Top

Published in:

01-10-2016 | CART and Immunotherapy (M Ruella, Section Editor)

Chimeric Antigen Receptor T cells for B Cell Neoplasms: Choose the Right CAR for You

Authors: Marco Ruella, Carl H. June

Published in: Current Hematologic Malignancy Reports | Issue 5/2016

Abstract

Genetic redirection of T lymphocytes allows us to unleash these potent cellular immune effectors against cancer. Chimeric antigen receptor (CAR) T cells are the best-in-class example that genetic engineering of T cells can lead to deep and durable responses, as has been shown in several clinical trials for CD19+ B cell malignancies. As a consequence, in the last few years, several academic institutions and commercial partners have started developing anti-CD19 CAR T cell products. Although most of these T cell products are highly effective in vivo, basic differences among them can generate different performance characteristics and thereby impact their long-term clinical outcome. Several strategies are being implemented in order to solve the current open issues of CART19 therapy: (i) increasing efficacy against indolent B cell leukemias and lymphomas, (ii) avoiding or preventing antigen-loss relapses, (iii) reducing and managing toxicity, and (iv) bringing this CART therapy to routine clinical practice. The field of CART therapies is thriving, and exciting new avenues are opening for both scientists and patients.

Ruella M, Gill S. How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia. Expert opinion on biological therapy. 2015;15(6):761–6. doi:10.1517/14712598.2015.1009888.PubMedCrossRef

June CH, Maus MV, Plesa G, Johnson LA, Zhao Y, Levine BL, et al. Engineered T cells for cancer therapy. Cancer immunology, immunotherapy : CII. 2014;63(9):969–75. doi:10.1007/s00262-014-1568-1.PubMedPubMedCentralCrossRef

Barbee MS, Ogunniyi A, Horvat TZ, Dang TO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. The Annals of pharmacotherapy. 2015;49(8):907–37. doi:10.1177/1060028015586218.PubMedCrossRef

Maude S, Barrett DM. Current status of chimeric antigen receptor therapy for haematological malignancies. British journal of haematology. 2016;172(1):11–22. doi:10.1111/bjh.13792.PubMedCrossRef

Ruella M, Kalos M. Adoptive immunotherapy for cancer. Immunological reviews. 2014;257(1):14–38. doi:10.1111/imr.12136.PubMedCrossRef

June CH, Riddell SR, Schumacher TN. Adoptive cellular therapy: a race to the finish line. Science translational medicine. 2015;7(280):280ps7. doi:10.1126/scitranslmed.aaa3643.PubMedCrossRef

Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proceedings of the National Academy of Sciences of the United States of America. 1989;86(24):10024–8.PubMedPubMedCentralCrossRef

Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, et al. Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C regions. Biochemical and biophysical research communications. 1987;149(3):960–8.PubMedCrossRef

Carpenito C, Milone MC, Hassan R, Simonet JC, Lakhal M, Suhoski MM, 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(9):3360–5. doi:10.1073/pnas.0813101106.PubMedPubMedCentralCrossRef

10.

Zhong XS, Matsushita M, Plotkin J, Riviere I, Sadelain M. Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. Molecular therapy : the journal of the American Society of Gene Therapy. 2010;18(2):413–20. doi:10.1038/mt.2009.210.CrossRef

11.

Till BG, Jensen MC, Wang J, Qian X, Gopal AK, Maloney DG, et al. CD20-specific adoptive immunotherapy for lymphoma using a chimeric antigen receptor with both CD28 and 4-1BB domains: pilot clinical trial results. Blood. 2012;119(17):3940–50. doi:10.1182/blood-2011-10-387969.PubMedPubMedCentralCrossRef

12.

Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert opinion on biological therapy. 2015;15(8):1145–54. doi:10.1517/14712598.2015.1046430.PubMedCrossRef

13.••

Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, et al. Inducible apoptosis as a safety switch for adoptive cell therapy. The New England journal of medicine. 2011;365(18):1673–83. doi:10.1056/NEJMoa1106152. Key report on the use of a suicide system to turn T cells off and reduce toxicity.

14.

Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Molecular therapy : the journal of the American Society of Gene Therapy. 2009;17(8):1453–64. doi:10.1038/mt.2009.83.CrossRef

15.

Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 2004;18(4):676–84. doi:10.1038/sj.leu.2403302.PubMedCrossRef

16.

Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, 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(95):95ra73. doi:10.1126/scitranslmed.3002842.PubMedPubMedCentralCrossRef

17.

Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725–33. doi:10.1056/NEJMoa1103849.PubMedPubMedCentralCrossRef

18.

Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. The New England journal of medicine. 2013;368(16):1509–18. doi:10.1056/NEJMoa1215134.PubMedPubMedCentralCrossRef

19.

Schuster SJ, Svoboda J, Dwivedy Nasta S, Porter DL, Chong EA, Mahnke Y, et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood. 2014;124(21):3087.

20.

Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Science translational medicine. 2015;7(303):303ra139. doi:10.1126/scitranslmed.aac5415.PubMedCrossRef

21.

Porter DL, Frey NV, Melenhorst JJ, Hwang W-T, Lacey SF, Shaw P, et al. Randomized, phase ii dose optimization study of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed, refractory CLL. Blood. 2014;124(21):1982.

22.

Schuster SJ, Svoboda J, Dwivedy Nasta S, Porter DL, Chong EA, Landsburg DJ, et al. Sustained remissions following chimeric antigen receptor modified T Cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood. 2015;126(23):183.

23.

Grupp SA, Maude SL, Shaw PA, Aplenc R, Barrett DM, Callahan C, et al. Durable remissions in children with relapsed/refractory all treated with t cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Blood. 2015;126(23):681.

24.

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. The New England journal of medicine. 2014;371(16):1507–17. doi:10.1056/NEJMoa1407222.PubMedPubMedCentralCrossRef

25.

Maude SL, Barrett DM, Ambrose DE, Rheingold SR, Aplenc R, Teachey DT, et al. Efficacy and safety of humanized chimeric antigen receptor (CAR)-modified T cells targeting CD19 in children with relapsed/refractory ALL. Blood. 2015;126(23):683.

26.

Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8(+) and CD4(+) subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492–500. doi:10.1038/leu.2015.247.PubMed

27.

Terakura S, Yamamoto TN, Gardner RA, Turtle CJ, Jensen MC, Riddell SR. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Blood. 2012;119(1):72–82. doi:10.1182/blood-2011-07-366419.PubMedPubMedCentralCrossRef

28.

Turtle CJ, Berger C, Sommermeyer D, Hanafi L-A, Pender B, Robinson EM, et al. Anti-CD19 chimeric antigen receptor-modified T Cell therapy for B cell non-Hodgkin lymphoma and chronic lymphocytic leukemia: fludarabine and cyclophosphamide lymphodepletion improves in vivo expansion and persistence of CAR-T cells and clinical outcomes. Blood. 2015;126(23):184.

29.

Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016. doi:10.1172/JCI85309

30.

Brentjens RJ, Santos E, Nikhamin Y, Yeh R, Matsushita M, La Perle K, et al. Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;13(18 Pt 1):5426–35. doi:10.1158/1078-0432.CCR-07-0674.CrossRef

31.

Kowolik CM, Topp MS, Gonzalez S, Pfeiffer T, Olivares S, Gonzalez N, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer research. 2006;66(22):10995–1004. doi:10.1158/0008-5472.CAN-06-0160.PubMedCrossRef

32.

Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, et al. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011;118(18):4817–28. doi:10.1182/blood-2011-04-348540.PubMedPubMedCentralCrossRef

33.

Park JH RI, Wang X, et al. Phase I trial of autologous CD19- targeted CAR-modified T cells as consolidation after purine analog-based first-line therapy in patients with previously untreated CLL. Blood. 2013;122(21):874.

34.

Davila ML, Riviere 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):224ra25. doi:10.1126/scitranslmed.3008226.PubMedPubMedCentralCrossRef

35.

Park JH, Riviere I, Wang X, Bernal Y, Purdon T, Halton E, et al. Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. J Clin Oncol 33, 2015 (suppl; abstr 7010).

36.

Curran KJ, Riviere I, Silverman LB, Kobos R, Shukla N, Steinherz PG, et al. Multi-center clinical trial of car t cells in pediatric/young adult patients with relapsed B-cell all. Blood. 2015;126(23):2533.

37.

Sauter CS, Riviere I, Bernal Y, Wang X, Purdon T, Yoo S, et al. Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CART) posthigh dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). J Clin Oncol 33, 2015 (suppl; abstr 8515).

