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Immuno-Oncology: The Third Paradigm in Early Drug Development

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Abstract

Clinical researchers in oncology face the difficulty of developing new drugs for treating cancer patients. This challenge nowadays extends towards new horizons since a high number of drugs are developed in each of the three paradigms: classical cytotoxics, new targeted agents, and emergent immunotherapeutic approaches. Over the last decade, there has been an unstoppable progress in this third paradigm, to the extent that in 2013 immunotherapy was granted the scientific breakthrough of the year. However, the novel mechanisms of action of these immunotherapeutic agents entail a whole new series of concepts, resulting in a number of unresolved questions to which clarification is crucial for their success: establishment of accurate preclinical models able to predict human toxicities, better selection of candidate populations, finding and validation of predictive biomarkers, definition of suitable endpoints, improvements in first-in-human study designs, proposal of more accurate radiological response criteria, management of novel immune-related toxicities and development of combinations based on a biological rationale. In this article, we review the major challenges to overcome in forthcoming years. The final role of immunotherapy in cancer will be determined by our capacity to shed some light on some of these key points.

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References

  1. Rodon J. An (only) partially established paradigm of drug development of targeted therapies. Eur J Cancer. 2014;50(12):2037–9.

  2. Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. J 2000;18(3):684–92.

  3. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis. 2010;30(1):52–60.

    Article  CAS  PubMed  Google Scholar 

  4. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25(13):1753–9.

  5. Institute NC. Common Terminology Criteria for Adverse Events v.4.0. In: NCI, NIH, DHHS. 2009.

  6. Lesterhuis WJ, Haanen JB, Punt CJ. Cancer immunotherapy--revisited. Nat Rev Drug Discov. 2011;10(8):591–600.

    Article  CAS  PubMed  Google Scholar 

  7. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411–22.

    Article  CAS  PubMed  Google Scholar 

  8. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Couzin-Frankel J. Breakthrough of the year 2013. Cancer immunotherapy. Science. 2013;342(6165):1432–3.

  10. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.

    Article  CAS  PubMed  Google Scholar 

  11. Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375–84.

    Article  CAS  PubMed  Google Scholar 

  12. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.

    Article  CAS  PubMed  Google Scholar 

  13. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627–39.

    Article  CAS  PubMed  Google Scholar 

  15. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.

    Article  CAS  PubMed  Google Scholar 

  16. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375(19):1823–1833.

  17. Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, et al. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med. 2015;373(11):1040–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gazdar AF, Hirsch FR, Minna JD. From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers. J Thorac Oncol. 2015;11(3):287–99.

  20. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355(10):1018–28.

    Article  CAS  PubMed  Google Scholar 

  21. Horvath CJ, Milton MN. The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event? Toxicol Pathol. 2009;37(3):372–83.

    Article  PubMed  Google Scholar 

  22. Hunig T. The storm has cleared: lessons from the CD28 superagonist TGN1412 trial. Nat Rev Immunol. 2012;12(5):317–8.

    PubMed  Google Scholar 

  23. Wolchok JD, Weber JS, Hamid O, Lebbe C, Maio M, Schadendorf D, et al. Ipilimumab efficacy and safety in patients with advanced melanoma: a retrospective analysis of HLA subtype from four trials. Cancer Immun. 2010;10:9.

    PubMed  PubMed Central  Google Scholar 

  24. Martin-Liberal J, Furness AJ, Joshi K, Peggs KS, Quezada SA, Larkin J. Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother. 2015;64(6):765–7.

  25. Linette GP, Stadtmauer EA, Maus MV, Rapoport AP, Levine BL, Emery L, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122(6):863–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Weber J, Thompson JA, Hamid O, Minor D, Amin A, Ron I, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15(17):5591–8.

    Article  CAS  PubMed  Google Scholar 

  27. Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–508.

    Article  CAS  PubMed  Google Scholar 

  28. Kyi C, Carvajal RD, Wolchok JD, Postow MA. Ipilimumab in patients with melanoma and autoimmune disease. J Immunother Cancer. 2014;2(1):35.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bostwick AD, Salama AK, Hanks BA. Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis. J Immunother Cancer. 2015;3:19.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gerlinger M, Quezada SA, Peggs KS, Furness AJ, Fisher R, Marafioti T, et al. Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. J Pathol. 2013;231(4):424–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Johnson DB, Wallender EK, Cohen DN, Likhari SS, Zwerner JP, Powers JG, et al. Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. Cancer Immunol Res. 2013;1(6):373–7.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20(19):5064–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62.

    Article  CAS  PubMed  Google Scholar 

  35. Ilie M, Long-Mira E, Bence C, Butori C, Lassalle S, Bouhlel L, et al. Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol. 2016;27(1):147–53.

