor specific antigens expressed by particular tumor cells. It has been almost 30 years since its initial development and its current clinical application as a successful immunotherapy begins to spread widely, which is why its concept, manufacture, cytotoxic action, and toxicities must be understood.

Key words

T lymphocytes with chimeric antigen receptor, toxicity, first generation, second generation.

Texto completo



1. Kochenderfer J, Wilson W, Janik J, Dudley M, Stetler-Stevenson M, Feldman S et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 2010; 116(20): 4099-4102.
2. Kolb H. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 2008; 112: 4371-4383.
3. Pule M, Finney H, and Lawson A. Artificial T-cell receptors. Cytotherapy 2003; 5(3), 211-226.
4. Gross G, Waks T, Eshhar Z. Expression of immunoglobin-T-cell receptor chimeric molecules as functional receptors with antibody-type specify. Proceedings of the National Academy of Sciences of the United States of America 1989; 86, 10024-10028.
5. Lee D, Kochenderfer J, Stetler-Stevenson M, Cui Y, Delbrook C, Feldman, S et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukemia in children and young adults: a phase 1 dose-escalation trial. The Lancet 2015; 385: 517-528.
6. Finney H, Akbar A, Lawson A. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. Journal of Immunology 2004; 172: 104-113.
7. Milone M, Fish J, Carpenito C, Riley J, Grupp S, June C. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells an increased antileukemic efficacy in vivo. Molecular Therapy 2009; 17: 1453-1464.
8. Eshhar Z, Waks T, Gross G, Schindler D. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chain consisting of antibody domains and the gamma or zeta subunits of the immunoglobulins and T-cell receptors. Proceedings of the National Academy of Sciences of the United States of America 1993; 90: 720-724.
9. Heuser C, Hombach A, Lösch C, Manista K, Abken H. T-cell activation by recombinant immunoreceptors: impact of the intracellular signaling domain on the stability of receptor expression and antigen-specific activation of grafted T cells. Gene Therapy 2003; 10: 1408-1419.
10. Gong M, Latouche J, Krause A, Heston, W, Bander, N Sadelain M. Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate specific membrane antigen. Neoplasia 1999; 1(2): 123-127.
11. Sadelain M, Brentjens R, Riviere I. The promise and potential pitfalls of chimeric antigen receptors. Current Opinion in Immunology 2009; 21: 215-223.
12. Haynes N, Trapani J, Teng M, Jackson J, Cerruti L, Jane S, et al. Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors. Blood 2002; 100: 3155-3163.
13. Maher J, Brentjens R, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nature Biotechnology 2002; 20: 70-75.
14. Harada Y, Ohgai D, Watanabe F, Okano k, Koiwai O, Tanabe k, et al. A single amino acid alteration in cytoplasmic domain determines IL-2 promoter activation by ligation of CD28 but no inducible costimulator (ICOS). Journal of Experimental Medicine 2003; 197: 257-262.
15. Imai C, Mihara K, Andreansky M, Nicholson I, Pui C, Geiger T, et al. Chimeric receptorswith 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 2004; 18(4): 676-684.
16. Carpenito C, Milone M, Hassan R, Simonet J, Lakhal M, Suhoski m, et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. Proceedings of the National Academy of Sciences of the United States of America 2009; 106: 3360-3365.
17. Chang L, Chang W, McNamara G, Aguilar B, Ostberg J, Jensen M. Transgene-enforced co-stimulation of CD4+ T cells leads to enhanced and sustained anti-tumor effector functioning. Cytotherapy 2007; 9(8): 771-784.
18. Zhao Y, Wang Q, Yang S, Kochenderfer J, Zheng Z, Zhong X, et al. A herceptin-based chimeric antigen receptor with modified signaling receptor with modified signaling of transduced T lymphocytes and antitumor activity. Journal of Immunology 2009; 183: 5563- 5574.
19. Wang J, Jensen M, Lin Y, Sui X, Chen E, Lindgren C, et al. Optimizing adoptative polyclonal T cell immunotherapy of lymphomas, using a chimeric T cell receptor possessing CD28 and CD137 costimulatory domains. Human Gene Therapy 2007; 18(8): 712-725.
20. Lee D, Barrett D, Mackall C, Orentass R, Grupp S. The future in now: Chimeric antigen receptors as new targeted therapies for childhood cancer. Clinical Cancer Research 2012; 18(10): 2780-2790.
21. Curran K, Pegram H, Brentjens R. Chimeric antigen receptors for T cell immunotherapy: current understanding and future directions. Journal of Gene Medicine 2012; 14: 405-415.
