Current Treatment Options in Oncology

, Volume 13, Issue 3, pp 340–353 | Cite as

Adoptive Immunotherapy of Advanced Melanoma

  • Ronnie Shapira-Frommer
  • Jacob Schachter
Skin Cancer (WH Sharfman, Section Editor)

Opinion statement

Adoptive cell therapy (ACT) has emerged as an effective therapy for patients with metastatic melanoma. Since the first introduction of the protocol in 1988 [1], major improvements have been achieved with response rates of 40%–72% among patients who were resistant to previous treatment lines. Both cell product and conditioning regimen are major determinants of treatment efficacy; therefore, developing ACT protocols explore diverse ways to establish autologous intra-tumoral lymphocyte cultures or peripheral effector cells as well as different lymphodepleting regimens. While a proof of feasibility and a proof of concept had been established with previous published results, ACT will need to move beyond single-center experiences, to confirmatory, multi-center studies. If ACT is to move into widespread practice, it will be necessary to develop reproducible high quality cell production methods and accepted lymphodepleting regimen. Two new drugs, ipilimumab (Yervoy, Bristol-Myers Squibb) and vemurafenib (Zelboraf, Roche), were approved in 2011 for the treatment of metastatic melanoma based on positive phase III trials. Both drugs show a clear overall survival benefit, so the timing of when to use ACT will need to be carefully thought out. In contrast to these 2 new, commercially available outpatient treatments, ACT is a personally-specified product and labor-intensive therapy that demands both acquisition of high standard laboratory procedures and close clinical inpatient monitoring during treatment. It is unique among other anti-melanoma treatments, providing the potential for a durable response following a single, self-limited treatment. This perspective drives the efforts to make this protocol accessible for more patients and to explore modifications that may optimize treatment results.


Adoptive immunotherapy ACT Metastatic melanoma Selected TIL Young-TIL Chimeric antigen receptor 



