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Tumor-Infiltrating Lymphocyte Therapy for Melanoma: Rationale and Issues for Further Clinical Development

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Abstract

Cancer immunotherapy has become an important area for the future development of cancer therapy; this includes T-cell-based therapies that involve adoptive transfer of autologous T cells derived from the tumors or peripheral blood of cancer patients, vaccines, oncolytic virus therapy, and immunomodulatory antibodies and ligands. Here, we summarize the current approaches and clinical data in the field of adoptive T-cell transfer therapy using tumor-infiltrating lymphocytes (TILs) for metastatic melanoma. We also discuss current knowledge on the mechanism of transferred TILs in mediating tumor regression and the growing need for and recent advances in the identification of predictive biomarkers to better select patients for TIL therapy. The current technical limitations of current TIL expansion methods for out-scaling are discussed as well as how these are being addressed in order to further “industrialize” this form of cell therapy. Lastly, how TIL adoptive transfer can be incorporated into the current melanoma treatment continuum, especially as combination therapy with other immunomodulators and targeted drugs, is discussed.

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References

  1. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342:1432–3.

    Article  PubMed  CAS  Google Scholar 

  2. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol. 2011;29:4828–36.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Davar D, Tarhini AA, Kirkwood JM. Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach. Clin Dermatol. 2013;31:237–50.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tarhini AA, Gogas H, Kirkwood JM. IFN-alpha in the treatment of melanoma. J Immunol. 2012;189:3789–93.

    Article  PubMed  CAS  Google Scholar 

  5. Park TS, Rosenberg SA, Morgan RA. Treating cancer with genetically engineered T cells. Trends Biotechnol. 2011;29:550–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. 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. Sci Transl Med. 2011;3:95ra73.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. 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;365:725–33.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358:2698–703.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know. Nat Rev Clin Oncol. 2011;8:577–85.

    Article  PubMed  CAS  Google Scholar 

  11. Rosenberg SA. Raising the bar: the curative potential of human cancer immunotherapy. Sci Transl Med. 2012;4:127ps8.

    Article  PubMed  CAS  Google Scholar 

  12. Yee C. Adoptive therapy using antigen-specific T-cell clones. Cancer J. 2010;16:367–73.

    Article  PubMed  CAS  Google Scholar 

  13. Baek HJ, Kim JS, Yoon M, Lee JJ, Shin MG, Ryang DW, et al. Ex vivo expansion of natural killer cells using cryopreserved irradiated feeder cells. Anticancer Res. 2013;33:2011–9.

    PubMed  CAS  Google Scholar 

  14. Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE. 2012;7:e30264.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Velardi A, Ruggeri L, Mancusi A. Killer-cell immunoglobulin-like receptors reactivity and outcome of stem cell transplant. Curr Opin Hematol. 2012;19:319–23.

    Article  PubMed  CAS  Google Scholar 

  16. 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;298:850–4.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol. 2012;124:192–8.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ye Q, Loisiou M, Levine BL, Suhoski MM, Riley JL, June CH, et al. Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes. J Transl Med. 2011;9:131.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Coukos G, Conejo-Garcia JR, Roden RB, Wu TC. Immunotherapy for gynaecological malignancies. Expert Opin Biol Ther. 2005;5:1193–210.

    Article  PubMed  CAS  Google Scholar 

  21. Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, et al. Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer. 2014;110:489–500.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73:128–38.

    Article  PubMed  CAS  Google Scholar 

  23. Hill VK, Gartner JJ, Samuels Y, Goldstein AM. The genetics of melanoma: recent advances. Annu Rev Genomics Hum Genet. 2013;14:257–79.

