Advertisement

Current Oncology Reports

, 20:1 | Cite as

Transformation of Old Concepts for a New Era of Cancer Immunotherapy: Cytokine Therapy and Cancer Vaccines as Combination Partners of PD1/PD-L1 Inhibitors

  • Romualdo Barroso-Sousa
  • Patrick A. OttEmail author
Melanoma (RJ Sullivan, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Melanoma

Abstract

Purpose of Review

Immune checkpoint inhibitors (ICI) are only effective in a subset of patients. Here, we will review the rationale and data supporting the combination of PD-1 pathway inhibition with recombinant cytokines and neoantigen-based cancer vaccines that can potentially increase the number of patients who will benefit from immunotherapy.

Recent Findings

The safety and tolerability of new interleukin(IL)-2 formulations, IL-15 super agonist, and PEGylated IL-10 have been evaluated in early phase clinical trials with promising efficacy data, both as monotherapy and in combination with ICI. Larger studies focusing on the efficacy of these combinations are ongoing. Personalized neoantigen-based cancer vaccines, enabled by improvements in sequencing computational capabilities, have been proven to be feasible, safe, and able to trigger a consistent vaccine-specific immune response in cancer patients.

Summary

New pharmacologically modified recombinant cytokines and personalized neoantigen-based vaccines may turn these approaches into powerful tools for effective combination immunotherapy.

Keywords

Atezolizumab Immune checkpoint inhibitors Interleukin-2 Interferon Interleukin 10 Interleukin 15 Ipilimumab NKTR-214 Neoantigens Nivolumab PD-1 inhibitors PD-l1 inhibitors Pembrolizumab Vaccines 

Notes

Funding Information

PAO receives consulting fees from: Bristol-Myers Squibb, Merck, Genentech, Celldex, CytomX, Alexion, Novartis, Pfizer, Amgen, and research funding from Bristol-Myers Squibb, Genentech, Merck, AZ/MedImmune, CytomX, Celldex, ArmoBiosciences.

Compliance with Ethical Standards

Conflict of Interest

Romualdo Barroso-Sousa declares that he has no conflict of interest.

Patrick A. Ott has received research funding from Bristol-Myers Squibb, Genentech, Merck, AstraZeneca/MedImmune, CytomX Therapeutics, Celldex, and Armo Biosciences; and has received compensation from Bristol-Myers Squibb, Merck, Genentech, Celldex, CytomX Therapeutics, Pfizer, Alexion, Amgen, and Novartis for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