No potential conflicts of interest relevant to this article were reported.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Rosenberg SA, Packard BS, Aebersold PM, 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.PubMedCrossRefGoogle Scholar
  2. 2.
    Muul LM, Spiess PJ, Director EP, Rosenberg SA. Identification of specific cytolitic immune responses against autologus tumor in humans bearing malignant melanoma. J Immunol. 1987;138:989–95.PubMedGoogle Scholar
  3. 3.
    Erickson C, Driscoll MS. Melanoma epidemic: facts and controversies. Clin Dermatol. 2010;28:281–6.PubMedCrossRefGoogle Scholar
  4. 4.
    Linos E, Swetter SM, Cockburn MG, et al. Increasing burden of melanoma in the united states. J Invest Dermatol. 2009;129:1666–74.PubMedCrossRefGoogle Scholar
  5. 5.
    Siegal R, Ward E, Brawley O, Jemal A. Cancer statistics,2011. CA Cancer J Clin. 2011;61:212–31.CrossRefGoogle Scholar
  6. 6.
    Altekrus S, Kosary C, Krapcho M, et al. SEER cancer statistics review, 1975–2007. 2009. Available at: 1975_2007.
  7. 7.
    SEER stat fact sheets: Melanoma of the Skin. Available at: 2011.
  8. 8.
    Draghiciu O, Nijman HW, Daemen T. From tumor immunosupression to eradication: targeting homing and activity of immune effector cells to tumors. Clin Dev Immunol. 2011.Google Scholar
  9. 9.•
    Mellman I, Coucos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–9. An outstanding review of immune-escape mechanisms of cancer and immunotherapy approaches.PubMedCrossRefGoogle Scholar
  10. 10.
    Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High dose recombinant high dose interleukin-2 therapy in patients with metastatic melanoma: long term survival update. Cancer J. 2000;1:S11–14.Google Scholar
  11. 11.
    Lotze M, Chang AE, Seipp CA, et al. High dose recombinant interleukin-2 in the treatment of patients with disseminated cancer: responses, treatment related morbidity and histologic findings. JAMA. 1986;256:3117–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Available at: 2012.vol.9, no 2.
  13. 13.
    Mohammad KS, Javelaud D, Fournier PGJ, et al. TGFβ-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastasis. Cancer Res. 2011;71:175–84.PubMedCrossRefGoogle Scholar
  14. 14.
    Rosenberg SA, Sherry RM, Morton KE, et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen specific CD8+ T-cells in patients with melanoma. J Immunol. 2005;175:6169–76.PubMedGoogle Scholar
  15. 15.
    Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10:919–5.Google Scholar
  16. 16.
    Schwartzentruber DJ, Lawson DH, Richards JM, et al. gp100 Peptide vaccine and Interleukin-2 in patients with advanced melanoma. N Engl J Med. 2011;364:2119–27.PubMedCrossRefGoogle Scholar
  17. 17.
    Klebanoff CA, Acquavella N, Yu Z, Restifo NP. Therapeutic cancer vaccines: are we there yet? Immunol Rev. 2011;239:27–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T-cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–94.PubMedCrossRefGoogle Scholar
  19. 19.
    Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.PubMedCrossRefGoogle Scholar
  20. 20.
    Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.PubMedCrossRefGoogle Scholar
  22. 22.
    Sznol M, Powderly J, Smith D. Safety and antitumor activity of biweekly MDX-1106(anti PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies. J Clin Oncol. 2010;28:15s. abstr 2506.Google Scholar
  23. 23.
    Rosenberg SA. Cell transfer immunotherapy for metastatic solid cancer-what clinicians need to know. Nat Rev Clin Oncol. 2011;8:577–85.PubMedCrossRefGoogle Scholar
  24. 24.
    Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients following clonal repopulation with anti-tumor lymphocytes. Science. 2002;298:850–4.PubMedCrossRefGoogle Scholar
  25. 25.•
    Besser MJ, Shapira-Frommer R, Treves AJ. Clinical responses in a phase II study using adoptive transfer of short- term cultured tumor infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res. 2010;16:2646–55. Using Young-TIL technology simplifies laboratory production of TIL. Feasibility and efficacy results of Young-TIL protocol in phase II trial.PubMedCrossRefGoogle Scholar
  26. 26.
    Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23:2346–57.PubMedCrossRefGoogle Scholar
  27. 27.
    Goff SL, Smith FO, Klapper JA, et al. Tumor infiltrating lymphocyte for metastatic melanoma: analysis of tumor resected for TIL. J Immunother. 2010;33:840–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Dudley ME, Wunderlich JR, Shelton TE, et al. Generation of tumor infiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother. 2003;26:332–42.PubMedCrossRefGoogle Scholar