    Article  PubMed  CAS  Google Scholar 

  24. Cifola I, Pietrelli A, Consolandi C, Severgnini M, Mangano E, Russo V, et al. Comprehensive genomic characterization of cutaneous malignant melanoma cell lines derived from metastatic lesions by whole-exome sequencing and SNP array profiling. PLoS ONE. 2013;8:e63597.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Robbins PF, Lu YC, El-Gamil M, Li YF, Gross C, Gartner J, et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med. 2013;19:747–52.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Nikolaev SI, Rimoldi D, Iseli C, Valsesia A, Robyr D, Gehrig C, et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat Genet. 2012;44:133–9.

    Article  CAS  Google Scholar 

  27. Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982;155:1823–41.

    Article  PubMed  CAS  Google Scholar 

  28. Mazumder A, Grimm EA, Zhang HZ, Rosenberg SA. Lysis of fresh human solid tumors by autologous lymphocytes activated in vitro with lectins. Cancer Res. 1982;42:913–8.

    PubMed  CAS  Google Scholar 

  29. Rosenberg SA, Eberlein TJ, Grimm EA, Lotze MT, Mazumder A, Rosenstein M. Development of long-term cell lines and lymphoid clones reactive against murine and human tumors: a new approach to the adoptive immunotherapy of cancer. Surgery. 1982;92:328–36.

    PubMed  CAS  Google Scholar 

  30. Gaugler B, Van den Eynde B, van der Bruggen P, Romero P, Gaforio JJ, De Plaen E, et al. Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes. J Exp Med. 1994;179:921–30.

    Article  PubMed  CAS  Google Scholar 

  31. Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Vetto JT, et al. A new approach to the therapy of cancer based on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2. Surgery. 1986;100:262–72.

    PubMed  CAS  Google Scholar 

  32. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319:1676–80.

    Article  PubMed  CAS  Google Scholar 

  33. 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;23:2346–57.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Radvanyi LG, Bernatchez C, Zhang M, Fox PS, Miller P, Chacon J, et al. Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2012;18:6758–70.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2010;16:2646–55.

    Article  PubMed  CAS  Google Scholar 

  36. Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Schallmach E, et al. Minimally cultured or selected autologous tumor-infiltrating lymphocytes after a lympho-depleting chemotherapy regimen in metastatic melanoma patients. J Immunother. 2009;32:415–23.

    Article  PubMed  CAS  Google Scholar 

  37. Wu R, Forget MA, Chacon J, Bernatchez C, Haymaker C, Chen JQ, et al. Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes for metastatic melanoma: current status and future outlook. Cancer J. 2012;18:160–75.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Ye Q, Song DG, Poussin M, Yamamoto T, Best A, Li C, et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin Cancer Res. 2013.

  39. Gros A, Turcotte S, Wunderlich JR, Ahmadzadeh M, Dudley ME, Rosenberg SA. Myeloid cells obtained from the blood but not from the tumor can suppress T-cell proliferation in patients with melanoma. Clin Cancer Res. 2012;18:5212–23.

    Article  PubMed  CAS  Google Scholar 

  40. Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, Schrump DS, Steinberg SM, Rosenberg SA, Robbins PF. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012;119(24):5688–96.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Dudley ME, Wunderlich JR, Shelton TE, Even J, Rosenberg SA. Generation of tumor-infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26:332–42.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):5233–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  43. Dudley ME, Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer. 2003;3:666–75.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. 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;86:1159–66.

    Article  PubMed  CAS  Google Scholar 

  45. Ellebaek E, Iversen TZ, Junker N, Donia M, Engell-Noerregaard L, Met O, et al. Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J Transl Med. 2012;10:169.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Ullenhag GJ, Sadeghi AM, Carlsson B, Ahlstrom H, Mosavi F, Wagenius G, et al. Adoptive T-cell therapy for malignant melanoma patients with TILs obtained by ultrasound-guided needle biopsy. Cancer Immunol Immunother. 2012;61:725–32.

    Article  PubMed  Google Scholar 

  47. Queirolo P, Ponte M, Gipponi M, Cafiero F, Peressini A, Semino C, et al. Adoptive immunotherapy with tumor-infiltrating lymphocytes and subcutaneous recombinant interleukin-2 plus interferon alfa-2a for melanoma patients with nonresectable distant disease: a phase I/II pilot trial. Melanoma Istituto Scientifico Tumori Group. Ann Surg Oncol. 1999;6:272–8.

