A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

Abstract

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II–IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 105 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4+ and CD8+ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

α-GalCer:

α-Galactosylceramide

AE:

Adverse event

AJCC:

American Joint Committee on Cancer

CDR3:

Complementary determining region 3

CTCAE:

Common terminology criteria for adverse events

DCV:

Dendritic cell vaccine

ECOG:

Eastern Cooperative Oncology Group performance status

FGF2:

Fibroblast growth factor 2

FWER:

Family wise error rate

IP-10:

IFN-γ-inducible protein-10

M1:

Influenza virus matrix protein 1

MCP-1:

Monocyte chemoattractant protein-1

MIP:

Macrophage inflammatory protein

NKT cell:

Natural killer T cell

NP:

Influenza virus nucleoprotein

NY-ESO-1:

New York esophageal squamous cell carcinoma-1

PB-1:

Influenza virus protein basic-1

PDGF-BB:

Platelet-derived growth factor BB

PGE2 :

Prostaglandin E2

RANTES:

Regulated on activation, normal T cell expressed and secreted

References

  1. 1.

    Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14(1):7–17

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Lens MB, Dawes M (2002) Interferon alfa therapy for malignant melanoma: a systematic review of randomized controlled trials. J Clin Oncol 20(7):1818–1825

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH Jr, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbe C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A (2016) Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 375(19):1845–1855

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchok JD (2015) Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 26(12):2375–2391

    CAS  PubMed  Google Scholar 

  9. 9.

    Weber JS, Kahler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30(21):2691–2697

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Coffman RL, Sher A, Seder RA (2010) Vaccine adjuvants: putting innate immunity to work. Immunity 33(4):492–503. https://doi.org/10.1016/j.immuni.2010.10.002

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Fujii S, Shimizu K, Smith C, Bonifaz L, Steinman RM (2003) Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med 198(2):267–279

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old L, Cerundolo V (2003) NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 171(10):5140–5147

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Leslie DS, Vincent MS, Spada FM, Das H, Sugita M, Morita CT, Brenner MB (2002) CD1-mediated gamma/delta T cell maturation of dendritic cells. J Exp Med 196(12):1575–1584

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Vincent MS, Leslie DS, Gumperz JE, Xiong X, Grant EP, Brenner MB (2002) CD1-dependent dendritic cell instruction. Nat Immunol 3(12):1163–1168. https://doi.org/10.1038/ni851

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Lantz O, Bendelac A (1994) An invariant T cell receptor alpha chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD48 T cells in mice and humans. J Exp Med 180(3):1097–1106

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Masuda K, Makino Y, Cui J, Ito T, Tokuhisa T, Takahama Y, Koseki H, Tsuchida K, Koike T, Moriya H, Amano M, Taniguchi M (1997) Phenotypes and invariant alpha beta TCR expression of peripheral V alpha 14 + NK T cells. J Immunol 158(5):2076–2082

    CAS  PubMed  Google Scholar 

  17. 17.

    Prussin C, Foster B (1997) TCR V alpha 24 and V beta 11 coexpression defines a human NK1 T cell analog containing a unique Th0 subpopulation. J Immunol 159(12):5862–5870

    CAS  PubMed  Google Scholar 

  18. 18.

    Mattner J, Debord KL, Ismail N, Goff RD, Cantu C 3rd, Zhou D, Saint-Mezard P, Wang V, Gao Y, Yin N, Hoebe K, Schneewind O, Walker D, Beutler B, Teyton L, Savage PB, Bendelac A (2005) Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434(7032):525–529. https://doi.org/10.1038/nature03408

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Wu D, Xing GW, Poles MA, Horowitz A, Kinjo Y, Sullivan B, Bodmer-Narkevitch V, Plettenburg O, Kronenberg M, Tsuji M, Ho DD, Wong CH (2005) Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells. Proc Natl Acad Sci USA 102(5):1351–1356. https://doi.org/10.1073/pnas.0408696102

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, Teneberg S, Wang D, Proia RL, Levery SB, Savage PB, Teyton L, Bendelac A (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306(5702):1786–1789. https://doi.org/10.1126/science.1103440

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Akimoto K, Natori T, Morita M (1993) Synthesis and stereochemistry of agelasphin-9b. Tetrahedron Lett 34:5593–5596

    CAS  Article  Google Scholar 

  22. 22.