38.

Gardner RA, Park JR, Kelly-Spratt KS, Finney O, Smithers H, Hoglund V, et al. T cell products of defined CD4:CD8 composition and prescribed levels of CD19CAR/Egfrt transgene expression mediate regression of acute lymphoblastic leukemia in the setting of post-allohsct relapse. Blood. 2014;124(21):3711.

39.

Kochenderfer JN, Feldman SA, Zhao Y, Xu H, Black MA, Morgan RA, et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother. 2009;32(7):689–702. doi:10.1097/CJI.0b013e3181ac6138.PubMedPubMedCentralCrossRef

40.

Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, 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):4099–102. doi:10.1182/blood-2010-04-281931.PubMedPubMedCentralCrossRef

41.

Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, 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):2709–20. doi:10.1182/blood-2011-10-384388.PubMedPubMedCentralCrossRef

42.

Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, 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. J Clin Oncol. 2015;33(6):540–9. doi:10.1200/JCO.2014.56.2025.PubMedCrossRef

43.

Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, 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. doi:10.1016/S0140-6736(14)61403-3.PubMedCrossRef

44.

Lee DW, Stetler-Stevenson M, Yuan CM, Fry TJ, Shah NN, Delbrook C, et al. Safety and response of incorporating CD19 chimeric antigen receptor T cell therapy in typical salvage regimens for children and young adults with acute lymphoblastic leukemia. Blood. 2015;126(23):684.

45.

Brudno JN, Somerville RP, Shi V, Rose JJ, Halverson DC, Fowler DH, et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J Clin Oncol. 2016. doi:10.1200/JCO.2015.64.5929

46.

Better M, Pugach O, Lu L, Somerville R, Kassim S, Kochenderfer J, et al. Rapid cell expansion (RACE) technology for production of engineered autologous T-cell therapy: Path toward manageable multicenter clinical trials in aggressive NHL with anti-CD19 CAR. ASCO Meeting Abstracts. 2014;32(15_suppl):3079.

47.

Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, et al. Phase 1 clinical results of the ZUMA-1 (KTE-C19-101) study: a phase 1-2 multi-center study evaluating the safety and efficacy of anti-CD19 CAR T cells (KTE-C19) in subjects with refractory aggressive non-Hodgkin lymphoma (NHL). Blood. 2015;126(23):3991.

48.••

Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. The Journal of clinical investigation. 2011;121(5):1822–6. doi:10.1172/JCI46110. Key report to demonstrate that second-generation CART19 can persist longer than first-generation in a direct comparison.

49.

Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nature medicine. 2008;14(11):1264–70. doi:10.1038/nm.1882.PubMedPubMedCentralCrossRef

50.

Ramos CA, Heslop HE, Brenner MK. CAR-T cell therapy for lymphoma. Annual review of medicine. 2016;67:165–83. doi:10.1146/annurev-med-051914-021702.PubMedCrossRef

51.

Sun J, Huye LE, Lapteva N, Mamonkin M, Hiregange M, Ballard B, et al. Early transduction produces highly functional chimeric antigen receptor-modified virus-specific T-cells with central memory markers: a production assistant for cell therapy (PACT) translational application. J Immunother Cancer. 2015;3:5. doi:10.1186/s40425-015-0049-1.PubMedPubMedCentralCrossRef

52.

Cruz CR, Micklethwaite KP, Savoldo B, Ramos CA, Lam S, Ku S, et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood. 2013;122(17):2965–73. doi:10.1182/blood-2013-06-506741.PubMedPubMedCentralCrossRef

53.

Singh H, Manuri PR, Olivares S, Dara N, Dawson MJ, Huls H, et al. Redirecting specificity of T-cell populations for CD19 using the Sleeping Beauty system. Cancer research. 2008;68(8):2961–71. doi:10.1158/0008-5472.CAN-07-5600.PubMedPubMedCentralCrossRef

54.

Singh H, Moyes JS, Huls MH, Cooper LJ. Manufacture of T cells using the Sleeping Beauty system to enforce expression of a CD19-specific chimeric antigen receptor. Cancer gene therapy. 2015;22(2):95–100. doi:10.1038/cgt.2014.69.PubMedCrossRef

55.