    Article  PubMed  CAS  Google Scholar 

  48. Joseph RW, Peddareddigari VR, Liu P, Miller PW, Overwijk WW, Bekele NB, et al. Impact of clinical and pathologic features on tumor-infiltrating lymphocyte expansion from surgically excised melanoma metastases for adoptive T-cell therapy. Clin Cancer Res. 2011;17:4882–91.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Besser MJ, Shapira-Frommer R, Itzhaki O, Treves AJ, Zippel DB, Levy D, et al. Adoptive transfer of tumor-infiltrating lymphocytes in patients with metastatic melanoma: intent-to-treat analysis and efficacy after failure to prior immunotherapies. Clin Cancer Res. 2013;19:4792–800.

    Article  PubMed  CAS  Google Scholar 

  50. Dudley ME, Gross CA, Langhan MM, Garcia MR, Sherry RM, Yang JC, et al. CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res. 2010;16:6122–31.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12:269–81.

    Article  PubMed  CAS  Google Scholar 

  52. Zhou J, Dudley ME, Rosenberg SA, Robbins PF. Persistence of multiple tumor-specific T-cell clones is associated with complete tumor regression in a melanoma patient receiving adoptive cell transfer therapy. J Immunother. 2005;28:53–62.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Zhou J, Shen X, Huang J, Hodes RJ, Rosenberg SA, Robbins PF. Telomere length of transferred lymphocytes correlates with in vivo persistence and tumor regression in melanoma patients receiving cell transfer therapy. J Immunol. 2005;175:7046–52.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Barrow C, Browning J, MacGregor D, Davis ID, Sturrock S, Jungbluth AA, et al. Tumor antigen expression in melanoma varies according to antigen and stage. Clin Cancer Res. 2006;12:764–71.

    Article  PubMed  CAS  Google Scholar 

  55. Grotz TE, Vaince F, Hieken TJ. Tumor-infiltrating lymphocyte response in cutaneous melanoma in the elderly predicts clinical outcomes. Melanoma Res. 2013;23:132–7.

    Article  PubMed  Google Scholar 

  56. Thomas NE, Busam KJ, From L, Kricker A, Armstrong BK, Anton-Culver H, et al. Tumor-infiltrating lymphocyte grade in primary melanomas is independently associated with melanoma-specific survival in the population-based genes, environment and melanoma study. J Clin Oncol. 2013;31:4252–9.

    Article  PubMed  Google Scholar 

  57. Alexe G, Dalgin GS, Scanfeld D, Tamayo P, Mesirov JP, DeLisi C, et al. High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. Cancer Res. 2007;67:10669–76.

    Article  PubMed  CAS  Google Scholar 

  58. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  PubMed  CAS  Google Scholar 

  59. Halama N, Michel S, Kloor M, Zoernig I, Benner A, Spille A, et al. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 2011;71:5670–7.

    Article  PubMed  CAS  Google Scholar 

  60. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res. 2008;14:5220–7.

    Article  PubMed  CAS  Google Scholar 

  61. Nelson BH. The impact of T-cell immunity on ovarian cancer outcomes. Immunol Rev. 2008;222:101–16.

    Article  PubMed  CAS  Google Scholar 

  62. Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, et al. CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA. 2007;104:3967–72.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, et al. T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 2009;11:R15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Wang E, Miller LD, Ohnmacht GA, Mocellin S, Perez-Diez A, Petersen D, et al. Prospective molecular profiling of melanoma metastases suggests classifiers of immune responsiveness. Cancer Res. 2002;62:3581–6.