    Article  CAS  PubMed  Google Scholar 

  36. Choueiri TK, Figueroa DJ, Fay AP, Signoretti S, Liu Y, Gagnon R, et al. Correlation of PD-L1 Tumor Expression and Treatment Outcomes in Patients with Renal Cell Carcinoma Receiving Sunitinib or Pazopanib: Results from COMPARZ, a Randomized Controlled Trial. Clin Cancer Res. 2015;21(5):1071–7.

    Article  CAS  PubMed  Google Scholar 

  37. Duraiswamy J, Freeman GJ, Coukos G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors--response. Cancer Res. 2014;74(2):633–4. discussion 5.

    Article  CAS  PubMed  Google Scholar 

  38. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying Cancers Based on T-cell Infiltration and PD-L1. Cancer Res. 2015;75(11):2139–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science New York, NY. 2015;348(6230):124–8.

    Article  CAS  Google Scholar 

  42. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371(23):2189–99.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.

  44. Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L, et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science. 2015;350(6257):207–11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 2016;13(3):143–58.

    Article  CAS  PubMed  Google Scholar 

  46. McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351(6280):1463–9.

  47. Yuan J, Hegde PS, Clynes R, Foukas PG, Harari A, Kleen TO, et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J Immunother Cancer. 2016;4:3.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hoos A, Eggermont AM, Janetzki S, Hodi FS, Ibrahim R, Anderson A, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102(18):1388–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47(1):207–14.

    Article  CAS  PubMed  Google Scholar 

  50. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–16.

    Article  CAS  Google Scholar 

  51. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

  52. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963–72.

    Article  PubMed  Google Scholar 

  53. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50 Suppl 1:122S–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gwyther SJ, Schwartz LH. How to assess anti-tumour efficacy by imaging techniques. Eur J Cancer. 2008;44(1):39–45.

  55. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.

    Article  CAS  PubMed  Google Scholar 

  56. Ribas A, Comin-Anduix B, Economou JS, Donahue TR, de la Rocha P, Morris LF, et al. Intratumoral immune cell infiltrates, FoxP3, and indoleamine 2,3-dioxygenase in patients with melanoma undergoing CTLA4 blockade. Clin Cancer Res. 2009;15(1):390–9.

    Article  CAS  PubMed  Google Scholar 

  57. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105(8):3005–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tirkes T, Hollar MA, Tann M, Kohli MD, Akisik F, Sandrasegaran K. Response criteria in oncologic imaging: review of traditional and new criteria. Radiographics. 2013;33(5):1323–41.

    Article  PubMed  Google Scholar 

  59. Ribas A, Chmielowski B, Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy? Clin Cancer Res. 2009;15(23):7116–8.

    Article  CAS  PubMed  Google Scholar 

  60. Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res. 2013;19(14):3936–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bohnsack OHA, Ludajic K. Adaptation of the immune-related response criteria: irRECIST. Ann Oncol. 2014;25(suppl_4):iv361–72.

    Article  Google Scholar 

  62. Hoos A, Parmiani G, Hege K, Sznol M, Loibner H, Eggermont A, et al. A clinical development paradigm for cancer vaccines and related biologics. J Immunother. 2007;30(1):1–15.

    Article  PubMed  Google Scholar 

  63. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803–13.

  64. Huang RR, Jalil J, Economou JS, Chmielowski B, Koya RC, Mok S, et al. CTLA4 blockade induces frequent tumor infiltration by activated lymphocytes regardless of clinical responses in humans. Clin Cancer Res. 2011;17(12):4101–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bellera CA, Pulido M, Gourgou S, Collette L, Doussau A, Kramar A, et al. Protocol of the Definition for the Assessment of Time-to-event Endpoints in CANcer trials (DATECAN) project: formal consensus method for the development of guidelines for standardised time-to-event endpoints’ definitions in cancer clinical trials. Eur J Cancer. 2013;49(4):769–81.

  66. Ciani O, Buyse M, Garside R, Peters J, Saad ED, Stein K, et al. Meta-analyses of randomized controlled trials show suboptimal validity of surrogate outcomes for overall survival in advanced colorectal cancer. J Clin Epidemiol. 2015;68(7):833–42.

    Article  PubMed  Google Scholar 

  67. Bilusic M, Gulley JL. Endpoints, patient selection, and biomarkers in the design of clinical trials for cancer vaccines. Cancer Immunol Immunother. 2012;61(1):109–17.