Huls H, Singh H, Olivares S, Figliola M, Kumar PR, Jena B, et al. First clinical trials employing sleeping beauty gene transfer system and artificial antigen presenting cells to generate and infuse T cells expressing CD19-specific chimeric antigen receptor. Blood. 2013;122(21):166.

56.

Kebriaei P, Poon LM. The role of allogeneic hematopoietic stem cell transplantation in the therapy of patients with acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2012;7(2):144–52. doi:10.1007/s11899-012-0116-3.PubMedCrossRef

57.

Kebriaei P, Huls H, Singh H, Olivares S, Figliola M, Maiti S, et al. Adoptive therapy using sleeping beauty gene transfer system and artificial antigen presenting cells to manufacture T cells expressing CD19-specific chimeric antigen receptor. Blood. 2014;124(21):311.

58.

Dai H, Zhang W, Li X, Han Q, Guo Y, Zhang Y, et al. Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Oncoimmunology. 2015;4(11):e1027469. doi:10.1080/2162402X.2015.1027469.PubMedPubMedCentralCrossRef

59.

Grupp SA, Kalos M, Barrett D, Aplenc R, Porter D, Rheingold S, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. New England Journal of Medicine. 2013;368(16):1509–18. doi:10.1056/NEJMoa1215134.PubMedPubMedCentralCrossRef

60.

Ruella M, Barrett DM, Kenderian SS, Shestova O, Hofmann TJ, Scholler J, et al. Combination of anti-CD123 and anti-CD19 chimeric antigen receptor T cells for the treatment and prevention of antigen-loss relapses occurring after CD19-targeted immunotherapies. Blood. 2015;126(23):2523.

61.••

Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5(12):1282–95. doi:10.1158/2159-8290.CD-15-1020. For the first time here, a mechanism of antigen-loss escape after CD19-directed therapies is described.PubMedPubMedCentralCrossRef

62.•

Haso W, Lee DW, Shah NN, Stetler-Stevenson M, Yuan CM, Pastan IH, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121(7):1165–74. doi:10.1182/blood-2012-06-438002. Important preclinical study on the development of anti-CD22 CART.PubMedPubMedCentralCrossRef

63.

Qin H, Zhang L, Orentas RJ, Fry TJ. CD22-targeted chimeric antigen receptor (CAR) T cells containing the 4-1BB costimulatory domain demonstrate enhanced persistence and superior efficacy against B-cell precursor acute lymphoblastic leukemia (ALL) compared to those containing CD28. Blood. 2013;122(21):1431.

64.

Fry TJ, Stetler-Stevenson M, Shah NN, Yuan CM, Yates B, Delbrook C, et al. Clinical activity and persistence of anti-CD22 chimeric antigen receptor in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood. 2015;126(23):1324.

65.

Teo EC, Chew Y, Phipps C. A review of monoclonal antibody therapies in lymphoma. Critical reviews in oncology/hematology. 2016;97:72–84. doi:10.1016/j.critrevonc.2015.08.014.PubMedCrossRef

66.

Jensen MC, Cooper LJ, Wu AM, Forman SJ, Raubitschek A. Engineered CD20-specific primary human cytotoxic T lymphocytes for targeting B-cell malignancy. Cytotherapy. 2003;5(2):131–8. doi:10.1080/14653240310001028.PubMedCrossRef

67.

Jensen M, Tan G, Forman S, Wu AM, Raubitschek A. CD20 is a molecular target for scFvFc:zeta receptor redirected T cells: implications for cellular immunotherapy of CD20+ malignancy. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 1998;4(2):75–83.CrossRef

68.

Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008;112(6):2261–71. doi:10.1182/blood-2007-12-128843.PubMedPubMedCentralCrossRef

69.

Wang Y, Zhang WY, Han QW, Liu Y, Dai HR, Guo YL, et al. Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells. Clin Immunol. 2014;155(2):160–75. doi:10.1016/j.clim.2014.10.002.PubMedCrossRef

70.

Vera J, Savoldo B, Vigouroux S, Biagi E, Pule M, Rossig C, et al. T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood. 2006;108(12):3890–7. doi:10.1182/blood-2006-04-017061.PubMedPubMedCentralCrossRef

71.

Savoldo B, Liu E, Gee AP, Mei Z, Grilley BJ, Rooney CM, et al. Clinical responses in patients infused with T lymphocytes redirected to target k-light immunoglobulin chain. Blood. 2013;122(21):506.