    PubMed  CAS  PubMed Central  Google Scholar 

  65. Weiss GR, Grosh WW, Chianese-Bullock KA, Zhao Y, Liu H, Slingluff CL Jr, et al. Molecular insights on the peripheral and intratumoral effects of systemic high-dose rIL-2 (aldesleukin) administration for the treatment of metastatic melanoma. Clin Cancer Res. 2011;17:7440–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Bedognetti D, Spivey TL, Zhao Y, Uccellini L, Tomei S, Dudley ME, et al. CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2. Br J Cancer. 2013;109:2412–23.

    Article  PubMed  CAS  Google Scholar 

  67. Ji RR, Chasalow SD, Wang L, Hamid O, Schmidt H, Cogswell J, et al. An immune-active tumor microenvironment favors clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61:1019–31.

    Article  PubMed  CAS  Google Scholar 

  68. Reis PP, Waldron L, Goswami RS, Xu W, Xuan Y, Perez-Ordonez B, et al. mRNA transcript quantification in archival samples using multiplexed, color-coded probes. BMC Biotechnol. 2011;11:46.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  69. Norton N, Sun Z, Asmann YW, Serie DJ, Necela BM, Bhagwate A, et al. Gene expression, single nucleotide variant and fusion transcript discovery in archival material from breast tumors. PLoS ONE. 2013;8:e81925.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123:615–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Ananiev J, Gulubova MV, Manolova IM. Prognostic significance of CD83 positive tumor-infiltrating dendritic cells and expression of TGF-beta 1 in human gastric cancer. Hepatogastroenterology. 2011;58:1834–40.

    PubMed  CAS  Google Scholar 

  72. Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009;27:5944–51.

    Article  PubMed  CAS  Google Scholar 

  73. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.

    Article  PubMed  CAS  Google Scholar 

  74. Shimizu K, Nakata M, Hirami Y, Yukawa T, Maeda A, Tanemoto K. Tumor-infiltrating Foxp3+ regulatory T cells are correlated with cyclooxygenase-2 expression and are associated with recurrence in resected non-small cell lung cancer. J Thorac Oncol. 2010;5:585–90.

    PubMed  Google Scholar 

  75. Mougiakakos D, Johansson CC, Trocme E, All-Ericsson C, Economou MA, Larsson O, et al. Intratumoral forkhead box P3-positive regulatory T cells predict poor survival in cyclooxygenase-2-positive uveal melanoma. Cancer. 2010;116:2224–33.

    PubMed  Google Scholar 

  76. Zitvogel L, Kepp O, Aymeric L, Ma Y, Locher C, Delahaye NF, et al. Integration of host-related signatures with cancer cell-derived predictors for the optimal management of anticancer chemotherapy. Cancer Res. 2010;70:9538–43.

    Article  PubMed  CAS  Google Scholar 

  77. Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 2011;8:151–60.

    Article  PubMed  CAS  Google Scholar 

  78. Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med. 2013;5:200ra116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Sabatino M, Kim-Schulze S, Panelli MC, Stroncek D, Wang E, Taback B, et al. Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol. 2009;27:2645–52.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  80. Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci. 2011;48:155–70.

    Article  PubMed  CAS  Google Scholar 

  81. Gogas H, Ioannovich J, Dafni U, Stavropoulou-Giokas C, Frangia K, Tsoutsos D, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med. 2006;354:709–18.

    Article  PubMed  CAS  Google Scholar 

  82. Bedikian AY, Millward M, Pehamberger H, Conry R, Gore M, Trefzer U, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006;24:4738–45.

    Article  PubMed  CAS  Google Scholar 

  83. Breunis WB, Tarazona-Santos E, Chen R, Kiley M, Rosenberg SA, Chanock SJ. Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade. J Immunother. 2008;31:586–90.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. 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;20:143–8.

    Article  PubMed  CAS  Google Scholar 

  85. 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;15:981–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  86. Butler MO, Friedlander P, Milstein MI, Mooney MM, Metzler G, Murray AP, et al. Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. Sci Transl Med. 2011;3:80ra34.