    Natori T, Koezuka Y, Higa T (1993) Agelasphins, novel alpha-galactosylceramides from the marine sponge agelas mauritianus. Tetrahedron Lett 34:5591–5592

    CAS  Article  Google Scholar 

  23. 23.

    Kobayashi E, Motoki K, Uchida T, Fukushima H, Koezuka Y (1995) KRN7000, a novel immunomodulator, and its antitumor activities. Oncol Res 7(10–11):529–534

    CAS  PubMed  Google Scholar 

  24. 24.

    Morita M, Motoki K, Akimoto K, Natori T, Sakai T, Sawa E, Yamaji K, Koezuka Y, Kobayashi E, Fukushima H (1995) Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice. J Med Chem 38(12):2176–2187

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Yamaguchi Y, Motoki K, Ueno H, Maeda K, Kobayashi E, Inoue H, Fukushima H, Koezuka Y (1996) Enhancing effects of (2S,3S,4R)-1-O-(alpha-d-galactopyranosyl)-2-(N-hexacosanoylamino)-1,3,4-octadecanetriol (KRN7000) on antigen-presenting function of antigen-presenting cells and antimetastatic activity of KRN7000-pretreated antigen-presenting cells. Oncol Res 8(10–11):399–407

    CAS  PubMed  Google Scholar 

  26. 26.

    Kitamura H, Iwakabe K, Yahata T, Nishimura S, Ohta A, Ohmi Y, Sato M, Takeda K, Okumura K, Van Kaer L, Kawano T, Taniguchi M, Nishimura T (1999) The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med 189(7):1121–1128

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Tomura M, Yu WG, Ahn HJ, Yamashita M, Yang YF, Ono S, Hamaoka T, Kawano T, Taniguchi M, Koezuka Y, Fujiwara H (1999) A novel function of Valpha14+CD4+NKT cells: stimulation of IL-12 production by antigen-presenting cells in the innate immune system. J Immunol 163(1):93–101

    CAS  PubMed  Google Scholar 

  28. 28.

    Petersen TR, Sika-Paotonu D, Knight DA, Dickgreber N, Farrand KJ, Ronchese F, Hermans IF (2010) Potent anti-tumor responses to immunization with dendritic cells loaded with tumor tissue and an NKT cell ligand. Immunol Cell Biol 88(5):596–604. https://doi.org/10.1038/icb.2010.9

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Chang DH, Osman K, Connolly J, Kukreja A, Krasovsky J, Pack M, Hutchinson A, Geller M, Liu N, Annable R, Shay J, Kirchhoff K, Nishi N, Ando Y, Hayashi K, Hassoun H, Steinman RM, Dhodapkar MV (2005) Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med 201(9):1503–1517. https://doi.org/10.1084/jem.20042592

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ishikawa A, Motohashi S, Ishikawa E, Fuchida H, Higashino K, Otsuji M, Iizasa T, Nakayama T, Taniguchi M, Fujisawa T (2005) A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res 11(5):1910–1917

    CAS  Article  PubMed  Google Scholar 

  31. 31.

    Nicol AJ, Tazbirkova A, Nieda M (2011) Comparison of clinical and immunological effects of intravenous and intradermal administration of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells. Clin Cancer Res 17(15):5140–5151

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Nieda M, Okai M, Tazbirkova A, Lin H, Yamaura A, Ide K, Abraham R, Juji T, Macfarlane DJ, Nicol AJ (2004) Therapeutic activation of Valpha24+Vbeta11+NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood 103(2):383–389. https://doi.org/10.1182/blood-2003-04-1155

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Jager E, Nagata Y, Gnjatic S, Wada H, Stockert E, Karbach J, Dunbar PR, Lee SY, Jungbluth A, Jager D, Arand M, Ritter G, Cerundolo V, Dupont B, Chen YT, Old LJ, Knuth A (2000) Monitoring CD8 T cell responses to NY-ESO-1: correlation of humoral and cellular immune responses. Proc Natl Acad Sci USA 97(9):4760–4765

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, Wunderlich JR, Nahvi AV, Helman LJ, Mackall CL, Kammula US, Hughes MS, Restifo NP, Raffeld M, Lee CC, Levy CL, Li YF, El-Gamil M, Schwarz SL, Laurencot C, Rosenberg SA (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29(7):917–924