  68. Kantoff PW, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(7):1099–105.

  69. Madan RA, Gulley JL, Fojo T, Dahut WL. Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression. Oncologist. 2010;15(9):969–75.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wolchok JD, Neyns B, Linette G, Negrier S, Lutzky J, Thomas L, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11(2):155–64.

    Article  CAS  PubMed  Google Scholar 

  71. Burch PA, Breen JK, Buckner JC, Gastineau DA, Kaur JA, Laus RL, et al. Priming tissue-specific cellular immunity in a phase I trial of autologous dendritic cells for prostate cancer. Clin Cancer Res. 2000;6(6):2175–82.

    CAS  PubMed  Google Scholar 

  72. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial. J Clin Oncol 2015;33(13):1430–7.

  73. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–28.

    Article  PubMed  Google Scholar 

  74. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013;19(5):997–1008.

    Article  CAS  PubMed  Google Scholar 

  76. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–48.

    Article  CAS  PubMed  Google Scholar 

  77. Champiat S, Lambotte O, Barreau E, Belkhir R, Berdelou A, Carbonnel F, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol. 2015;27(4):559–74.

  78. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375–91.

    CAS  PubMed  Google Scholar 

  79. Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book. 2015:76–83.

  80. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015;33(18):2092–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer immunotherapy. Nat Rev Clin Oncol. 2014;11(2):91–9.

    Article  CAS  PubMed  Google Scholar 

  82. Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013;98(4):1361–75.

    Article  CAS  PubMed  Google Scholar 

  83. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7.

    Article  CAS  PubMed  Google Scholar 

  84. Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol. 2012;12(4):269–81.

    Article  CAS  PubMed  Google Scholar 

  85. 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(4):299–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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(17):4792–800.

    Article  CAS  PubMed  Google Scholar 

  87. Aplenc R, Shaw PA, Frey N, Maude SL, Chew A, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;16:1507–17.

  88. 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;16:1509–18.

  89. Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, et al. Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood. 2009;114(3):535–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DAN, Feldman SA, et al. T Cells Targeting Carcinoembryonic Antigen Can Mediate Regression of Metastatic Colorectal Cancer but Induce Severe Transient Colitis. Mol Ther. 2011;19(3):620–6.

    Article  CAS  Google Scholar 

  91. Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng ZL, et al. Cancer Regression and Neurological Toxicity Following Anti-MAGE-A3 TCR Gene Therapy. J Immunother. 2013;36(2):133–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Rahma OE, Gammoh E, Simon RM, Khleif SN. Is the “3+3” dose-escalation phase I clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design. Clin Cancer Res. 2014;20(18):4758–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Dieperink E, Willenbring M, Ho SB. Neuropsychiatric Symptoms Associated With Hepatitis C and Interferon Alpha: A Review. Am J Psychiatry. 2000;157(6):867–76.

  94. Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist. 2001;6(1):34–55.

    Article  CAS  PubMed  Google Scholar 

  95. Dutcher JP, Schwartzentruber DJ, Kaufman HL, Agarwala SS, Tarhini AA, Lowder JN, et al. High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. J Immunother Cancer. 2014; 2:26.

  96. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Original Article: Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:23–34.

    Article  PubMed  CAS  Google Scholar 

  97. Hodi FS, Oeday SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;8:711–23.

  98. Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Articles: Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14:1104–11.

    Article  PubMed  CAS  Google Scholar 

  99. Bagcchi S. Pembrolizumab for treatment of refractory melanoma. Lancet Oncol. 2014;15(10):e419.

  100. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;7528:558.

    Article  CAS  Google Scholar 

  101. Curti BD, Kovacsovics-Bankowski M, Morris N, Walker E, Chisholm L, Floyd K, et al. OX40 Is a Potent Immune-Stimulating Target in Late-Stage Cancer Patients. Cancer Res. 2013;73(24):7189–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lamers CH, Sleijfer S, Vulto AG, Kruit W, Kliffen M, Debets R, et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. 2006:e20–2.

  103. Lamers CHJ, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, et al. Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity. Mol Ther. 2013;21(4):904–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA. Case Report of a Serious Adverse Event Following the Administration of T Cells Transduced With a Chimeric Antigen Receptor Recognizing ERBB2. Mol Ther. 2010;18(4):843–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood. 2012;119(12):2709–20.

  106. Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. 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(7):917–24.

    Article  PubMed  PubMed Central  Google Scholar 

  107. 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(5594):850–4.

  108. 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(10):2346–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Hinrichs CS SS, Drape L, et al. HPV-targeted, tumor-infiltrating lymphocytes for cervical cancer. J Clin Oncol. 32(suppl, LBA3008):5s.