    Article  PubMed  CAS  Google Scholar 

  87. Butler MO, Lee JS, Ansen S, Neuberg D, Hodi FS, Murray AP, et al. Long-lived antitumor CD8+ lymphocytes for adoptive therapy generated using an artificial antigen-presenting cell. Clin Cancer Res. 2007;13:1857–67.

    Article  PubMed  CAS  Google Scholar 

  88. Jin J, Sabatino M, Somerville R, Wilson JR, Dudley ME, Stroncek DF, et al. Simplified method of the growth of human tumor infiltrating lymphocytes in gas-permeable flasks to numbers needed for patient treatment. J Immunother. 2012;35:283–92.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Vera JF, Brenner LJ, Gerdemann U, Ngo MC, Sili U, Liu H, et al. Accelerated production of antigen-specific T cells for preclinical and clinical applications using gas-permeable rapid expansion cultureware (G-Rex). J Immunother. 2010;33:305–15.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  90. Somerville RP, Dudley ME. Bioreactors get personal. Oncoimmunology. 2012;1:1435–7.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Watts TH. TNF/TNFR family members in costimulation of T cell responses. Annu Rev Immunol. 2005;23:23–68.

    Article  PubMed  CAS  Google Scholar 

  92. Turcotte S, Gros A, Hogan K, Tran E, Hinrichs CS, Wunderlich JR, et al. Phenotype and function of T cells infiltrating visceral metastases from gastrointestinal cancers and melanoma: implications for adoptive cell transfer therapy. J Immunol. 2013;191:2217–25.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  93. Klebanoff CA, Finkelstein SE, Surman DR, Lichtman MK, Gattinoni L, Theoret MR, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci USA. 2004;101:1969–74.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  94. Klebanoff CA, Gattinoni L, Torabi-Parizi P, Kerstann K, Cardones AR, Finkelstein SE, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA. 2005;102:9571–6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  95. Powell DJ Jr, Dudley ME, Robbins PF, Rosenberg SA. Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood. 2005;105:241–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Duttagupta PA, Boesteanu AC, Katsikis PD. Costimulation signals for memory CD8+ T cells during viral infections. Crit Rev Immunol. 2009;29:469–86.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  97. Bertram EM, Lau P, Watts TH. Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T cell numbers late in the primary response and regulates the size of the T cell memory response following influenza infection. J Immunol. 2002;168:3777–85.

    Article  PubMed  CAS  Google Scholar 

  98. Kim YH, Seo SK, Choi BK, Kang WJ, Kim CH, Lee SK, et al. 4-1BB costimulation enhances HSV-1-specific CD8+ T cell responses by the induction of CD11c+CD8+ T cells. Cell Immunol. 2005;238:76–86.

    Article  PubMed  CAS  Google Scholar 

  99. DeBenedette MA, Wen T, Bachmann MF, Ohashi PS, Barber BH, Stocking KL, et al. Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T cell response to influenza virus. J Immunol. 1999;163:4833–41.

    PubMed  CAS  Google Scholar 

  100. Salek-Ardakani S, Moutaftsi M, Crotty S, Sette A, Croft M. OX40 drives protective vaccinia virus-specific CD8 T cells. J Immunol. 2008;181:7969–76.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  101. Myers L, Lee SW, Rossi RJ, Lefrancois L, Kwon BS, Mittler RS, et al. Combined CD137 (4-1BB) and adjuvant therapy generates a developing pool of peptide-specific CD8 memory T cells. Int Immunol. 2006;18:325–33.

    Article  PubMed  CAS  Google Scholar 

  102. Hernandez-Chacon JA, Li Y, Wu RC, Bernatchez C, Wang Y, Weber JS, et al. Costimulation through the CD137/4-1BB pathway protects human melanoma tumor-infiltrating lymphocytes from activation-induced cell death and enhances antitumor effector function. J Immunother. 2011;34:236–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  103. Qui HZ, Hagymasi AT, Bandyopadhyay S, St Rose MC, Ramanarasimhaiah R, Menoret A, et al. CD134 plus CD137 dual costimulation induces Eomesodermin in CD4 T cells to program cytotoxic Th1 differentiation. J Immunol. 2011;187:3555–64.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  104. Daniel-Meshulam I, Horovitz-Fried M, Cohen CJ. Enhanced antitumor activity mediated by human 4-1BB-engineered T cells. Int J Cancer. 2013;133:2903–13.

