1932

Abstract

Lymphomas arise from clonal expansions of B, T, or NK cells at different stages of differentiation. Because they occur in the immunocyte-rich lymphoid tissues, they are easily accessible to antibodies and cell-based immunotherapy. Expressing chimeric antigen receptors (CARs) on T cells is a means of combining the antigen-binding site of a monoclonal antibody with the activating machinery of a T cell, enabling antigen recognition independent of major histocompatibility complex restriction, while retaining the desirable antitumor properties of a T cell. Here, we discuss the basic design of CARs and their potential advantages and disadvantages over other immune therapies for lymphomas. We review current clinical trials in the field and consider strategies to improve the in vivo function and safety of immune cells expressing CARs. The ultimate driver of CAR development and implementation for lymphoma will be the demonstration of their ability to safely and cost-effectively cure these malignancies.

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2016-01-14
2024-03-29
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Literature Cited

  1. Weinstock DM, Dalla-Favera R, Gascoyne RD. 1.  et al. 2015. A roadmap for discovery and translation in lymphoma. Blood 125:2175–77 [Google Scholar]
  2. Kuppers R, Engert A, Hansmann ML. 2.  2012. Hodgkin lymphoma. J. Clin. Invest. 122:3439–47 [Google Scholar]
  3. Schuster SJ, Neelapu SS, Gause BL. 3.  et al. 2011. Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J. Clin. Oncol. 29:2787–94 [Google Scholar]
  4. Bollard CM, Gottschalk S, Torrano V. 4.  et al. 2014. Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J. Clin. Oncol. 32:798–808 [Google Scholar]
  5. Heslop HE, Slobod KS, Pule MA. 5.  et al. 2010. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood 115:925–35 [Google Scholar]
  6. Moskowitz CH, Nademanee A, Masszi T. 6.  et al. 2015. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 385:1853–62 [Google Scholar]
  7. Becker ML, Near R, Mudgett-Hunter M. 7.  et al. 1989. Expression of a hybrid immunoglobulin-T cell receptor protein in transgenic mice. Cell 58:911–21 [Google Scholar]
  8. Stancovski I, Schindler DG, Waks T. 8.  et al. 1993. Targeting of T lymphocytes to Neu/HER2-expressing cells using chimeric single chain Fv receptors. J. Immunol. 151:6577–82 [Google Scholar]
  9. Hudecek M, Lupo-Stanghellini MT, Kosasih PL. 9.  et al. 2013. Receptor affinity and extracellular domain modifications affect tumor recognition by ROR1-specific chimeric antigen receptor T cells. Clin. Cancer Res. 19:3153–64 [Google Scholar]
  10. Haso W, Lee DW, Shah NN. 10.  et al. 2013. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood 121:1165–74 [Google Scholar]
  11. Hombach AA, Schildgen V, Heuser C. 11.  et al. 2007. T cell activation by antibody-like immunoreceptors: the position of the binding epitope within the target molecule determines the efficiency of activation of redirected T cells. J. Immunol. 178:4650–57 [Google Scholar]
  12. Savoldo B, Ramos CA, Liu E. 12.  et al. 2011. CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J. Clin. Investig. 121:1822–26 [Google Scholar]
  13. Hudecek M, Sommermeyer D, Kosasih PL. 13.  et al. 2015. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol. Res. 3:125–35 [Google Scholar]
  14. Irving BA, Weiss A. 14.  1991. The cytoplasmic domain of the T cell receptor zeta chain is sufficient to couple to receptor-associated signal transduction pathways. Cell 64:891–901 [Google Scholar]
  15. Krause A, Guo HF, Latouche JB. 15.  et al. 1998. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J. Exp. Med. 188:619–26 [Google Scholar]
  16. Finney HM, Lawson AD, Bebbington CR, Weir AN. 16.  1998. Chimeric receptors providing both primary and costimulatory signaling in T cells from a single gene product. J. Immunol. 161:2791–97 [Google Scholar]
  17. Pule MA, Straathof KC, Dotti G. 17.  et al. 2005. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol. Ther. 12:933–41 [Google Scholar]
  18. Vera J, Savoldo B, Vigouroux S. 18.  et al. 2006. T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 108:3890–97 [Google Scholar]
  19. Imai C, Mihara K, Andreansky M. 19.  et al. 2004. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18:676–84 [Google Scholar]
  20. Jakobsen MK, Restifo NP, Cohen PA. 20.  et al. 1995. Defective major histocompatibility complex class I expression in a sarcomatoid renal cell carcinoma cell line. J. Immunother. Emphasis Tumor Immunol. 17:222–28 [Google Scholar]
  21. Lou Y, Basha G, Seipp RP. 21.  et al. 2008. Combining the antigen processing components TAP and Tapasin elicits enhanced tumor-free survival. Clin. Cancer Res. 14:1494–501 [Google Scholar]
  22. Singh R, Paterson Y. 22.  2007. Immunoediting sculpts tumor epitopes during immunotherapy. Cancer Res. 67:1887–92 [Google Scholar]
  23. Vago L, Perna SK, Zanussi M. 23.  et al. 2009. Loss of mismatched HLA in leukemia after stem-cell transplantation. N. Engl. J. Med. 361:478–88 [Google Scholar]
  24. Rosenberg SA, Aebersold P, Cornetta K. 24.  et al. 1990. Gene transfer into humans—immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N. Engl. J. Med. 323:570–78 [Google Scholar]
  25. Varmus H. 25.  1988. Retroviruses. Science 240:1427–35 [Google Scholar]
  26. Geurts AM, Yang Y, Clark KJ. 26.  et al. 2003. Gene transfer into genomes of human cells by the sleeping beauty transposon system. Mol. Ther. 8:108–17 [Google Scholar]
  27. Wilson MH, Coates CJ, George AL Jr. 27.  2007. PiggyBac transposon-mediated gene transfer in human cells. Mol. Ther. 15:139–45 [Google Scholar]
  28. Gattinoni L, Klebanoff CA, Restifo NP. 28.  2012. Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12:671–84 [Google Scholar]
  29. Restifo NP, Dudley ME, Rosenberg SA. 29.  2012. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol. 12:269–81 [Google Scholar]
  30. Rooney CM, Smith CA, Ng CY. 30.  et al. 1998. Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92:1549–55 [Google Scholar]
  31. Hislop AD, Taylor GS, Sauce D, Rickinson AB. 31.  2007. Cellular responses to viral infection in humans: lessons from Epstein-Barr virus. Annu. Rev. Immunol. 25:587–617 [Google Scholar]
  32. Pule MA, Savoldo B, Myers GD. 32.  et al. 2008. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat. Med. 14:1264–70 [Google Scholar]
  33. Rischer M, Pscherer S, Duwe S. 33.  et al. 2004. Human gammadelta T cells as mediators of chimaeric-receptor redirected anti-tumour immunity. Br. J. Haematol. 126:583–92 [Google Scholar]
  34. Imai C, Iwamoto S, Campana D. 34.  2005. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood 106:376–83 [Google Scholar]
  35. Carpenter RO, Evbuomwan MO, Pittaluga S. 35.  et al. 2013. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin. Cancer Res. 19:2048–60 [Google Scholar]
  36. Gottschalk S, Ng CY, Perez M. 36.  et al. 2001. An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs. Blood 97:835–43 [Google Scholar]
  37. Yee C, Thompson JA, Byrd D. 37.  et al. 2002. 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. PNAS 99:16168–73 [Google Scholar]
  38. Dunn GP, Old LJ, Schreiber RD. 38.  2004. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22:329–60 [Google Scholar]
  39. Hegde M, Corder A, Chow KK. 39.  et al. 2013. Combinational targeting offsets antigen escape and enhances effector functions of adoptively transferred T cells in glioblastoma. Mol. Ther. 21:2087–101 [Google Scholar]
  40. Scheuermann RH, Racila E. 40.  1995. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk. Lymphoma 18:385–97 [Google Scholar]
  41. Davila ML, Riviere I, Wang X. 41.  et al. 2014. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med. 6:224ra25 [Google Scholar]
  42. Maude SL, Frey N, Shaw PA. 42.  et al. 2014. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371:1507–17 [Google Scholar]
  43. Jensen MC, Popplewell L, Cooper LJ. 43.  et al. 2010. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol. Blood Marrow Transplant. 16:1245–56 [Google Scholar]
  44. Antony PA, Piccirillo CA, Akpinarli A. 44.  et al. 2005. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J. Immunol. 174:2591–601 [Google Scholar]
  45. Gattinoni L, Finkelstein SE, Klebanoff CA. 45.  et al. 2005. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J. Exp. Med. 202:907–12 [Google Scholar]
  46. Kochenderfer JN, Wilson WH, Janik JE. 46.  et al. 2010. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116:4099–102 [Google Scholar]
  47. Porter DL, Levine BL, Kalos M. 47.  et al. 2011. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365:725–33 [Google Scholar]
  48. Williams KM, Hakim FT, Gress RE. 48.  2007. T cell immune reconstitution following lymphodepletion. Semin. Immunol. 19:318–30 [Google Scholar]
  49. Kalos M, Levine BL, Porter DL. 49.  et al. 2011. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3:95ra73 [Google Scholar]
  50. Kochenderfer J, Dudley M, Feldman S. 50.  et al. 2012. 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 119:2709–20 [Google Scholar]
  51. Kochenderfer JN, Dudley ME, Kassim SH. 51.  et al. 2015. 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. 33:540–49 [Google Scholar]
  52. Brentjens R, Rivière I, Park J. 52.  et al. 2011. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118:4817–28 [Google Scholar]
  53. Cruz CR, Micklethwaite KP, Savoldo B. 53.  et al. 2013. 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 122:2965–73 [Google Scholar]
  54. Kochenderfer JN, Dudley ME, Carpenter RO. 54.  et al. 2013. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122:4129–39 [Google Scholar]
  55. Till BG, Jensen MC, Wang J. 55.  et al. 2008. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 112:2261–71 [Google Scholar]
  56. Ramos C, Ballard B, Liu E. 56.  et al. 2015. Chimeric T cells for therapy of CD30+ Hodgkin and non-Hodgkin lymphomas (HL & NHL). ASCGT Annu. Meet. Abstr.. Mol. Ther. 23:Abstr. C–9 [Google Scholar]
  57. Ramos CA, Savoldo B, Liu E. 57.  et al. 2013. Clinical responses in patients infused with T lymphocytes redirected to target κ-light immunoglobulin chain. ASH Annu. Meet. Abstr.. Blood 122:506 [Google Scholar]
  58. Grupp SA, Kalos M, Barrett D. 58.  et al. 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368:1509–18 [Google Scholar]
  59. Brentjens RJ, Riviere I, Park JH. 59.  et al. 2011. Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood 118:4817–28 [Google Scholar]
  60. Kochenderfer JN, Dudley ME, Feldman SA. 60.  et al. 2012. 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 119:2709–20 [Google Scholar]
  61. Zhao Y, Moon E, Carpenito C. 61.  et al. 2010. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70:9053–61 [Google Scholar]
  62. Barrett DM, Zhao Y, Liu X. 62.  et al. 2011. Treatment of advanced leukemia in mice with mRNA engineered T cells. Hum. Gene Ther. 22:1575–86 [Google Scholar]
  63. Almasbak H, Rian E, Hoel HJ. 63.  et al. 2011. Transiently redirected T cells for adoptive transfer. Cytotherapy 13:629–40 [Google Scholar]
  64. Bear AS, Morgan RA, Cornetta K. 64.  et al. 2012. Replication-competent retroviruses in gene-modified T cells used in clinical trials: Is it time to revise the testing requirements?. Mol. Ther. 20:246–49 [Google Scholar]
  65. Cavazzana-Calvo M, Fischer A, Hacein-Bey-Abina S, Aiuti A. 65.  2012. Gene therapy for primary immunodeficiencies: part 1. Curr. Opin. Immunol. 24:580–84 [Google Scholar]
  66. Brenner MK, Rill DR, Moen RC. 66.  et al. 1993. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet 341:85–86 [Google Scholar]
  67. Hackett PB, Largaespada DA, Switzer KC, Cooper LJ. 67.  2013. Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy. Transl. Res. 161:265–83 [Google Scholar]
  68. Nakazawa Y, Huye LE, Salsman VS. 68.  et al. 2011. PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor. Mol. Ther. 19:2133–43 [Google Scholar]
  69. Di Stasi A, Tey SK, Dotti G. 69.  et al. 2011. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365:1673–83 [Google Scholar]
  70. Zhou X, Di Stasi A, Tey SK. 70.  et al. 2014. Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood 123:3895–905 [Google Scholar]
  71. Ninomiya S, Narala N, Huye L. 71.  et al. 2015. Tumor indoleamine 2,3-dioxygenase (IDO) inhibits CD19-CAR T cells and is downregulated by lymphodepleting drugs. Blood 125:3905–16 [Google Scholar]
  72. Ansell SM, Lesokhin AM, Borrello I. 72.  et al. 2015. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372:311–19 [Google Scholar]
  73. Li XC, Demirci G, Ferrari-Lacraz S. 73.  et al. 2001. IL-15 and IL-2: a matter of life and death for T cells in vivo. Nat. Med. 7:114–18 [Google Scholar]
  74. Mueller K, Schweier O, Pircher H. 74.  2008. Efficacy of IL-2- versus IL-15-stimulated CD8 T cells in adoptive immunotherapy. Eur. J. Immunol. 38:2874–85 [Google Scholar]
  75. Ochoa MC, Mazzolini G, Hervas-Stubbs S. 75.  et al. 2013. Interleukin-15 in gene therapy of cancer. Curr. Gene Ther. 13:15–30 [Google Scholar]
  76. Hoyos V, Savoldo B, Quintarelli C. 76.  et al. 2010. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety. Leukemia 24:1160–70 [Google Scholar]
  77. Hsu C, Hughes MS, Zheng Z. 77.  et al. 2005. Primary human T lymphocytes engineered with a codon-optimized IL-15 gene resist cytokine withdrawal-induced apoptosis and persist long-term in the absence of exogenous cytokine. J. Immunol. 175:7226–34 [Google Scholar]
  78. Perna SK, De Angelis B, Pagliara D. 78.  et al. 2013. Interleukin 15 provides relief to CTLs from regulatory T cell-mediated inhibition: implications for adoptive T cell-based therapies for lymphoma. Clin. Cancer Res. 19:106–17 [Google Scholar]
  79. Quintarelli C, Vera JF, Savoldo B. 79.  et al. 2007. Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes. Blood 110:2793–802 [Google Scholar]
  80. Brentjens RJ, Latouche JB, Santos E. 80.  et al. 2003. Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat. Med. 9:279–86 [Google Scholar]
  81. Klebanoff CA, Finkelstein SE, Surman DR. 81.  et al. 2004. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. PNAS 101:1969–74 [Google Scholar]
  82. Akhurst RJ. 82.  2004. TGF beta signaling in health and disease. Nat. Genet. 36:790–92 [Google Scholar]
  83. Thomas DA, Massague J. 83.  2005. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8:369–80 [Google Scholar]
  84. Bollard CM, Rossig C, Calonge MJ. 84.  et al. 2002. Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity. Blood 99:3179–87 [Google Scholar]
  85. Bollard CM, Dotti G, Gottschalk S. 85.  et al. 2010. Administration of tumor-specific cytotoxic T lymphocytes engineered to resist TGF-β to patients with EBV-associated lymphomas. ASH Annu. Meet. Abstr.. Blood 116:560 [Google Scholar]
  86. Cirri P, Chiarugi P. 86.  2011. Cancer associated fibroblasts: the dark side of the coin. Am. J. Cancer Res. 1:482–97 [Google Scholar]
  87. Kakarla S, Song XT, Gottschalk S. 87.  2012. Cancer-associated fibroblasts as targets for immunotherapy. Immunotherapy 4:1129–38 [Google Scholar]
  88. Marx J. 88.  2008. Cancer biology. All in the stroma: cancer's Cosa Nostra. Science 320:38–41 [Google Scholar]
  89. Mueller MM, Fusenig NE. 89.  2004. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4:839–49 [Google Scholar]
  90. 90. National Cancer Institute 2014. Anti-CD22 chimeric receptor T cells in pediatric and young adults with recurrent or refractory CD22-expressing B cell malignancies. ClinicalTrials.gov. Bethesda, MD, Natl. Libr. Med. http://clinicaltrials.gov/show/NCT02315612
  91. 91. MD Anderson Cancer Center, CLL Global Research Foundation Alliance 2014. Autologous ROR1R-CAR-T cells for chronic lymphocytic leukemia (CLL). ClinicalTrials.gov. Bethesda, MD, Natl. Libr. Med. http://clinicaltrials.gov/show/NCT02194374
  92. Cruz CR, Micklethwaite KP, Savoldo B. 92.  et al. 2013. Infusion of donor-derived CD19-redirected-virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase I study. Blood 122:2965–73 [Google Scholar]
  93. Kochenderfer J, Dudley M, Carpenter R. 93.  et al. 2013. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122:4129–39 [Google Scholar]
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