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Melief CJ, van der Burg SH (2008) Immunotherapy of established (pre)malignant disease by synthetic long peptide vaccines. Nat Rev Cancer 8(5):351–360

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Fujii S, Shimizu K, Kronenberg M, Steinman RM (2002) Prolonged IFN-gamma-producing NKT response induced with alpha-galactosylceramide-loaded DCs. Nat Immunol 3(9):867–874. https://doi.org/10.1038/ni827

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Giaccone G, Punt CJ, Ando Y, Ruijter R, Nishi N, Peters M, von Blomberg BM, Scheper RJ, van der Vliet HJ, van den Eertwegh AJ, Roelvink M, Beijnen J, Zwierzina H, Pinedo HM (2002) A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 8(12):3702–3709

    CAS  PubMed  Google Scholar 

  38. 38.

    McEwen-Smith RM, Salio M, Cerundolo V (2015) The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunol Res 3(5):425–435

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Snyder-Cappione JE, Tincati C, Eccles-James IG, Cappione AJ, Ndhlovu LC, Koth LL, Nixon DF (2010) A comprehensive ex vivo functional analysis of human NKT cells reveals production of MIP1-alpha and MIP1-beta, a lack of IL-17, and a Th1-bias in males. PLoS ONE 5(11):e15412

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Martinuzzi E, Scotto M, Enee E, Brezar V, Ribeil JA, van Endert P, Mallone R (2008) Serum-free culture medium and IL-7 costimulation increase the sensitivity of ELISpot detection. J Immunol Methods 333(1–2):61–70. https://doi.org/10.1016/j.jim.2008.01.003

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Moodie Z, Huang Y, Gu L, Hural J, Self SG (2006) Statistical positivity criteria for the analysis of ELISpot assay data in HIV-1 vaccine trials. J Immunol Methods 315(1–2):121–132

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    R Core Team (2015) R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.r-project.org. Accessed 1 Mar 2016

  43. 43.

    Richter J, Neparidze N, Zhang L, Nair S, Monesmith T, Sundaram R, Miesowicz F, Dhodapkar KM, Dhodapkar MV (2013) Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood 121(3):423–430. https://doi.org/10.1182/blood-2012-06-435503

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Exley MA, Hou R, Shaulov A, Tonti E, Dellabona P, Casorati G, Akbari O, Akman HO, Greenfield EA, Gumperz JE, Boyson JE, Balk SP, Wilson SB (2008) Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop. Eur J Immunol 38(6):1756–1766

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Gibney GT, Kudchadkar RR, DeConti RC, Thebeau MS, Czupryn MP, Tetteh L, Eysmans C, Richards A, Schell MJ, Fisher KJ, Horak CE, Inzunza HD, Yu B, Martinez AJ, Younos I, Weber JS (2015) Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma. Clin Cancer Res 21(4):712–720

    CAS  Article  PubMed  Google Scholar 

  46. 46.

    Krishnadas DK, Shusterman S, Bai F, Diller L, Sullivan JE, Cheerva AC, George RE, Lucas KG (2015) A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol Immunother 64(10):1251–1260

    CAS  Article  PubMed  Google Scholar 

  47. 47.

    Chen JL, Dawoodji A, Tarlton A, Gnjatic S, Tajar A, Karydis I, Browning J, Pratap S, Verfaille C, Venhaus RR, Pan L, Altman DG, Cebon JS, Old LL, Nathan P, Ottensmeier C, Middleton M, Cerundolo V (2015) NY-ESO-1 specific antibody and cellular responses in melanoma patients primed with NY-ESO-1 protein in ISCOMATRIX and boosted with recombinant NY-ESO-1 fowlpox virus. Int J Cancer 136(6):E590–E601

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Dhodapkar MV, Steinman RM, Sapp M, Desai H, Fossella C, Krasovsky J, Donahoe SM, Dunbar PR, Cerundolo V, Nixon DF, Bhardwaj N (1999) Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. J Clin Invest 104(2):173–180

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Bijker MS, van den Eeden SJ, Franken KL, Melief CJ, van der Burg SH, Offringa R (2008) Superior induction of anti-tumor CTL immunity by extended peptide vaccines involves prolonged, DC-focused antigen presentation. Eur J Immunol 38(4):1033–1042

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Seder RA, Darrah PA, Roederer M (2008) T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 8(4):247–258

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Yuan J, Gnjatic S, Li H, Powel S, Gallardo HF, Ritter E, Ku GY, Jungbluth AA, Segal NH, Rasalan TS, Manukian G, Xu Y, Roman RA, Terzulli SL, Heywood M, Pogoriler E, Ritter G, Old LJ, Allison JP, Wolchok JD (2008) CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci USA 105(51):20410–20415

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Berinstein NL, Karkada M, Oza AM, Odunsi K, Villella JA, Nemunaitis JJ, Morse MA, Pejovic T, Bentley J, Buyse M, Nigam R, Weir GM, MacDonald LD, Quinton T, Rajagopalan R, Sharp K, Penwell A, Sammatur L, Burzykowski T, Stanford MM, Mansour M (2015) Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients. Oncoimmunology 4(8):e1026529

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Lin Y, Gallardo HF, Ku GY, Li H, Manukian G, Rasalan TS, Xu Y, Terzulli SL, Old LJ, Allison JP, Houghton AN, Wolchok JD, Yuan J (2009) Optimization and validation of a robust human T-cell culture method for monitoring phenotypic and polyfunctional antigen-specific CD4 and CD8 T-cell responses. Cytotherapy 11(7):912–922

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Sabado RL, Pavlick A, Gnjatic S, Cruz CM, Vengco I, Hasan F, Spadaccia M, Darvishian F, Chiriboga L, Holman RM, Escalon J, Muren C, Escano C, Yepes E, Sharpe D, Vasilakos JP, Rolnitzsky L, Goldberg JD, Mandeli J, Adams S, Jungbluth A, Pan L, Venhaus R, Ott PA, Bhardwaj N (2015) Resiquimod as an immunologic adjuvant for NY-ESO-1 protein vaccination in patients with high-risk melanoma. Cancer Immunol Res 3(3):278–287

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to thank the Hugh Green Cytometry Core for flow cytometry support.

Funding

This work was funded by Health Research Council programme Grant 10/667 and the Health Research Council of New Zealand IROF fund 14/1003.

Author information

Affiliations

Authors

Contributions

Olivier Gasser developed the cellular methodology and performed the immunogenicity analyses. Katrina J. Sharples prepared the statistical plan and performed the analysis. Catherine Barrow chaired the trial management committee, oversaw patient recruitment and treated patients. Geoffrey M. Williams, P. Rod Dunbar, and Margaret A. Brimble developed the synthetic methodology and manufactured GMP grade peptides. Evelyn Bauer and Brigitta Mester developed the methodology and manufactured the cellular vaccine to GMP standards. Graham Caygill, Jeremy Jones, Colin M. Hayman, and Gavin F. Painter developed the synthetic methodology and manufactured α-GalCer to GMP standards. Catherine E. Wood, Marina Dzhelali, and Robert Weinkove provided local clinical support. Victoria A. Hinder, Jerome Macapagal, Monica McCusker, Catherine E. Wood, Marina Dzhelali, Catherine Barrow, Katrina J. Sharples, and Michael P. Findlay undertook clinical project development, management, analysis and reporting. Olivier Gasser, Katrina J. Sharples, P. Rod Dunbar, and Ian F. Hermans analyzed the immunological data and wrote the manuscript, with input from the other authors. Catherine Barrow, Katrina J. Sharples, Michael P. Findlay, P. Rod Dunbar, and Ian F. Hermans conceived and designed the study.

Corresponding author

Correspondence to Ian F. Hermans.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The study was approved by the Northern B Health and Disability Ethics Committee (Ref 13/NTB/5) and registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612001101875). The study was monitored by an independent Data Monitoring Committee appointed by the Health Research Council of New Zealand.

Informed consent

All patients gave written informed consent.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 4894 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gasser, O., Sharples, K.J., Barrow, C. et al. A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients. Cancer Immunol Immunother 67, 285–298 (2018). https://doi.org/10.1007/s00262-017-2085-9

Download citation

Keywords

  • Melanoma
  • Dendritic cell
  • NKT cell
  • α-Galactosylceramide
  • NY-ESO-1