    PubMed  CAS  Google Scholar 

  105. Griffith KD, Read EJ, Carrasquillo JA, Carter CS, Yang JC, Fisher B, et al. In vivo distribution of adoptively transferred indium-111-labeled tumor infiltrating lymphocytes and peripheral blood lymphocytes in patients with metastatic melanoma. J Natl Cancer Inst. 1989;81:1709–17.

    Article  PubMed  CAS  Google Scholar 

  106. Fisher B, Packard BS, Read EJ, Carrasquillo JA, Carter CS, Topalian SL, et al. Tumor localization of adoptively transferred indium-111 labeled tumor infiltrating lymphocytes in patients with metastatic melanoma. J Clin Oncol. 1989;7:250–61.

    PubMed  CAS  Google Scholar 

  107. Singh SP, Han L, Murali R, Solis L, Roth J, Ji L, et al. SSTR2-based reporters for assessing gene transfer into non-small cell lung cancer: evaluation using an intrathoracic mouse model. Hum Gene Ther. 2011;22:55–64.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  108. Peng W, Ye Y, Rabinovich BA, Liu C, Lou Y, Zhang M, et al. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin Cancer Res. 2010;16:5458–68.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  109. Charo J, Finkelstein SE, Grewal N, Restifo NP, Robbins PF, Rosenberg SA. Bcl-2 overexpression enhances tumor-specific T-cell survival. Cancer Res. 2005;65:2001–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  110. Lin CM, Wang FH. Selective modification of antigen-specific CD4(+) T cells by retroviral-mediated gene transfer and in vitro sensitization with dendritic cells. Clin Immunol. 2002;104:58–66.

    Article  PubMed  CAS  Google Scholar 

  111. Eaton D, Gilham DE, O’Neill A, Hawkins RE. Retroviral transduction of human peripheral blood lymphocytes with Bcl-X(L) promotes in vitro lymphocyte survival in pro-apoptotic conditions. Gene Ther. 2002;9:527–35.

    Article  PubMed  CAS  Google Scholar 

  112. Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, Yu Z, Rosenberg SA, Restifo NP. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010;33(1):1–7.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Robbins PF, Dudley ME, Wunderlich J, El-Gamil M, Li YF, Zhou J, et al. Cutting edge: persistence of transferred lymphocyte clonotypes correlates with cancer regression in patients receiving cell transfer therapy. J Immunol. 2004;173:7125–30.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  114. Huang J, Khong HT, Dudley ME, El-Gamil M, Li YF, Rosenberg SA, et al. Survival, persistence, and progressive differentiation of adoptively transferred tumor-reactive T cells associated with tumor regression. J Immunother. 2005;28:258–67.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  115. Shen X, Zhou J, Hathcock KS, Robbins P, Powell DJ Jr, Rosenberg SA, et al. Persistence of tumor infiltrating lymphocytes in adoptive immunotherapy correlates with telomere length. J Immunother. 2007;30:123–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  116. Chapuis AG, Thompson JA, Margolin KA, Rodmyre R, Lai IP, Dowdy K, et al. Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype. Proc Natl Acad Sci USA. 2012;109:4592–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Robins HS, Campregher PV, Srivastava SK, Wacher A, Turtle CJ, Kahsai O, et al. Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood. 2009;114:4099–107.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  118. Robins HS, Srivastava SK, Campregher PV, Turtle CJ, Andriesen J, Riddell SR, et al. Overlap and effective size of the human CD8+ T cell receptor repertoire. Sci Transl Med. 2010;2:47ra64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature. 2007;450:903–7.

    Article  PubMed  CAS  Google Scholar 

  120. Manuel M, Tredan O, Bachelot T, Clapisson G, Courtier A, Parmentier G, et al. Lymphopenia combined with low TCR diversity (divpenia) predicts poor overall survival in metastatic breast cancer patients. Oncoimmunology. 2012;1:432–40.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, et al. Levels of peripheral CD4(+)FoxP3(+) regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012;119:5688–96.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  122. Nijenhuis CM, Haanen JB, Schellens JH, Beijnen JH. Is combination therapy the next step to overcome resistance and reduce toxicities in melanoma? Cancer Treat Rev. 2013;39:305–12.

    Article  PubMed  CAS  Google Scholar 

  123. Apel M, Brüning M, Granzin M, Essl M, Stuth J, Blaschke J, et al. Integrated clinical scale manufacturing system for cellular products derived by magnetic cell separation, centrifugation and cell culture. Chemie Ingenieur Technik. 2013;85:103–10.

    Article  CAS  Google Scholar 

  124. Heaton KM, Ju G, Grimm EA. Human interleukin 2 analogues that preferentially bind the intermediate-affinity interleukin 2 receptor lead to reduced secondary cytokine secretion: implications for the use of these interleukin 2 analogues in cancer immunotherapy. Cancer Res. 1993;53(11):2597–602.

    PubMed  CAS  Google Scholar 

  125. Heaton KM, Ju G, Grimm EA. Induction of lymphokine-activated killing with reduced secretion of interleukin-1 beta, tumor necrosis factor-alpha, and interferon-gamma by interleukin-2 analogs. Ann Surg Oncol. 1994;1(3):198–203.

    Article  PubMed  CAS  Google Scholar 

  126. Sim GC, Martin-Orozco N, Jin L, Yang Y, Wu S, Washington E, Sanders D, Lacey C, Wang Y, Vence L, Hwu P, Radvanyi L. IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients. J Clin Invest. 2014;124(1):99–110.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  127. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75.

    Article  PubMed  CAS  Google Scholar 

  128. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31:4311–8.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments and Disclosures

The authors have declared that no conflict of interest exists. This work is supported by NIH research grants 1R21CA178580-01, 1RO1 CA111999-01A2, and 5 P0 CA093459-05-DRP21, and grants from the Melanoma Research Alliance, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF), and the Gillson Longenbough Foundation. Support from a multi-investigator grant (RP110553 P4 01) from the Cancer Prevention and Research Institute of Texas (CPRIT) is also acknowledged. We would like to thank the members of the surgical staff, melanoma medical oncology nurses and physicians, and pathology staff for their contribution to the success of the TIL therapy program at the MD Anderson Cancer Center (Houston, TX, USA). We also would like to thank our “TIL Lab” members, including Chantale Bernatchez, Rhamatu Mansaray, Orenthial J. Fulbright, Christopher Toth, Renjith Ramachandran, Seth Wardell, Audrey Gonzalez, Kathryn Bushnell, and Marissa Gonzalez, for their hard work and contribution to the TIL therapy program.

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Authors and Affiliations

  1. Department of Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Box 904, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    Geok Choo Sim, Jessica Chacon, Cara Haymaker, Krit Ritthipichai, Patrick Hwu & Laszlo Radvanyi

  2. Lion Biotechnologies, 21900 Burbank Blvd., 3rd floor, Woodland Hills, CA, 91367, USA

    Manish Singh

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  1. Geok Choo Sim
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  2. Jessica Chacon
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  3. Cara Haymaker
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  6. Patrick Hwu
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  7. Laszlo Radvanyi
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Correspondence to Laszlo Radvanyi.

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Sim, G.C., Chacon, J., Haymaker, C. et al. Tumor-Infiltrating Lymphocyte Therapy for Melanoma: Rationale and Issues for Further Clinical Development. BioDrugs 28, 421–437 (2014). https://doi.org/10.1007/s40259-014-0097-y

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