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

  1. 1.
    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27(4):450–61.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined Nivolumab and Ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345–56.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol (Baltimore, Md : 1950). 2014;192(12):5451–8.CrossRefGoogle Scholar
  8. 8.
    Wang X, Rickert M, Garcia KC. Structure of the quaternary complex of interleukin-2 with its alpha, beta, and gammac receptors. Science. 2005;310(5751):1159–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Wrangle JM, Patterson A, Johnson CB, Neitzke DJ, Mehrotra S, Denlinger CE, et al. IL-2 and beyond in Cancer immunotherapy. J Interf Cytokine Res. 2018;38(2):45–68.CrossRefGoogle Scholar
  10. 10.
    Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–90.PubMedCrossRefGoogle Scholar
  11. 11.
    Lafreniere R, Rosenberg SA. Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res. 1985;45(8):3735–41.PubMedGoogle Scholar
  12. 12.
    Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–96.PubMedCrossRefGoogle Scholar
  13. 13.
    Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113(2):293–301.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907–13.PubMedCrossRefGoogle Scholar
  15. 15.
    Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17(7):2105–16.PubMedCrossRefGoogle Scholar
  16. 16.
    Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am. 2000;6(Suppl 1):S11–4.PubMedGoogle Scholar
  17. 17.
    Alva A, Daniels GA, Wong MK, et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunol Immunother: CII. 2016;65(12):1533–44.PubMedCrossRefGoogle Scholar
  18. 18.
    Milla P, Dosio F, Cattel L. PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery. Curr Drug Metab. 2012;13(1):105–19.PubMedCrossRefGoogle Scholar
  19. 19.
    Chantale Bernatchez CH, Tannir NM, Kluger H, Tetzlaff M, Bentebibel SE, Jackson N, Gergel I, Tagliaferri M, Zalevsky J, Hoch U, Imperiale M, Aung S, Hwu P, Sznol M, Hurwitz M, Diab A (2016) A CD122-biased agonist increases CD8+ T cells and natural killer cells in the tumor microenvironment; making cold tumors hot with NKTR-214 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016)Google Scholar
  20. 20.
    Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily--CTLA-4. Nature. 1987;328(6127):267–70.PubMedCrossRefGoogle Scholar
  21. 21.
    Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459–65.PubMedCrossRefGoogle Scholar
  22. 22.
    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027–34.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    West EE, Jin HT, Rasheed AU, Penaloza-MacMaster P, Ha SJ, Tan WG, et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J Clin Invest. 2013;123(6):2604–15.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    • AdiDiab NT, Cho D, Papadimitrakopoulou V, Bernatchez C, Haymaker C, Bentebibel SE, Curti B, Wong M, Tykodi S, Puzanov I, Smalberg I, Gergel I, Tagliaferri M, Zalevsky J, Hoch U, Aung S, Imperiale M, Clemens W, Kluger H, Hurwitz M, Hwu P, Sznol M (2017) Preliminary safety, efficacy and biomarker results from the Phase 1/2 study of CD-122-biased agonist NKTR-214 plus nivolumab in patients with locally advanced/metastatic solid tumors. 32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017).This study shows that the combination of NKTR-214 with the PD-1 inhibitor nivolumab is safely administered, With promissing clinical activity in patients with advanced cancers. Google Scholar
  27. 27.
    Munger W, DeJoy SQ, Jeyaseelan R Sr, et al. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor: comparison with interleukin-2. Cell Immunol. 1995;165(2):289–93.PubMedCrossRefGoogle Scholar
  28. 28.
    Rubinstein MP, Kadima AN, Salem ML, Nguyen CL, Gillanders WE, Cole DJ. Systemic administration of IL-15 augments the antigen-specific primary CD8+ T cell response following vaccination with peptide-pulsed dendritic cells. J Immunol (Baltimore, Md : 1950). 2002;169(9):4928–35.CrossRefGoogle Scholar
  29. 29.
    Liu RB, Engels B, Schreiber K, et al. IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. Proc Natl Acad Sci U S A. 2013;110(20):8158–63.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Conlon KC, Lugli E, Welles HC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol. 2015;33(1):74–82.PubMedCrossRefGoogle Scholar
  31. 31.
    Bergamaschi C, Rosati M, Jalah R, Valentin A, Kulkarni V, Alicea C, et al. Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity. The. J Biol Chem. 2008;283(7):4189–99.PubMedCrossRefGoogle Scholar
  32. 32.
    Rubinstein MP, Kovar M, Purton JF, et al. Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U S A. 2006;103(24):9166–71.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Stoklasek TA, Schluns KS, Lefrancois L. Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol (Baltimore, Md : 1950). 2006;177(9):6072–80.PubMedCentralCrossRefGoogle Scholar
  34. 34.
    Mortier E, Quemener A, Vusio P, et al. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins. J Biol Chem. 2006;281(3):1612–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Dubois S, Patel HJ, Zhang M, Waldmann TA, Muller JR. Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol (Baltimore, Md : 1950). 2008;180(4):2099–106.CrossRefGoogle Scholar
  36. 36.
    Rhode PR, Egan JO, Xu W, Hong H, Webb GM, Chen X, et al. Comparison of the Superagonist complex, ALT-803, to IL15 as Cancer Immunotherapeutics in animal models. Cancer Immunol Res. 2016;4(1):49–60.PubMedCrossRefGoogle Scholar
  37. 37.
    • Wrangle JM, Velcheti V, Patel MR, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2018;19(5):694–704 This study shows that the combination of the IL-15 superagonist ALT-803 with the PD-1 inhibitor nivolumab is safely administered in an outpatient setting, with promissing clinical activity in patients with refractory NSCLC. PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the eastern cooperative oncology group trial EST 1684. J Clin Oncol. 1996;14(1):7–17.PubMedCrossRefGoogle Scholar
  39. 39.
    Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001;19(9):2370–80.PubMedCrossRefGoogle Scholar
  40. 40.
    Mocellin S, Pasquali S, Rossi CR, Nitti D. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7):493–501.PubMedCrossRefGoogle Scholar
  41. 41.
    Weber J, Mandala M, Del Vecchio M, et al. Adjuvant Nivolumab versus Ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377(19):1824–35.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Eggermont AMM, Blank CU, Mandala M, Long GV. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med. 2018;378(19):1789–801.PubMedCrossRefGoogle Scholar