72.

Ramos CA, Savoldo B, Liu E, Gee AP, Mei Z, Grilley B, et al. Clinical responses in patients infused with T lymphocytes redirected to target kappa-light immunoglobulin chain. Biology of Blood and Marrow Transplant.20(2):S26. doi:10.1016/j.bbmt.2013.12.009.

73.

Berger C, Sommermeyer D, Hudecek M, Berger M, Balakrishnan A, Paszkiewicz PJ, et al. Safety of targeting ROR1 in primates with chimeric antigen receptor-modified T cells. Cancer immunology research. 2015;3(2):206–16. doi:10.1158/2326-6066.CIR-14-0163.PubMedCrossRef

74.

Hudecek M, Lupo-Stanghellini MT, Kosasih PL, Sommermeyer D, Jensen MC, Rader C, et al. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19(12):3153–64. doi:10.1158/1078-0432.CCR-13-0330.CrossRef

75.

Hudecek M, Schmitt TM, Baskar S, Lupo-Stanghellini MT, Nishida T, Yamamoto TN, et al. 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. doi:10.1182/blood-2010-05-283309.PubMedPubMedCentralCrossRef

76.

Savoldo B, Rooney CM, Di Stasi A, Abken H, Hombach A, Foster AE, et al. Epstein Barr virus specific cytotoxic T lymphocytes expressing the anti-CD30zeta artificial chimeric T-cell receptor for immunotherapy of Hodgkin disease. Blood. 2007;110(7):2620–30. doi:10.1182/blood-2006-11-059139.PubMedPubMedCentralCrossRef

77.

Di Stasi A, De Angelis B, Rooney CM, Zhang L, Mahendravada A, Foster AE, et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood. 2009;113(25):6392–402. doi:10.1182/blood-2009-03-209650.PubMedPubMedCentralCrossRef

78.

Ramos CA, Ballard B, Liu E, Dakhova O, Mei Z, Liu H, et al. Chimeric T cells for therapy of CD30+ Hodgkin and non-Hodgkin lymphomas. Blood. 2015;126(23):185.

79.

Bollard CM, Gottschalk S, Torrano V, Diouf O, Ku S, Hazrat Y, et al. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol. 2014;32(8):798–808. doi:10.1200/JCO.2013.51.5304.PubMedCrossRef

80.

Tang X, Zhou Y, Li W, Tang Q, Chen R, Zhu J, et al. T cells expressing a LMP1-specific chimeric antigen receptor mediate antitumor effects against LMP1-positive nasopharyngeal carcinoma cells in vitro and in vivo. Journal of biomedical research. 2014;28(6):468–75. doi:10.7555/JBR.28.20140066.PubMedPubMedCentral

81.

Kasamon YL, Jacene HA, Gocke CD, Swinnen LJ, Gladstone DE, Perkins B, et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012;119(18):4129–32. doi:10.1182/blood-2012-01-402792.PubMedPubMedCentralCrossRef

82.

Jones RJ, Gocke CD, Kasamon YL, Miller CB, Perkins B, Barber JP, et al. Circulating clonotypic B cells in classic Hodgkin lymphoma. Blood. 2009;113(23):5920–6. doi:10.1182/blood-2008-11-189688.PubMedPubMedCentralCrossRef

83.

Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunother. 2012;35(9):651–60. doi:10.1097/CJI.0b013e31827806e6.PubMedPubMedCentralCrossRef

84.

Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, et al. A human memory T cell subset with stem cell-like properties. Nature medicine. 2011;17(10):1290–7. doi:10.1038/nm.2446.PubMedPubMedCentralCrossRef

85.

Singh N, Perazzelli J, Grupp SA, Barrett DM. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Science translational medicine. 2016;8(320):320ra3. doi:10.1126/scitranslmed.aad5222.PubMedCrossRef

86.

Yang S, Ji Y, Gattinoni L, Zhang L, Yu Z, Restifo NP, et al. Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails. Cancer immunology, immunotherapy : CII. 2013;62(4):727–36. doi:10.1007/s00262-012-1378-2.

87.••

Brentjens RJ, Latouche JB, Santos E, Marti F, Gong MC, Lyddane C, et al. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nature medicine. 2003;9(3):279–86. doi:10.1038/nm827. First paper demonstrating the preclinical efficacy of a second-generation CART.