  110. Becker JC, Andersen MH, Hofmeister-Muller V, Wobser M, Frey L, Sandig C, et al. Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma. Cancer Immunol Immunother. 2012;61(11):2091–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Pectasides D, Dafni U, Bafaloukos D, Skarlos D, Polyzos A, Tsoutsos D, et al. Randomized Phase III Study of 1 Month Versus 1 Year of Adjuvant High-Dose Interferon Alfa-2b in Patients With Resected High-Risk Melanoma. J Clin Oncol. 2009;27(6):939–44.

    Article  CAS  PubMed  Google Scholar 

  112. Alwan LM, Grossmann K, Sageser D, Van Atta J, Agarwal N, Gilreath JA. Comparison of acute toxicity and mortality after two different dosing regimens of high-dose interleukin-2 for patients with metastatic melanoma. Target Oncol. 2014;9(1):63–71.

    Article  PubMed  Google Scholar 

  113. Hanzly M, Aboumohamed A, Yarlagadda N, Creighton T, Digiorgio L, Fredrick A, et al. Medical Oncology: High-dose Interleukin-2 Therapy for Metastatic Renal Cell Carcinoma: A Contemporary Experience. Urology. 2014;83:1129–34.

    Article  PubMed  Google Scholar 

  114. Melero I, Berman DM, Aznar MA, Korman AJ, Pérez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15(8):457–72.

    Article  CAS  PubMed  Google Scholar 

  115. Rini BI, Stein M, Shannon P, Eddy S, Tyler A, Stephenson JJ, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2011;117(4):758–67.

    Article  CAS  PubMed  Google Scholar 

  116. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368(14):1365–6.

    Article  CAS  PubMed  Google Scholar 

  117. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046–54.

    Article  CAS  PubMed  Google Scholar 

  118. Reck M, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24(1):75–83.

    Article  CAS  PubMed  Google Scholar 

  119. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(10):925–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hiniker SM, Chen DS, Knox SJ. Abscopal effect in a patient with melanoma. N Engl J Med. 2012;366(21):2035. author reply −6.

    Article  CAS  PubMed  Google Scholar 

  121. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, Brownell I. The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys. 2013;85(2):293–5.

    Article  PubMed  Google Scholar 

  122. Hiniker SM, Chen DS, Reddy S, Chang DT, Jones JC, Mollick JA, et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol. 2012;5(6):404–7.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol. 2015;16(7):795–803.

    Article  CAS  PubMed  Google Scholar 

  124. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15(17):5379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Schaue D, Ratikan JA, Iwamoto KS, McBride WH. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys. 2012;83(4):1306–10.

    Article  CAS  PubMed  Google Scholar 

  127. Ascierto PA, Del Vecchio M, Robert C, Mackiewicz A, Chiarion-Sileni V, Fernandez AMA, et al. Overall survival (OS) and safety results from a phase 3 trial of ipilimumab (IPI) at 3 mg/kg vs 10 mg/kg in patients with metastatic melanoma (MEL). Ann Oncol. 2016;27(suppl 6).

  128. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.

    Article  CAS  PubMed  Google Scholar 

  131. Hammers HJ, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol 32:5s, 2014 (suppl; abstr 4504)

  132. Postel-Vinay S, Aspeslagh S, Lanoy E, Robert C, Soria JC, Marabelle A. Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies. Ann Oncol. 2016;27(2):214–24.

    Article  CAS  PubMed  Google Scholar 

  133. Antonia SJ, Larkin J, Ascierto PA. Immuno-oncology combinations: a review of clinical experience and future prospects. Clin Cancer Res. 2014;20(24):6258–68.

    Article  CAS  PubMed  Google Scholar 

  134. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373(1):23–34.

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    Authors and Affiliations

    1. Molecular Therapeutics Research Unit, Medical Oncology Department, Vall d’Hebron University Hospital, P. Vall d’Hebron 119-129, 08035, Barcelona, Spain

      Juan Martin-Liberal, Cinta Hierro, Maria Ochoa de Olza & Jordi Rodon

    2. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

      Juan Martin-Liberal, Cinta Hierro, Maria Ochoa de Olza & Jordi Rodon

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    1. Juan Martin-Liberal
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    2. Cinta Hierro
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    Jordi Rodon has been member of advisory boards for Novartis, Lilly, Servier, and Oncompass. The other authors declare no conflict of interest.

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    Juan Martin-Liberal and Cinta Hierro contributed equally to this work.

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    Martin-Liberal, J., Hierro, C., Ochoa de Olza, M. et al. Immuno-Oncology: The Third Paradigm in Early Drug Development. Targ Oncol 12, 125–138 (2017). https://doi.org/10.1007/s11523-016-0471-4

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