Skip to main content

Advertisement

SpringerLink
Log in

A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Adoptive transfer of in vitro-expanded tumor-infiltrating lymphocytes (TIL) has shown great clinical benefit in patients with malignant melanoma. TIL therapy itself has little side effects, but conditioning chemo- or radiotherapy and postinfusion interleukin 2 (IL-2) injections are associated with severe adverse advents. We reasoned that combining TIL infusion with dendritic cell (DC) vaccination could circumvent the need for conditioning and IL-2 support and thus represent a milder treatment approach. Eight patients with stage IV melanoma were enrolled in the MAT01 study, consisting of vaccination with autologous tumor-lysate-loaded DC, followed by TIL infusion. Six of eight patients were treated according to protocol, while one patient received only TIL and one only DC. Treatments were well tolerated with a single grade 3 adverse event. The small study size precludes analysis of clinical responses, though interestingly one patient showed a complete remission and two had stable disease. Analysis of the infusion products revealed that mature DC were generated in all cases. TIL after expansion were CD3+ T cells, dominated by effector memory CD8+ cytotoxic T cells. Analysis of the T cell receptor repertoire revealed presence of highly dominant clones in most infusion products, and many of these could be detected in the circulation for weeks after T cell transfer. Here, we report the first combination of DC vaccination and TIL infusion in malignant melanoma. This combined treatment was safe and feasible, though after evaluating both clinical and immunological parameters, we expect that administration of lymphodepleting chemotherapy and IL-2 will likely increase treatment efficacy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

ACT:

Adoptive T cell transfer

AJCC:

American Joint Committee on Cancer

CDR3:

Complimentarity determining region 3

Ct:

Threshold cycle value

CR:

Complete response

CT:

Computer tomography

CYP:

Cyclophosphamide

DC:

Dendritic cells

DTH:

Delayed type hypersensitivity

GM-CSF:

Granulocyte macrophage colony-stimulating factor

IL:

Interleukin

MDSC:

Myeloid-derived suppressor cells

MRI:

Magnetic resonance imaging

LN:

Lymph node

OS:

Overall survival

PBMC:

Peripheral blood mononuclear cells

PD:

Progressive disease

PET:

Positron emission tomography

PR:

Partial response

RESIST:

Response evaluation criteria in solid tumors

SD:

Stable disease

SOP:

Standard operating procedure

TCR:

T cell receptor

TIL:

Tumor-infiltrating lymphocytes

TNF:

Tumor necrosis factor

TNM:

Tumor node metastasis

Tregs:

Regulatory T cells

SC:

Subcutaneous

WHO/ECOG:

World Health Organization/Eastern Cooperative Oncology Group

References

  1. Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L, Levy D, Kubi A, Hovav E, Chermoshniuk N, Shalmon B, Hardan I, Catane R, Markel G, Apter S, Ben-Nun A, Kuchuk I, Shimoni A, Nagler A, Schachter J (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16(9):2646–2655

    Article  PubMed  CAS  Google Scholar 

  2. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23(10):2346–2357

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  4. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH (2011) T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3(95):95ra73

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Zhao Y, Moon E, Carpenito C, Paulos CM, Liu X, Brennan AL, Chew A, Carroll RG, Scholler J, Levine BL, Albelda SM, June CH (2010) Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res 70(22):9053–9061

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365(8):725–733

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Dudley ME, Gross CA, Langhan MM, Garcia MR, Sherry RM, Yang JC, Phan GQ, Kammula US, Hughes MS, Citrin DE, Restifo NP, Wunderlich JR, Prieto PA, Hong JJ, Langan RC, Zlott DA, Morton KE, White DE, Laurencot CM, Rosenberg SA (2010) CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma. Clin Cancer Res 16(24):6122–6131

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  8. Johnson LA, Morgan RA, Dudley ME, Cassard L, Yang JC, Hughes MS, Kammula US, Royal RE, Sherry RM, Wunderlich JR, Lee CC, Restifo NP, Schwarz SL, Cogdill AP, Bishop RJ, Kim H, Brewer CC, Rudy SF, VanWaes C, Davis JL, Mathur A, Ripley RT, Nathan DA, Laurencot CM, Rosenberg SA (2009) Gene therapy with human and mouse T cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114(3):535–546

