Linfocitos T CAR como tratamiento de malignidades hematológicas

Inicio>>Volumen>>Vol 25, N ° 2 mayo – agosto 2019>>Linfocitos T CAR como tratamiento de malignidades hematológicas

Linfocitos T CAR como tratamiento de malignidades hematológicas


Diego Molina-Leiva, Marianela Amador-Araya


Los linfocitos T con receptor de antígeno quimérico (CAR) han demostrado ser una prometedora terapia contra las malignidades hematológicas y algunos tumores sólidos refractarios al tratamiento tradicional disponible. Desde su descubrimiento hace casi 30 años los esfuerzos se han enfocado en determinar su potencial clínico y el riesgo asociado a su uso. En la actualidad se realizan cientos de investigaciones contra diversas patologías, en especial las malignidades hematológicas refractarias o en recaída. En el presente artículo se exponen los resultados de los principales estudios clínicos con el fin evidenciar y dar a conocer su eficacia; con un enfoque especial en los linfocitos T CAR anti CD19 empleados para tratar linfomas B no Hodgkin y leucemia linfoblástica B, que recientemente recibieron aprobación de la FDA.

Palabras clave


T lymphocytes with chimeric antigen receptor (CAR) have been shown to be a promising therapy against refractory or relapsed hematological malignancies as well as some refractory solid tumors. Since its discovery almost 30 years ago, efforts have focused on determining its clinical potential and the risk associated with its use. In the present times hundreds of investigations are carried out against various pathologies, especially refractory or relapsed hematological malignancies that no longer have another therapeutic alternative. In this paper, we present the results of the main clinical studies in order to exhibit their effectiveness; especially anti CD19 CAR T lymphocytes that recently received approval from the FDA for non-Hodgkin’s B-lymphomas and B-lymphoblastic leukemia.