88.

Wang X, Popplewell LL, Wagner JR, Naranjo A, Blanchard MS, Mott MR, et al. Phase I studies of central-memory-derived CD19 CAR T cell therapy following autologous HSCT in patients with B-cell NHL. Blood. 2016. doi:10.1182/blood-2015-12-686725

89.

Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, et al. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biology of blood and marrow transplantation. 2010;16(9):1245–56. doi:10.1016/j.bbmt.2010.03.014.PubMedPubMedCentralCrossRef

90.

Hombach AA, Abken H. Costimulation by chimeric antigen receptors revisited the T cell antitumor response benefits from combined CD28-OX40 signalling. International journal of cancer Journal international du cancer. 2011;129(12):2935–44. doi:10.1002/ijc.25960.PubMedCrossRef

91.

Shen CJ, Yang YX, Han EQ, Cao N, Wang YF, Wang Y, et al. Chimeric antigen receptor containing ICOS signaling domain mediates specific and efficient antitumor effect of T cells against EGFRvIII expressing glioma. Journal of hematology & oncology. 2013;6:33. doi:10.1186/1756-8722-6-33.CrossRef

92.

Guedan S, Chen X, Madar A, Carpenito C, McGettigan SE, Frigault MJ, et al. ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood. 2014;124(7):1070–80. doi:10.1182/blood-2013-10-535245.PubMedPubMedCentralCrossRef

93.

Song DG, Ye Q, Poussin M, Harms GM, Figini M, Powell Jr DJ. CD27 costimulation augments the survival and antitumor activity of redirected human T cells in vivo. Blood. 2012;119(3):696–706. doi:10.1182/blood-2011-03-344275.PubMedCrossRef

94.

Foster AE, Chang P, Lin P-Y, Crisostomo J, Mahendravada A, Lu A, et al. MyD88/CD40-based costimulation to enhance survival and proliferation of chimeric antigen receptor (CAR)-modified T cells. ASCO Meeting Abstracts. 2015;33(15_suppl):3064.

95.

Cheadle EJ, Rothwell DG, Bridgeman JS, Sheard VE, Hawkins RE, Gilham DE. Ligation of the CD2 co-stimulatory receptor enhances IL-2 production from first-generation chimeric antigen receptor T cells. Gene Ther. 2012;19(11):1114–20. doi:10.1038/gt.2011.192.PubMedCrossRef

96.

Altvater B, Landmeier S, Pscherer S, Temme J, Juergens H, Pule M, et al. 2B4 (CD244) signaling via chimeric receptors costimulates tumor-antigen specific proliferation and in vitro expansion of human T cells. Cancer immunology, immunotherapy : CII. 2009;58(12):1991–2001. doi:10.1007/s00262-009-0704-9.PubMedCrossRef

97.

Finney HM, Akbar AN, Lawson AD. 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. J Immunol. 2004;172(1):104–13.PubMedCrossRef

98.

Pule MA, Straathof KC, Dotti G, Heslop HE, Rooney CM, Brenner MK. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Molecular therapy : the journal of the American Society of Gene Therapy. 2005;12(5):933–41. doi:10.1016/j.ymthe.2005.04.016.CrossRef

99.

Dong L, Chang L-J, Gao Z, Lu D-P, Zhang J-P, Wang J-B, et al. Chimeric antigen receptor 4SCAR19-modified T cells in acute lymphoid leukemia: a phase II multi-center clinical trial in china. Blood. 2015;126(23):3774.

100.

Hoyos V, Savoldo B, Quintarelli 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. 2010;24(6):1160–70. doi:10.1038/leu.2010.75.PubMedPubMedCentralCrossRef

101.

Bollard CM, Rossig C, Calonge MJ, Huls MH, Wagner HJ, Massague J, et al. Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood. 2002;99(9):3179–87.PubMedCrossRef

102.

Zhang L, Kerkar SP, Yu Z, Zheng Z, Yang S, Restifo NP, et al. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Molecular therapy : the journal of the American Society of Gene Therapy. 2011;19(4):751–9. doi:10.1038/mt.2010.313.CrossRef

103.