  29. 29.•
    Rosenberg SA, Yang JC, Sherry RM. Durable complete response in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17:4550–7. This paper summarizes the long term follow up of patients treated at the NIH in three adoptive immunotherapy protocols, using selected TIL with non-myeloablative chemotherapy either with or without total body irradiation. 93 patients followed over median 62 months.PubMedCrossRefGoogle Scholar
  30. 30.
    Schwartzentruber DJ. Guidelined for the safe administration of high dose interleukin-2. J Immunother. 2001;24:287–93.PubMedCrossRefGoogle Scholar
  31. 31.
    Tran KQ, Ahou J, Durflinger KH, et al. Minimally Cultured tumor infiltrating lymphocytes display optimal charachteristics for adoptive cell therapy. J Immunother. 2008;31:742–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Gattinoni L, Klebanoff CA, Palmer DC, et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T-cells. J Clin Inv. 2005;115:1616–26.CrossRefGoogle Scholar
  33. 33.
    Itzhaki O, Hovav E, Ziporen Y. Establishment and large scale expansion of minimally cultures "young" tumor infiltrating lymphocytes for adoptive transfer therapy. J Immunother. 2011;34:212–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Shapira-Frommer R, Besser M, Kuchuk I. Adoptive transfer of short term cultured tumor infiltrating lymphocytes (Young-TIL) in metastatic melanoma patients. J Clin Onc. 2011;29:8510.Google Scholar
  35. 35.
    Prieto PA, Durflinger KH, Wunderlich JR, et al. Enrichment of CD8+ cells from melanoma tumor infiltrating lymphocytes cultures reveals tumor reactivity for use in adoptive cell therapy. J Immunother. 2010;33:547–56.PubMedCrossRefGoogle Scholar
  36. 36.
    Dudley ME, Gross CA, Langhan MM, et al. CD8+ enriched "young" tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res. 2010;16:6122–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Muranski P, Boni A, Wrzesinski C, et al. Increased intensity lymphdepletion and adoptive immunotherapy: how far can we go? Nat Rev Clin Oncol. 2006;3:668–81.Google Scholar
  38. 38.
    Wrzesinski C, Paulos CM, Gattinoni L, et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred anti tumor CD8 T-cells. J Clin Invest. 2007;117:492–501.PubMedCrossRefGoogle Scholar
  39. 39.
    Gattinoni L, Finkelstein SE, Klebanoff CA, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor specific CD8+ T cell. J Exp Med. 2005;202:907–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Antony PA, Ciriaco CA, Akpinarli A, 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;174:2591–601.PubMedGoogle Scholar
  41. 41.
    Paulos CM, Wrezinski C, Kaiser A, et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J Clin Invest. 2007;117:2197–204.PubMedCrossRefGoogle Scholar
  42. 42.
    Dudley ME, Young JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preperative regimens. J Clin Oncol. 2008;26:5233–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Louis CU, Stratoff K, Bollard CM, et al. Enhancing the in vivo expansion of adoptively transferred EBV specific CTL's with lymphodepleting anti CD45 monoclonal antibodied in NPC patients. Blood. 2009;13:2442–50.CrossRefGoogle Scholar
  44. 44.
    Morgan RA, Dudley ME, Yu YY, et al. High efficacy TCR gene transfer into primary human lymphocytes affords avid recognition of melanoma tumor antigen glycoprotein 100 and does not alter the recognition of autologus melanoma antigens. J Immunol. 2003;171:3287–95.PubMedGoogle Scholar
  45. 45.
    Sadelain M, Riviere I, Brentjens R. Targeting tumors with genetically enhanced T lymphocytes. Nat Rev Cancer. 2003;3:35–45.PubMedCrossRefGoogle Scholar
  46. 46.
    Morgan RA, Dudley ME, Wunderlich JR. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;b314:126–9.CrossRefGoogle Scholar
  47. 47.•
    Johnson LA, Morgan RA, Dudley ME. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009;114:535–46. ACT using engineered peripheral lymphocytes targeting MART-1 and gp-100. Specific toxicity of treatment related to the shared antigens of tumor and normal tissue and efficacy results. As author claims- response rates lower than historical reports of autologus/not specifically targeted TIL, may suggest that shared melanoma/melanocytes antigens are not the predominant target of therapeutic TIL (and maybe also reflects the need to target multiple antigens).PubMedCrossRefGoogle Scholar
  48. 48.
    Zhao Y, Zheng Z, Robbins PF, et al. Primary human lymphocytes transduced with NY-ESO-1 antigen specific TCR genes recognize and kill diverse human tumor cell lines. J Immunol. 2005;174:4415–23.PubMedGoogle Scholar
  49. 49.•
    Robbins PF, Morgan RA, Feldman SA. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917–724. Clinical results of ACT using engineered T cells. Responses achieved both in melanoma and synovial cell sarcoma- a highly resistant tumor .Proof of concept for using targeted T cells in solid tumors, others than melanoma, when target tumor antigen available.PubMedCrossRefGoogle Scholar
  50. 50.•
    Ramos CA, Dotti G. Chimeric antigen receptor (CAR)-engineered lymphocytes for cancer therapy. Expert opinion in biological therapeutics. 2011;11:855–73. Authors review CAR cells structureand function, potential advantage over other immunotherapy strategies, and developing directions in CAR use for cancer immunotherapy.CrossRefGoogle Scholar
  51. 51.
    Westwood J, Kershaw MH. Genetic redirection of T cells for cancer therapy. J Leukoc Biol. 2010;87:791–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B lineage cells and regression of lymphoma in a patient treated with autologus T-cells genetically engineered to recognize CD19. Blood. 2010;116:4099–102.PubMedCrossRefGoogle Scholar
  53. 53.•
    Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor modified T-cells in chronic lymphoid leukemia. N Engl J Med. 2011:365:725–33. Recent published results of adoptive cell therapy using genetically altered autologus periphera T cells (CARs). Google Scholar
  54. 54.
    Kochenderfer JN, Dudley ME, Feldman SA, 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;119:2709–20.PubMedCrossRefGoogle Scholar
  55. 55.•
    Rosenberg SA. Raising the bar: The curative potential of human cancer immunotherapy. Sci Transl Med. 2012;4:8. Author perspective of adoptive immunotherapy aiming to achieve cure in metastatic cancer. The review contains a table that summarizes active adoptive immunotherapy trials using T cells with chimeric antigen receptors.CrossRefGoogle Scholar
  56. 56.
    Robbins PF, Dudley ME, Wunderlich 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.PubMedGoogle Scholar
  57. 57.
    Huang J, Khong HT, Dudley ME, et al. Survival, persistence and progressive differentiation of adoptively transferred tumor reactive T-cells associated with tumor regression. J Immunother. 2005;28:258–67.PubMedCrossRefGoogle Scholar
  58. 58.
    Powel Jr DJ, Dudley ME, Robbins PF, Rosenberg SA. Transition of late stage effector T-cells to CD27 + CD28+ tumor reactive effector memory cells in human after adoptive cell transfer therapy. Blood. 2005;105:241–50.CrossRefGoogle Scholar
  59. 59.
    Ochsenbein AF, Riddell SR, Brown M, et al. CD27 expression promotes long term survival of functional effector memory CD8+ cytotoxic T lymphocytes in HIV-infected patients. J Exp Med. 2004;200:1407–17.PubMedCrossRefGoogle Scholar
  60. 60.
    Zhou J, Shen X, Huang J, et al. 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.PubMedGoogle Scholar
  61. 61.
    Yao X, Ahmazdeh M, Rosenberg S, Robbins P. Reconstitution of pheripheral CD4 + FOXP3+ T-cells in cancer patients receiving adoptive immunotherapy is related to the clinical response to therapy. J Immunol. 2010;184:131.8.Google Scholar
  62. 62.
    Kalos M. Biomarkers in T-cell therapy clinical trials. J Transl Med. 201;9:138Google Scholar
  63. 63.
    Sapoznik S, Ortenberg R, Galore- Haskel G, et al. CXCR1 as a novel target for directing reactive T-cells towards melanoma: implications for adoptive cell transfer immunotherapy. Cancer Immunol Immunothe 2012. (Epub ahead of print Mar24)Google Scholar
  64. 64.•
    Weber J, Atkins M, Hwu P. White paper on adoptive cell therapy for cancer with tumor–infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. Clin Cancer Res. 2011;17:1664–73. Author reviews the options for clinical validation of adoptive immunotherapy protocol as multicenter study.PubMedCrossRefGoogle Scholar
  65. 65.•
    Stroneck DF, Berger C, Cheever MA. New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer. J Transl Med. 2012;10:48. A summary of current and future investigational directions in cellular therapy for cancer that had been presented in a summit on November 2011. Methods to facilitate cell culture production and options for use of other cytokines, targeted cells and vaccines.CrossRefGoogle Scholar
  66. 66.
    Waldman TA. The biology of interleukin-2 and Interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2007;167:6356–65.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ronnie Shapira-Frommer
    • 1
  • Jacob Schachter
    • 1
    • 2
  1. 1.Ella Institute for the Treatment and Research of MelanomaSheba Medical CenterRamat-GanIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv University, Ramat AvivTel AvivIsrael

Personalised recommendations