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1. U.S. National Institutes of Health. Clinical trials 2018. Disponible en 2018.. Visitado por última vez el 12/10/2018
2. 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.
3. Novartis. Novartis destaca los datos del CTL019 que demuestra su potencial en el tratamiento de subtipos concretos de linfoma no Hodgkin difíciles de tratar. Comunidos de prensa especializada 2015. Disponible en Visitado por última vez el 12/10/2018.
4. Mato A, Porter D. A drive through cellular therapy for CLL in 2015: allogeneic cell transplantation and CARs. Blood 2015; 126(8): 478-486.
5. 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.
6. Kochenderfer J, Dudley M, Feldman S, Wilson W, Spaner D, 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): 2709-2720.
7. Kochenderfer J, Dudley M, Kassim S, Somerville R, Carpenter R, 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.
8. Porter D, Hwang W, Frey N, Lacey S, Shaw P. Loren A, et al. Chimeric antigen recpetor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Science Translational Medicine 2015; 7(303):303-329.
9. Levine B, Svoboda J, Nasta S, Porter D. Chimeric antigen receptor modified T cells directed againts CD19 (CTL019) induce clinical responses in patients with relapsed or refractary CD19+ lymphomas. Cytotherapy 2015; 17(6): S13.
10. Shuster S, Svoboda J, Chong E, Nasta S, Mato A, Anak Ö, Brondon J, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. The New England Journal of Medicine 2017; 377(26):2545-2554.
11. Novartis. Kymriah® (tisagenlecleucel), first-in-class CAR-T therapy from Novartis, receives second FDA approval to treat appropriate r/r patients with large B-cell lymphoma. Media release 2018. Disponible en kymriahr-tisagenlecleucel-first-class-car-t-therapy-from-novartis-receives-secondfda- approval-treat-appropriate-rr-patients-large-b-cell-lymphoma. Visitado por última vez el 15/10/2018.
12. Grady D.FDA approves first gene-altering leukemia treatment, costing $475 000. New York Times 2017. Disponible en cancer.html. Visitado por última vez el 15/10/2018.
13. Locke F, Neelapu S, Bartlett N, Siddiqi T, Chavez J, Hosing C, et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-CD19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Molecular Therapy 2017; 25(1): 285-295.
14. Kite Pharma. YESCARTA™ (axicabtagene ciloleucel) suspension for intravenous infusion. Highlights of prescribing information 2017. Disponible en Visitado por última vez el 15/10/2018.
15. Brudno J, Kochendefer J. Toxicities of chimeric antigen receptor T cell: recognition and management. Blood 2016; 127(26): 3321-3330.
16. Jiang H, Zhang W, Shang P, Zhang H, Fu W, Ye F, et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Molecular Oncology 2014; 8: 297-310.
17. Guo B, Chen M, Han Q, Hui F, Dai H,Zhang W, et al. CD 138- directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. Journal of Cellular Immunotherapy 2016; 2(1): 28-35.,.
18. Gargall A, Valderrama M, Lacey S, Mahnke Y, Mlenhorst J, Zheng Z, et al. Safety and effocacy of anti-CD19 chimeric antigen receptor (CAR)-modified autologous T cells (CTL019) in advanced multiple myeloma. Journal of Clinical Oncology 12015; 33: 8517.
19. Gargall A, Maus M, Hwang W, Lacey S, Mahnke Y, Melenhorst J, et al. Chimeric antigen receptor T cells againts CD19 for multiple myeloma. New England Journal og Medicine 2015; 373(11): 1040-1047.
20. Alí S, Shi V, Maric I, Wang M, Stroncek D, Rose J, et al. T cells expressing an anti- B-cell-maturation-antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016; 128(13): 1688-1700.
21. 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.
22. 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.
23. Maude, S, Frey, N, Shaw, P, Aplenc R, Barret D, Bunin N, et al. Chimeric antigen receptors T cells for sistained remissions in leukemia. The New England Journal of Medicine 2014; 371(16): 1507-1517.
24. Stauss H. Engineered T cells can fight malignant T cells. Blood 2015; 126(8): 927- 928.
25. Mamonkin M, Rouce R, Tashiro H, Brenner M. A T cell-directed chimeric antigen receptor for the selective treatment of T cell malignancies. Blood 2015; 126(8): 983-992.
26. Maude S, Laetsch J, Buechner S, Rives M, Boyer M, Bittencourt H, et al. Tisadenlecleucel in children and young adults with B-cell lymphoblastic leukemia. The New England Journal of Medicine 2018; 378: 439-447.
27. Kenderian S, Ruella M, Shestova O, Klichinsky M, Aikawa V, Morrisstte J, et al. CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Leukemia 2015; 29: 1637-1647.
28. Pizzitola I, Anjjos-Afonso F, Rouault-Pierre K, Lassailly F, Tettamanti S, Spinelli O, et al. Chimeric antigen receptors against CD333/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Leukemia 2014; 28: 1596-1605.
29. O'Hear C, Heiber J, Schubert I, Fey G, geiger T. Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. Haematologica 2015; 100(3): 336-344.