Zhang L, Feldman SA, Zheng Z, Chinnasamy N, Xu H, Nahvi AV, et al. Evaluation of gamma-retroviral vectors that mediate the inducible expression of IL-12 for clinical application. J Immunother. 2012;35(5):430–9. doi:10.1097/CJI.0b013e31825898e8.PubMedPubMedCentralCrossRef

104.

Chmielewski M, Kopecky C, Hombach AA, Abken H. IL-12 release by engineered T cells expressing chimeric antigen receptors can effectively Muster an antigen-independent macrophage response on tumor cells that have shut down tumor antigen expression. Cancer research. 2011;71(17):5697–706. doi:10.1158/0008-5472.CAN-11-0103.PubMedCrossRef

105.

Pegram HJ, Lee JC, Hayman EG, Imperato GH, Tedder TF, Sadelain M, 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. doi:10.1182/blood-2011-12-400044.PubMedPubMedCentralCrossRef

106.

Torikai H, Reik A, Liu PQ, Zhou Y, Zhang L, Maiti S, et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood. 2012;119(24):5697–705. doi:10.1182/blood-2012-01-405365.PubMedPubMedCentralCrossRef

107.

Torikai H, Reik A, Soldner F, Warren EH, Yuen C, Zhou Y, et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood. 2013;122(8):1341–9. doi:10.1182/blood-2013-03-478255.PubMedPubMedCentralCrossRef

108.

Poirot L, Philip B, Schiffer-Mannioui C, Le Clerre D, Chion-Sotinel I, Derniame S, et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer research. 2015;75(18):3853–64. doi:10.1158/0008-5472.CAN-14-3321.PubMedCrossRef

109.

Qasim W, Amrolia PJ, Samarasinghe S, Ghorashian S, Zhan H, Stafford S, et al. First clinical application of Talen Engineered Universal CAR19 T cells in B-ALL. Blood. 2015;126(23):2046.

110.

Osborn MJ, Webber BR, Knipping F, Lonetree CL, Tennis N, DeFeo AP, et al. Evaluation of TCR gene editing achieved by TALENs, CRISPR/Cas9, and megaTAL nucleases. Molecular therapy : the journal of the American Society of Gene Therapy. 2016;24(3):570–81. doi:10.1038/mt.2015.197.CrossRef

111.

Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, 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. J Clin Oncol. 2014. doi:10.1200/JCO.2014.56.2025

112.

Maude SL, Barrett D, Teachey DT, Grupp SA. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 2014;20(2):119–22. doi:10.1097/PPO.0000000000000035.PubMedPubMedCentralCrossRef

113.

Frey NV LB, Lacey SF, Grupp SA, Maude SL, Schuster SJ, Shaw P, Hwang WT, Wasik MA, Obstfeld A, Leung M, Shen A, Ericson SG, Melenhorst JJ, June CH and Porter D. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. American Society of Hematology Annual (ASH) Meeting 2014. 2014;Abs #2296.

114.

Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188–95. doi:10.1182/blood-2014-05-552729.PubMedPubMedCentralCrossRef

115.

Bole-Richard E, Deschamps M, Ferrand C, Robinet E. Editorial: Improving the safety of cell therapy products by suicide gene transfer. Frontiers in pharmacology. 2015;6:174. doi:10.3389/fphar.2015.00174.PubMedPubMedCentralCrossRef

116.

Jones BS, Lamb LS, Goldman F, Di Stasi A. Improving the safety of cell therapy products by suicide gene transfer. Frontiers in pharmacology. 2014;5:254. doi:10.3389/fphar.2014.00254.PubMedPubMedCentralCrossRef

117.

Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, et al. An inducible caspase 9 safety switch for T-cell therapy. Blood. 2005;105(11):4247–54. doi:10.1182/blood-2004-11-4564.PubMedPubMedCentralCrossRef

118.

Budde LE, Berger C, Lin Y, Wang J, Lin X, Frayo SE, et al. Combining a CD20 chimeric antigen receptor and an inducible caspase 9 suicide switch to improve the efficacy and safety of t cell adoptive immunotherapy for lymphoma. PloS one. 2013;8(12):e82742. doi:10.1371/journal.pone.0082742.PubMedPubMedCentralCrossRef

119.