22. Goldberger O, Volovitz I, Machlenkin A, Vadai E, tzehoval E, Eisenbach L. Exuberated numbers of tumors-specific T cells a result in tumor escape. Cancer Research 2008; 68: 3450-3457.
23. Chmielewski M, Hombach A, Heurser C, Finnern R, Gilham D, Abken H. T cellactivation by antibody-like immunoreceptors: increase in affinity of the single-chain fragment domain above threshold does not increase T cell activation against antigen-positive target cells but decrease selectivity. Journal of Immunology 2004; 173: 7647-7653.
24. Ang S, Hartline C, Mi T, Maiti S, Jackson G, Hul H, et al. Generating a chimeric antigen receptor to redirect T-cell specify after infusion. Molecular Therapy 2011; 19: S137.
25. Tamada K, Gend D, Sakoda Y, Basal N, Srivastava R, Li Z, et al. Redirecting genemodified T cells toward various cancer types using tagged antibodies. Clinical Cancer Research 2012; 18: 6436-6445.
26. Urbanska K, Lanitis E, Pussin M, Lynn R, Gavin B, Kelderman S, et al. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Research 2012; 72: 1844-1852.
27. Selider B. Different regulation of MCH class I antigen processing components in human tumors. Journal of Immunotoxicology 2008; 5: 361-367.
28. Sadelain M, Riviere I, Brentjens R. Targeting tumors with genetically enhanced T lymphocytes. Nature Reviews Cancer 2003; 3: 35-45.
29. Schreiber R, Old L, Smyth M. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Sciense 2011; 331: 1565-1570.
30. Du X, Beers R, FitzGerald D, Pastan I. Differential cellular internalization of anti-CD19 and CD22 immunotoxins results in different cytotoxic activity. Cancer Research 2008; 68: 6300-6305.
31. Baskar S, Kwong K, Hofer T, Levy J, Kennedy M, Lee E, et al. Unique cell surface expression of receptor tyrosine ROR1 in human B-cell chronic lymphocytic leukemia. Clinical Cancer Research 2008; 14: 396-404.
32. Kerkar S, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z, et al. Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancer in lymphodepeleted hosts. Cancer Research 2010; 70: 6725-6734.
33. Becker C, Pohla H, Frankenberger B, Schüler T, Assenmacher M, Schendel D et al. Adoptive tumor therapy with T lymphocytes enriched through an IFN-gamma capture assay. Nature Medicine 2001; 7: 1159-1162.
34. Ho W, Blattman J, Dossett M, Yee C, Greenberg P. Adoptive inmunotherapy: engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell 2003; 3: 431-437.
35. Gattinoni L, Lugli E, JI Y. A human memory T cell subset with stem cell-like properties. Nature Medicine 2011; 17: 1290-1297.
36. Jensen M, Ridell S. Design and implementation of adoptive therapy with chimeric antigen receptor-modified T cells. Immunology Reviews 2014; 257: 127-144.
37. Hinrichs C, Borman Z, Cassar L, Gattinoni L, Spolski R, Yu Z, et al. Adoptive transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proceedings of the National Academy of Sciences of the United States of America 2009; 106: 17469-17474.
38. Dudley M, Wunderlich J, Yang J, Hwu P, Schwartzentruber D, Topalian S, et al. A phase I study of nonmyeloablative chemotherapy and adoptive transfer of autologous tumor antigen-specific T lymphocytes in patients with metastic melanoma. Journal of Immunotherapy 2002; 25: 243-251.
39. Garlie N, LeFever A, Siebenlist R, Levine B, June C, Lum L. T cells coactived with immobilized anti-Cd3 and anti-Cd28 as potential immunotherapy for cancer. Journal of Immunotherapy 1999; 22: 336-345.
40. Maus M, Thomas A, Leonard D, Allman D, Addya K, Schlienger K, et al.. Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor. Clinical Cancer 2002; 20: 143-148.
41. Suhoski M, Golovina T, Aqui N, Tai V, Varela-Rochena A, Milone M, et al. Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules. Molecular Therapy 2007; 15: 981-988.
42. Howland L, Haynes N, Darcy P. Generation of chimeric T-cell receptor transgenes and their efficient transfer in primary mouse T lymphocytes. In P. Yotnda (Ed.), Immunotherapy of cancer 2010; 291-306.
43. Cleadle E, Gornall H, Baldan V, Hanson V, Hawkins R, Gilaham D. CAR T cells: driving the road from the laboratory to the clinic. Immunological Reviews 2014; 257: 91-106.
44. Zhao Y, Moon E, Carpenito C, Paulos C, Liu X, Brennan A, et al. Multiple injection of elecctroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Research 2010; 70: 9053-9061.
45. Lee J, Sadelain M, Brentjens R. Retroviral transduction of murine primary T lymphocytes. In C. Baum (Ed.), Genetic modification of hematopoietic stem cells 2009: 83- 96.
46. Walter E, Greenberg P, Gilbert M, Finch R, Watanabe K, Thomas E, et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. The New England Journal of Medicine 1995; 333: 1038-1044.
47. Yee C, Thompson J, Byrd D, Ridell S, Roche P, Celis E, et al. Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: in vivo persistence, migration and antitumor effect of transferred T cells. Proceedings of the National Academy of Sciences of the United States of America 2002; 99: 16168-16173.
48. Blattman J, Grayson J, Wherry E, Kaech S, Smith K, Ahmed R. Therapeutic use of IL-2 to enhance antiviral T-cell responses in vivo. Nature Medicine; 9: 540-547.
49. Till B, Jensen M, Wang J, Chen E, Wood B, Greisman H, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008; 112: 2261-2271.
50. Torihata H, Ishikawa F, Okada Y, Tanaka Y, Uchida T, Suguro T, et al. Irradiation upregulates CD80 expression through two different mechanisms in spleen B cells, B lymphoma cells, and dendritic cells. Immunology 2004; 112: 219-227.
51. Fry T, Connick E, Falloon J, Lederman M, Liewehr D, Spritzler J, et al. A potential role for interleukin-7 in T-cell homeostasis. Blood 2001; 97: 2983-2990.
52. Klebanoff C, Khong H, Antony P, Palmer D, restifo N. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends in Immunology 2005; 26(2): 111-117.
53. Zhang H, Chua K, Guimond M, Kapoor V, Brown M, Fleisher T, et al. Lymphopenia and interleukin-2 therapy after homeostasis of CD4+ CD25+ regulatory T cells. Nature Medicine 2005; 11: 1238-1243.
54. Savoldo B, Almeida C, Liu E, Mims M. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. Journal of Clinical Investigation 2011; 121(5): 1822-1826.
55. Gill S, June C. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunological Reviews 2015; 263: 68-89.
56. Parente-Pereira A. Trafficking of CAR-engineered human T cells following regional or systemic adoptive transfer in SCID beige mice. Journal of Clinical Immunology 2011; 31: 710-718.
57. Morgan R, Yang J, Kitano M, Dudley M, Laurencot C, Rosenberg S. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular Therapy 2010; 18: 843-851.
58. Kalos M, Levine B, Porter D, Katz S, Grupp S, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Science Translational Medicine 2011; 3: 73.
59. Zhu Y, Tan Y, Ou R, Zhong Q, Du Y, Zhang Q, et al. Anti-CD19 chimeric antigen receptor-modified T cells for B-cell malignancies: a systematic review of efficacy and safety in clinical trial. European Journal of Haematology 2016; 96:389-396.
60. Kochenderfer J, Dudley M, Feldman S, Wilson W, Spaner D, Maric I, et al. B-cell depetion 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): 2709-2720.
61. Kochenderfer J, Dudley M, Kassim S, Somerville R, Carpenter Rm 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. Journal of Clinical Oncology 2015; 33(6): 540-549.
62. Davila M, Rievere 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. Science Translational Medicine 2014; 6(224): 1-9.
63. Riet T, Abken H. Chimeric antigen receptor T cells: power tools to wipe out leukemia and lymphoma. Expert Review of Hematology 2015; 8(4): 383-385.
64. Gill S, Porter D. CAR-modified anti-CD19 T cells for the treatment of B-cell malignancies: rules of the road. Expert Opinion on Biological Therapy 2014; 14(1): 37-49.
65. Wilkins O, Keeler A, Flotte T. CAR T-Cell Therapy: Progress and prospects. Human Gene Therapy 2017; 28: 62-66.
66. Nelapu S, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke F, et al. Chimeric antigen receptor T-cell therapy: assessment and management of toxicities. Nature Reviews Clinical Oncology 2018; 15: 47-62.
67. Thomis D, Marktel S, Bonini C, Traversari C, Gilman M, Bordignon C, et al. A Fasbased suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 2001; 97: 1249-1257.
68. Springer C, Niculescu-Duvaz I. Prodrug-activating systems in suicide gene therapy. Journal of Clinical Investigation 200; 105: 1161-1167.
69. Hoyos V, Savoldo B, Quintareli C, Mahendravada A. Zhang M; Vera J, et al. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 201; 24: 1160-1170.
70. Di Satasi A, Tey S, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as safety switch for adoptative cell therapy. The New England Journal of Medicine 2011; 365: 1673-1683.
71. Kloss C, Condomines M, Cartelliere M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nature Biotechnology 2012; 31: 71-75.