30. Kim Y, Yu K, Kenderian S, Ruella M, Chen S, Shin T, et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CART T cell immunotherapy for acute myeloid leukemia. Cell 2018; 173:1439-1453.
31. Liu K, Zhu M, Huang Y, Wei S, Xie J, Xiao Y. CD123 and its potential clinical application in leukemias. Life Scienses 2015; 122: 59-64.
32. Gill S, Tasian S, Ruella M, Shestova O, Li Y, Porter D, et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor -modified T cells. Blood 2014; 123: 2343-2354.
33. Lynn R, Poussin M, Kalota A, Feng Y, Low, P, Dimitrov D, Powell D. Targeting of folate receptor-beta on acute myeloid leukemia blast with chimeric antigen receptor expressing T cells. Blood 2015; 125(22):3466-3476.
34. Wang Q, Wang Y, Lv H, Han H, Guo B, Wang L, et al. Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Molecular Therapy 2015; 23(1): 184-191.
35. Rictchie D, Neeson P, Khot A, Peinert S, Tai Tm, Tainton K, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Molecular Therapy 2013; 21(11): 2122-2129.
36. D’Aloia M, Grazia I, Sacchetti B, Pierelli L, alimandi M. CAR-T cells: the long and winding road to solid tumors. Cell Death and Disease 2018; 9: 282-294.
37. Yong C, Dardalhon V, Devaud Cm Taylor N Darcy P, Kershaw M. CAR T-cell therapy of solid tumors. Immunology and cell biology 2017; 95: 356-363.
38. Brown C, Alizadeh D, Starr R, Weng L, Wagner J, Naranjo a et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. The New England Journal of Medicine 2016, 375: 2561-2569.
39. Louis C, Savoldo B, Dotti G, Pule M, Yvon E, Myers D, et al. Anti-tumor activity and long-term fate of chimeric antigen receptor positive T-cells in patients with neuroblastoma. Blood 2011; 118: 6050-6056.
40. Lamers C, Sleijfer, S, Vulto A, Kruit W, Kliffen M, Debets R. Autolous TLymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. Journal of Clinical Oncology 2006; 24: e20-e22.
41. Luo C, Wei J, Han W. spotlight on chimeric antigen receptor engineered T cell research and clinicla trials in China. Science China Life Science 2016; 59: 349-359.
42. Gill S, Maus M, Porter D. Chimeric antigen receptor T cell therapy: 25 years in the making. Blood Reviews 2016; 30:157-167.
43. Aranda F, Buqué A, Bloy N, Castoldi F, Eggermont A, Cremer I et al. Trial Watch; Adoptive cell transfer for oncological indications. Oncoimmunology 2015; 4: e1046673.
44. Wang Q, Yu z, Hanada K, Patel K, Kleiner D, restifo N, Yang J. Preclinical evaluation of chimeric antigen receptors targeting CD70-expressing cancers. Clinical Cancer Research
2017; 23: 2267-2276. 45. Zhang C, Wang Z, Yang Z, Wang M, Li S, Li Y, et al. Phase I escalating-dose trial of CAR-T therapy targeting CEA+ metastatic colorectal cancers. Molecular Therapy 2017; 25: 1248–1258.
46. Katz S, Burga R, McCormark E, Wang L, Mooring W, Point G, et al. Phase I hepatic immunotherapy for metastases study of intraarterial chimeric antigen receptor-modified Tcell therapy for CEA+ liver metastases. Clinical Cancer Research 2015; 21: 3149–3159.
47. Jackson H, Rafig S, Brentjens R. Driving CAR T-cells forward. Nature Reviews in Clinical Oncology 2016; 13: 370-383.
48. Feng K, Guo Y, Liu Y, Dai H, Wang Y, Ly H, et al. Cocktail treatment with EGFRspecific and CD133-specific chimeric antigen receptor-modified T cells in a patient with advanced cholangiocarcinoma. Journal of Hematological Oncolology 2017; 10.
49. Badhiwala J, Decker W, Berens M, BhardwajR. Clinical trials in cellular immunotherapy for brain/CNS tumors. Expert Rev. Neurotherapy 2013; 13: 405–424.
50. Morgan R, Johnson L, Davis J, Zheng Z, Woolard K, Reap E, et al. Recognition of glioma stem cells by genetically modified T cells targeting EGFRvIII and development of adoptive cell therapy for glioma. Human Gene Therapy 2012; 23: 1043–1053.
51. Richman S, Nunez-Cruz S, Moghimi B, Li L, Gershenson Z, Mourelatos Z, Barrett D, et al. High-affinity GD2-specific CAR T cells induce fatal encephalitis in a preclinical neuroblastoma model. Cancer Immunology Research 2017; 6: 36–46.
52. Heczey A, Louis C, Savoldo B, Dakhova O, Durett A, Grilley B, et al. CAR T cells administered in combination with lymphodepletion and PD-1 inhibition to patients with neuroblastoma. Molecular Therapy 25: 2214–2224.
53. Kamran N, Calinescu A, Candolfi M, Mineharu Y, Asad A, Koschman C, et al. Recent advances and future of immunotherapy for glioblastoma. Expert Opinion in Biological Therapy 2016; 16: 1245-1264.
54. Tanyi J, Stashwick C, Plesa G, Morgan M, Porte D, Maus, M et al. Possible compartmental cytokine release syndrome in a patient with recurrent ovarian cancer after treatment with mesothelintargeted CAR-T cells. Journal of Immunotherapy 2017; 40: 104–107.
55. Fesnak A, June C, Levine B. Engineered T cells; the promise and challenges of cancer inmmunotherapy. Nature Reviews in Cancer 2016; 16: 566-581.
56. Junghans R, Ma Q, Rathore R, Gomes E, Bais A, Lo A, Abedi M,et al. Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. The Prostate 2016; 76: 1257–1270.