Tasian SK, Kenderian SS, Shen F, Li Y, Ruella M, Fix WC, et al. Efficient termination of CD123-redirected chimeric antigen receptor T cells for acute myeloid leukemia to mitigate toxicity. Blood. 2015;126(23):565.

120.

Jensen MC, Riddell SR. Designing chimeric antigen receptors to effectively and safely target tumors. Curr Opin Immunol. 2015;33:9–15. doi:10.1016/j.coi.2015.01.002.PubMedPubMedCentralCrossRef

121.

Philip B, Kokalaki E, Mekkaoui L, Thomas S, Straathof K, Flutter B, et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood. 2014;124(8):1277–87. doi:10.1182/blood-2014-01-545020.PubMedCrossRef

122.

Wang X, Chang WC, Wong CW, Colcher D, Sherman M, Ostberg JR, et al. A transgene-encoded cell surface polypeptide for selection, in vivo tracking, and ablation of engineered cells. Blood. 2011;118(5):1255–63. doi:10.1182/blood-2011-02-337360.PubMedPubMedCentralCrossRef

123.

Bonger KM, Chen LC, Liu CW, Wandless TJ. Small-molecule displacement of a cryptic degron causes conditional protein degradation. Nat Chem Biol. 2011;7(8):531–7. doi:10.1038/nchembio.598.PubMedPubMedCentralCrossRef

124.

Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS, et al. Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell. 2016;164(4):770–9. doi:10.1016/j.cell.2016.01.011.PubMedCrossRef

125.

Jacoby E, Nguyen SM, Welp KM, Qin H, Yang Y, Chien CD, et al. Lineage switch as a relapse mechanism of pre-B acute lymphoblastic leukemia following CD19 CAR. Blood. 2015;126(23):2524.

126.

Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19 negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T cell therapy. Blood. 2016. doi:10.1182/blood-2015-08-665547

127.

Qin H, Haso W, Nguyen SM, Fry TJ. Preclinical development of bispecific chimeric antigen receptor targeting both CD19 and CD22. Blood. 2015;126(23):4427.

128.

Peng W, Lizee G, Hwu P. Blockade of the PD-1 pathway enhances the efficacy of adoptive cell therapy against cancer. Oncoimmunology. 2013;2(2):e22691. doi:10.4161/onci.22691.PubMedPubMedCentralCrossRef

129.

Kuramitsu S, Ohno M, Ohka F, Shiina S, Yamamichi A, Kato A, et al. Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses. Cancer gene therapy. 2015;22(10):487–95. doi:10.1038/cgt.2015.47.PubMedCrossRef

130.

Otahal P, Prukova D, Kral V, Fabry M, Vockova P, Lateckova L, et al. Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells. Oncoimmunology. 2016;5(4):e1115940. doi:10.1080/2162402X.2015.1115940.PubMedCrossRef

131.

Ninomiya S, Narala N, Huye L, Yagyu S, Savoldo B, Dotti G, et al. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood. 2015;125(25):3905–16. doi:10.1182/blood-2015-01-621474.PubMedPubMedCentralCrossRef

132.

Ruella M, Kenderian SS, Shestova O, Fraietta JA, Qayyum S, Zhang Q, et al. The Addition of the BTK inhibitor Ibrutinib to anti-CD19 chimeric antigen receptor T cells (CART19) improves responses against mantle cell lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2016. doi:10.1158/1078-0432.CCR-15-1527

133.

Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016. doi:10.1182/blood-2015-11-679134

134.

Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016. doi:10.1158/2159-8290.CD-16-0040

Title: Chimeric Antigen Receptor T cells for B Cell Neoplasms: Choose the Right CAR for You
Authors: Marco Ruella
Carl H. June
Publication date: 01-10-2016
Publisher: Springer US
Published in: Current Hematologic Malignancy Reports / Issue 5/2016
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI: https://doi.org/10.1007/s11899-016-0336-z

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

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.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2016

The Use of Anagrelide in Myeloproliferative Neoplasms, with Focus on Essential Thrombocythemia

How We Identify and Manage Patients with Inadequately Controlled Polycythemia Vera

Transient Abnormal Myelopoiesis and AML in Down Syndrome: an Update

What Is the Optimal Induction Therapy for Younger Fit Patients With AML?

Treatment of Childhood Acute Lymphoblastic Leukemia: Prognostic Factors and Clinical Advances

Investigation and Management of Erythrocytosis

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage