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Adoptive immunotherapy: good habits instilled at youth have long-term benefits

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Abstract

Many recent advances in basic cell biology and immunology are a harbinger of progress in adoptive cell therapy (ACT) including (1) the finding that host lymphodepletion enhances engraftment and efficacy, (2) the recognition that in vitro T cell functions may not correlate with in vivo efficacy, and (3) the development of advanced ex vivo culture methods to expand lymphocytes to therapeutically effective numbers. In this article, we focus on the development of artificial antigen presenting cells (aAPCs) in our laboratory and their applicability to augment ACT protocols. We also describe how aAPCs can be used to broaden ACT to treat patients with a wide variety of cancers, chronic infectious diseases, and autoimmune manifestations.

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References

  1. June CH. Adoptive T cell therapy for cancer in the clinic. J Clin Invest. 2007;117:1466.

    Article  PubMed  CAS  Google Scholar 

  2. June CH. Principles of adoptive T cell cancer therapy. J Clin Invest. 2007;117:1204.

    Article  PubMed  CAS  Google Scholar 

  3. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299.

    Article  PubMed  CAS  Google Scholar 

  4. Blattman JN, Greenberg PD. Cancer immunotherapy: a treatment for the masses. Science. 2004;305:200.

    Article  PubMed  CAS  Google Scholar 

  5. Leen AM, Rooney CM, Foster AE. Improving T cell therapy for cancer. Annu Rev Immunol. 2007;25:243.

    Article  PubMed  CAS  Google Scholar 

  6. Collins RH Jr, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. 1997;15:433.

    PubMed  Google Scholar 

  7. Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, et al. Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res. 2002;8:1767.

    PubMed  CAS  Google Scholar 

  8. Dreno B, Nguyen JM, Khammari A, Pandolfino MC, Tessier MH, Bercegeay S, et al. Randomized trial of adoptive transfer of melanoma tumor-infiltrating lymphocytes as adjuvant therapy for stage III melanoma. Cancer Immunol Immunother. 2002;51:539.

    Article  PubMed  CAS  Google Scholar 

  9. Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994;86:1159.

    Article  PubMed  CAS  Google Scholar 

  10. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, et al. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999;17:2521.

    PubMed  CAS  Google Scholar 

  11. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298:850.

    Article  PubMed  CAS  Google Scholar 

  12. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346.

    Article  PubMed  CAS  Google Scholar 

  13. Laport GG, Levine BL, Stadtmauer EA, Schuster SJ, Luger SM, Grupp S, et al. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation. Blood. 2003;102(6):2004–13.

    Article  PubMed  CAS  Google Scholar 

  14. Rapoport AP, Stadtmauer EA, Aqui N, Badros A, Cotte J, Chrisley L, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med. 2005;11:1230.

    Article  PubMed  CAS  Google Scholar 

  15. Gattinoni L, Klebanoff CA, Palmer DC, Wrzesinski C, Kerstann K, Yu Z, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J Clin Invest. 2005;115:1616.

    Article  PubMed  CAS  Google Scholar 

  16. Berger C, Jensen MC, Lansdorp PM, Gough M, Elliott C, Riddell SR. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest. 2008;118:294.

    Article  PubMed  CAS  Google Scholar 

  17. Levine BL, Bernstein WB, Connors M, Craighead N, Lindsten T, Thompson CB, et al. Effects of CD28 costimulation on long-term proliferation of CD4+ T cells in the absence of exogenous feeder cells. J Immunol. 1997;159:5921.

    PubMed  CAS  Google Scholar 

  18. Guenechea G, Gan OI, Dorrell C, Dick JE. Distinct classes of human stem cells that differ in proliferative and self-renewal potential. Nat Immunol. 2001;2:75.

    Article  PubMed  CAS  Google Scholar 

  19. Levine BL. T lymphocyte engineering ex vivo for cancer and infectious disease. Expert Opin Biol Ther. 2008;8:475.

    Article  PubMed  CAS  Google Scholar 

  20. Varela-Rohena A, Carpenito C, Perez EE, Richardson M, Parry RV, Milone M, et al. Genetic engineering of T cells for adoptive immunotherapy. Immunol Res. 2008 [Epub ahead of print].

  21. Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, et al. Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005;174:6477.

    PubMed  CAS  Google Scholar 

  22. Zemon H. An artificial solution for adoptive immunotherapy. Trends Biotechnol. 2003;21:418.

    Article  PubMed  CAS  Google Scholar 

  23. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392:245.

    Article  PubMed  CAS  Google Scholar 

  24. Almand B, Resser JR, Lindman B, Nadaf S, Clark JI, Kwon ED, et al. Clinical significance of defective dendritic cell differentiation in cancer. Clin Cancer Res. 2000;6:1755.

    PubMed  CAS  Google Scholar 

  25. Weng NP, Palmer LD, Levine BL, Lane HC, June CH, Hodes RJ. Tales of tails: regulation of telomere length and telomerase activity during lymphocyte development, differentiation, activation, and aging. Immunol Rev. 1997;160:43.

    Article  PubMed  CAS  Google Scholar 

  26. Carroll RG, Riley JL, Levine BL, Blair PJ, St L, June CH. The role of co-stimulation in regulation of chemokine receptor expression and HIV-1 infection in primary T lymphocytes. Semin Immunol. 1998;10:195.

    Article  PubMed  CAS  Google Scholar 

  27. Levine BL, Mosca JD, Riley JL, Carroll RG, Vahey MT, Jagodzinski LL, et al. Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation. Science. 1996;272:1939.

    Article  PubMed  CAS  Google Scholar 

  28. Levine BL, Bernstein WB, Aronson NE, Schlienger K, Cotte J, Perfetto S, et al. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med. 2002;8:47.

    Article  PubMed  CAS  Google Scholar 

  29. Levine BL, Humeau LM, Boyer J, MacGregor RR, Rebello T, Lu X, et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci USA. 2006;103:17372.

    Article  PubMed  CAS  Google Scholar 

  30. Porter DL, Levine BL, Bunin N, Stadtmauer EA, Luger SM, Goldstein S, et al. A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. Blood. 2006;107:1325.

    Article  PubMed  CAS  Google Scholar 

  31. Laport GG, Levine BL, Stadtmauer EA, Schuster SJ, Luger SM, Grupp S, et al. Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation. Blood. 2003;102:2004.

    Article  PubMed  CAS  Google Scholar 

  32. Rapoport AP, Levine BL, Badros A, Meisenberg B, Ruehle K, Nandi A, et al. Molecular remission of CML after autotransplantation followed by adoptive transfer of costimulated autologous T cells. Bone Marrow Transplant. 2004;33:53.

    Article  PubMed  CAS  Google Scholar 

  33. Maus MV, Thomas AK, Leonard DG, 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, CD28 and 4–1BB. Nat Biotechnol. 2002;20:143.

    Article  PubMed  CAS  Google Scholar 

  34. Zhang H, Snyder KM, Suhoski MM, Maus MV, Kapoor V, June CH, et al. 4–1BB is superior to CD28 costimulation for generating CD8+ cytotoxic lymphocytes for adoptive immunotherapy. J Immunol. 2007;179:4910.

    PubMed  CAS  Google Scholar 

  35. Suhoski MM, Golovina TN, Aqui NA, Tai VC, Varela-Rohena A, Milone MC, et al. Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules. Mol Ther. 2007;15:981.

    Article  PubMed  CAS  Google Scholar 

  36. Carroll RG, June CH. Programming the next generation of dendritic cells. Mol Ther. 2007;15:846.

    Article  PubMed  CAS  Google Scholar 

  37. Bertozzi CC, Chang CY, Jairaj S, Shan X, Huang J, Weber BL, et al. Multiple initial culture conditions enhance the establishment of cell lines from primary ovarian cancer specimens. In Vitro Cell Dev Biol Anim. 2006;42:58.

    Article  PubMed  CAS  Google Scholar 

  38. Ward S, Casey D, Labarthe MC, Whelan M, Dalgleish A, Pandha H, et al. Immunotherapeutic potential of whole tumour cells. Cancer Immunol Immunother. 2002;51:351.

    Article  PubMed  Google Scholar 

  39. Gordan JD, Vonderheide RH. Universal tumor antigens as targets for immunotherapy. Cytotherapy. 2002;4:317.

    Article  PubMed  CAS  Google Scholar 

  40. Vonderheide RH, June CH. A translational bridge to cancer immunotherapy: exploiting costimulation and target antigens for active and passive T cell immunotherapy. Immunol Res. 2003;27:341.

    Article  PubMed  CAS  Google Scholar 

  41. Nadler LM, Schultze JL. From genomics to cancer vaccines: patient-tailored or universal vaccines? Curr Opin Mol Ther. 2002;4:572.

    PubMed  CAS  Google Scholar 

  42. Parmiani G, De FA, Novellino L, Castelli C. Unique human tumor antigens: immunobiology and use in clinical trials. J Immunol. 2007;178:1975.

    PubMed  CAS  Google Scholar 

  43. Kusmartsev S, Gabrilovich DI. Effect of tumor-derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer. Cancer Metastasis Rev. 2006;25:323.

    Article  PubMed  CAS  Google Scholar 

  44. Perez EE, Jouvenot Y, Wang J, Miller JC, Kim KA, Liu O, et al. Establishment of HIV-1 resistance in CD4(+) T cells by genome editing using zinc-finger nucleases. Nature Biotechnol. 2008;26(7):808–16.

    Article  CAS  Google Scholar 

  45. Emens LA. A new twist on autologous cancer vaccines. Cancer Biol Ther. 2003;2:161.

    PubMed  Google Scholar 

  46. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8.

    Article  PubMed  CAS  Google Scholar 

  47. Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167.

    Article  PubMed  CAS  Google Scholar 

  48. Turk MJ, Guevara-Patino JA, Rizzuto GA, Engelhorn ME, Sakaguchi S, Houghton AN. Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J Exp Med. 2004;200:771.

    Article  PubMed  CAS  Google Scholar 

  49. Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, et al. 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. 2005;174:2591.

    PubMed  CAS  Google Scholar 

  50. June CH, Blazar BR. Clinical application of expanded CD4+25+ cells. Semin Immunol. 2006;18:78.

    Article  PubMed  CAS  Google Scholar 

  51. Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr Opin Immunol. 2005;17:638.

    Article  PubMed  CAS  Google Scholar 

  52. Golovina TN, Mikheeva T, Suhoski MM, Aqui NA, Tai VC, Shan X, et al. CD28 costimulation is essential for human T regulatory cell expansion and function. J Immunol. 2008 (In Press).

  53. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood. 2005;105:4743.

    Article  PubMed  CAS  Google Scholar 

  54. Valmori D, Tosello V, Souleimanian NE, Godefroy E, Scotto L, Wang Y, et al. Rapamycin-mediated enrichment of T cells with regulatory activity in stimulated CD4+ T cell cultures is not due to the selective expansion of naturally occurring regulatory T cells but to the induction of regulatory functions in conventional CD4+ T cells. J Immunol. 2006;177:944.

    PubMed  CAS  Google Scholar 

  55. Fox CJ, Hammerman PS, Thompson CB. The Pim kinases control rapamycin-resistant T cell survival and activation. J Exp Med. 2005;201:259.

    Article  PubMed  CAS  Google Scholar 

  56. Basu S, Golovina T, Mikheeva T, June CH, Riley JL. Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol. 2008;180:5794.

    PubMed  CAS  Google Scholar 

  57. Maus MV, Kovacs B, Kwok WW, Nepom GT, Schlienger K, Riley JL, et al. Extensive replicative capacity of human central memory T cells. J Immunol. 2004;172:6675.

    PubMed  CAS  Google Scholar 

  58. Laurence A, O’Shea JJ. T (H)-17 differentiation: of mice and men. Nat Immunol. 2007;8:958.

    Article  Google Scholar 

  59. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today. 1993;14:335.

    Article  PubMed  CAS  Google Scholar 

  60. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994;84:4008.

    PubMed  CAS  Google Scholar 

  61. Constant SL, Bottomly K. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches. Annu Rev Immunol. 1997;15:297.

    Article  PubMed  CAS  Google Scholar 

  62. Broeren CP, Gray GS, Carreno BM, June CH. Costimulation light: activation of CD4+ T cells with CD80 or CD86 rather than anti-CD28 leads to a Th2 cytokine profile. J Immunol. 2000;165:6908.

    PubMed  CAS  Google Scholar 

  63. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. 2008;112(2):362–73.

    Article  PubMed  CAS  Google Scholar 

  64. Yang L, Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, et al. IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature. 2008;454(7202):350–2.

    Article  PubMed  CAS  Google Scholar 

  65. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007;448:484.

    Article  PubMed  CAS  Google Scholar 

  66. Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345.

    Article  PubMed  CAS  Google Scholar 

  67. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235.

    Article  PubMed  CAS  Google Scholar 

  68. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 2006;24:677.

    Article  PubMed  CAS  Google Scholar 

  69. Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol. 2006;18:349.

    Article  PubMed  CAS  Google Scholar 

  70. Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8:942.

    Article  PubMed  CAS  Google Scholar 

  71. Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol. 2008;9:641.

    Article  PubMed  CAS  Google Scholar 

  72. Du J, Huang C, Zhou B, Ziegler SF. Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol. 2008;180:4785.

    PubMed  CAS  Google Scholar 

  73. McGeachy MJ, Cua DJ. Th17 cell differentiation: the long and winding road. Immunity.. 2008;28:445.

    Article  PubMed  CAS  Google Scholar 

  74. Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC, et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med. 1996;335:157.

    Article  PubMed  CAS  Google Scholar 

  75. Kurtzberg J. State of the art in umbilical cord transplantation. Oncology (Williston. Park). 1996;10:1086, 1091.

    Google Scholar 

  76. Stevens CE, Gladstone J, Taylor PE, Scaradavou A, Migliaccio AR, Visser J, et al. Placental/umbilical cord blood for unrelated-donor bone marrow reconstitution: relevance of nucleated red blood cells. Blood. 2002;100:2662.

    Article  PubMed  CAS  Google Scholar 

  77. Godfrey WR, Spoden DJ, Ge YG, Baker SR, Liu B, Levine BL, et al. Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood. 2005;105:750.

    Article  PubMed  CAS  Google Scholar 

  78. Huang X, Guo H, Kang J, Choi S, Zhou TC, Tammana S, et al. Sleeping Beauty transposon-mediated engineering of human primary T cells for therapy of CD19+ lymphoid malignancies. Mol Ther. 2008;16:580.

    Article  PubMed  CAS  Google Scholar 

  79. Hexner EO, net-Desnoyers GA, Zhang Y, Frank DM, Riley JL, Levine BL, et al. Umbilical cord blood xenografts in immunodeficient mice reveal that T cells enhance hematopoietic engraftment beyond overcoming immune barriers by stimulating stem cell differentiation. Biol Blood Marrow Transplant. 2007;13:1135.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Angie Mexas and Matthew Frigault for critically reading this manuscript, and NIH 5T32CA101968 Cancer Research Training Grant for support of CMP and NIH 1R01CA120409, and the Leukemia and Lymphoma Society for support of CHJ. We would like to thank Chanelle Case, Kathleen Haines Ronghua Liu and Ben Paramonte for their excellent technical support. We would also like to thank the clinical team and the patients at the University of Pennsylvania for help and guidance in the development of new cancer immunotherapies.

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III, Room 554, 421 Curie Boulevard, Philadelphia, PA, 19104-6160, USA

    Chrystal M. Paulos, Megan M. Suhoski, Gabriela Plesa, Tianying Jiang, Samik Basu, Tatiana N. Golovina, Shuguang Jiang, Nicole A. Aqui, Daniel J. Powell Jr., Bruce L. Levine, Richard G. Carroll, James L. Riley & Carl H. June

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania, 421 Curie Blvd – 543BRB II/III, Philadelphia, PA, 19104, USA

    Nicole A. Aqui, Bruce L. Levine, James L. Riley & Carl H. June

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  1. Chrystal M. Paulos
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  2. Megan M. Suhoski
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  12. James L. Riley
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Correspondence to Carl H. June.

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Paulos, C.M., Suhoski, M.M., Plesa, G. et al. Adoptive immunotherapy: good habits instilled at youth have long-term benefits. Immunol Res 42, 182–196 (2008). https://doi.org/10.1007/s12026-008-8070-9

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