  43. 43.
    Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med. 2017;376(4):354–66.PubMedCrossRefGoogle Scholar
  44. 44.
    Terawaki S, Chikuma S, Shibayama S, Hayashi T, Yoshida T, Okazaki T, et al. IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol (Baltimore, Md : 1950). 2011;186(5):2772–9.CrossRefGoogle Scholar
  45. 45.
    Atkins MB, Hodi FS, Thompson JA, et al. Pembrolizumab plus Pegylated interferon alfa-2b or Ipilimumab for advanced melanoma or renal cell carcinoma: dose-finding results from the phase Ib KEYNOTE-029 study. Clin Cancer Res. 2018;24:1805–15.PubMedCrossRefGoogle Scholar
  46. 46.
    Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy--review of a new approach. Pharmacol Rev. 2003;55(2):241–69.PubMedCrossRefGoogle Scholar
  47. 47.
    Fujii S, Shimizu K, Shimizu T, Lotze MT. Interleukin-10 promotes the maintenance of antitumor CD8(+) T-cell effector function in situ. Blood. 2001;98(7):2143–51.PubMedCrossRefGoogle Scholar
  48. 48.
    Emmerich J, Mumm JB, Chan IH, et al. IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs. Cancer Res. 2012;72(14):3570–81.PubMedCrossRefGoogle Scholar
  49. 49.
    Chan IH, Wu V, Bilardello M, Mar E, Oft M, van Vlasselaer P, et al. The potentiation of IFN-gamma and induction of cytotoxic proteins by Pegylated IL-10 in human CD8 T cells. J Interf Cytokine Res. 2015;35(12):948–55.CrossRefGoogle Scholar
  50. 50.
    Naing A, Papadopoulos KP, Autio KA, Ott PA, Patel MR, Wong DJ, et al. Safety, antitumor activity, and immune activation of Pegylated recombinant human Interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol. 2016;34(29):3562–9.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    • Aung Naing DJW, Infante JR, Papadopoulos K, Aljumaily R, Korn WM, Schneider JG, Patel M, Autio KA, Falckook GS, Gabrail NY, Rojo B, Ratti N, McCauley S, Hung A, Van Vlasselaer P, Brown GL, Garon EB, Tannir NM, Oft M (2017) Immune and tumor responses to human IL-10 (AM0010, Pegilodecakin) alone or in combination with immune checkpoint blockade. 32nd Annual Meeting and Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2017). This study shows that the combination of the PEGylated IL-10 with PD-1 inhibitors is safely administered, With promissing clinical activity in patients with advanced cancers.Google Scholar
  52. 52.
    Hu Z, Ott PA, Wu CJ. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat Rev Immunol. 2018;18(3):168–82.PubMedCrossRefGoogle Scholar
  53. 53.
    Brown SD, Warren RL, Gibb EA, Martin SD, Spinelli JJ, Nelson BH, et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 2014;24(5):743–50.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015;160(1–2):48–61.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, et al. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep. 2016;17(4):1206.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Howitt BE, Shukla SA, Sholl LM, Ritterhouse LL, Watkins JC, Rodig S, et al. Association of Polymerase e-mutated and microsatellite-instable endometrial cancers with Neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 2015;1(9):1319–23.PubMedCrossRefGoogle Scholar
  57. 57.
    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;371:2189–99.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B, et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol. 2013;31(32):e439–42.PubMedCrossRefGoogle Scholar
  62. 62.
    Matsushita H, Vesely MD, Koboldt DC, Rickert CG, Uppaluri R, Magrini VJ, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature. 2012;482(7385):400–4.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    DuPage M, Mazumdar C, Schmidt LM, Cheung AF, Jacks T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature. 2012;482(7385):405–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Castle JC, Kreiter S, Diekmann J, Löwer M, van de Roemer N, de Graaf J, et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 2012;72(5):1081–91.PubMedCrossRefGoogle Scholar
  65. 65.
    Yadav M, Jhunjhunwala S, Phung QT, Lupardus P, Tanguay J, Bumbaca S, et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature. 2014;515(7528):572–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641–5.PubMedCrossRefGoogle Scholar
  67. 67.
    Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515(7528):577–81.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kreiter S, Vormehr M, van de Roemer N, Diken M, Löwer M, Diekmann J, et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature. 2015;520(7549):692–6.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Tran E, Robbins PF, Lu YC, Prickett TD, Gartner JJ, Jia L, et al. T-cell transfer therapy targeting mutant KRAS in Cancer. N Engl J Med. 2016;375(23):2255–62.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    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.PubMedCrossRefGoogle Scholar
  71. 71.
    Kuai R, Ochyl LJ, Bahjat KS, Schwendeman A, Moon JJ. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat Mater. 2017;16(4):489–96.PubMedCrossRefGoogle Scholar
  72. 72.
    •• Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70. References 72–74 are the first clinical studies showing that neoantigen-based anticancer vaccines are safely administered, the manufacturing is timely feasible and induce durable neoantigen-specific T cell responses in patients with locally advanced and metastatic melanoma. PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    •• Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, et al. Cancer immunotherapy A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015;348(6236):803–8. References 72–74 are the first clinical studies showing that neoantigen-based anticancer vaccines are safely administered, the manufacturing is timely feasible and induce durable neoantigen-specific T cell responses in patients with locally advanced and metastatic melanoma. PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    •• Ott PA, Hu Z, Keskin DB, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547(7662):217–21 References 72–74 are the first clinical studies showing that neoantigen-based anticancer vaccines are safely administered, the manufacturing is timely feasible and induce durable neoantigen-specific T cell responses in patients with locally advanced and metastatic melanoma. PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547(7662):222–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Medical OncologyDana-Farber Cancer InstituteBostonUSA

Personalised recommendations