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Parkhurst MR, Yang JC, Langan RC, Dudley ME, Nathan DA, Feldman SA, Davis JL, Morgan RA, Merino MJ, Sherry RM, Hughes MS, Kammula US, Phan GQ, Lim RM, Wank SA, Restifo NP, Robbins PF, Laurencot CM, Rosenberg SA (2011) T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19(3):620–626

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Muranski P, Boni A, Wrzesinski C, Citrin DE, Rosenberg SA, Childs R, Restifo NP (2006) Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? Nat Clin Pract Oncol 3(12):668–681

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  12. Petrella T, Quirt I, Verma S, Haynes AE, Charette M, Bak K (2007) Single-agent interleukin-2 in the treatment of metastatic melanoma: a systematic review. Cancer Treat Rev 33(5):484–496

    Article  PubMed  CAS  Google Scholar 

  13. Ellebaek E, Iversen TZ, Junker N, Donia M, Engell-Noerregaard L, Met O, Holmich LR, Andersen RS, Hadrup SR, Andersen MH, thor Straten P, Svane IM (2012) Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. J Transl Med 10:169

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Galluzzi L, Senovilla L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G (2012) Trial watch: dendritic cell-based interventions for cancer therapy. Oncoimmunology 1(7):1111–1134

    Article  PubMed  PubMed Central  Google Scholar 

  15. Rosenberg SA, Yang JC, Restifo NP (2004) Cancer immunotherapy: moving beyond current vaccines. Nat Med 10(9):909–915

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Lee WC, Wang HC, Hung CF, Huang PF, Lia CR, Chen MF (2005) Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: a clinical trial. J Immunother 28(5):496–504

    Article  PubMed  Google Scholar 

  17. Lopez MN, Pereda C, Segal G, Munoz L, Aguilera R, Gonzalez FE, Escobar A, Ginesta A, Reyes D, Gonzalez R, Mendoza-Naranjo A, Larrondo M, Compan A, Ferrada C, Salazar-Onfray F (2009) Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol 27(6):945–952

    Article  PubMed  CAS  Google Scholar 

  18. Ridolfi L, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E, Scarpi E, Guidoboni M, Migliori G, Sanna S, Tauceri F, Verdecchia GM, Riccobon A, Valmorri L, Ridolfi R (2010) Unexpected high response rate to traditional therapy after dendritic cell-based vaccine in advanced melanoma: update of clinical outcome and subgroup analysis. Clin Dev Immunol 2010:504979

    Article  PubMed  PubMed Central  Google Scholar 

  19. Salcedo M, Bercovici N, Taylor R, Vereecken P, Massicard S, Duriau D, Vernel-Pauillac F, Boyer A, Baron-Bodo V, Mallard E, Bartholeyns J, Goxe B, Latour N, Leroy S, Prigent D, Martiat P, Sales F, Laporte M, Bruyns C, Romet-Lemonne JL, Abastado JP, Lehmann F, Velu T (2006) Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate. Cancer Immunol Immunother 55(7):819–829

    Article  PubMed  CAS  Google Scholar 

  20. Schwaab T, Schwarzer A, Wolf B, Crocenzi TS, Seigne JD, Crosby NA, Cole BF, Fisher JL, Uhlenhake JC, Mellinger D, Foster C, Szczepiorkowski ZM, Webber SM, Schned AR, Harris RD, Barth RJ Jr, Heaney JA, Noelle RJ, Ernstoff MS (2009) Clinical and immunologic effects of intranodal autologous tumor lysate-dendritic cell vaccine with Aldesleukin (Interleukin 2) and IFN-{alpha}2a therapy in metastatic renal cell carcinoma patients. Clin Cancer Res 15(15):4986–4992

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Boniface JD, Poschke I, Mao Y, Kiessling R (2012) Tumor-dependent down-regulation of the zeta-chain in T cells is detectable in early breast cancer and correlates with immune cell function. Int J Cancer 131(1):129–139

    Article  PubMed  Google Scholar 

  22. Poschke I, De Boniface J, Mao Y, Kiessling R (2012) Tumor-induced changes in the phenotype of blood-derived and tumor-associated T cells of early stage breast cancer patients. Int J Cancer 131(7):1611–1620

    Article  PubMed  CAS  Google Scholar 

  23. Palma M, Hansson L, Choudhury A, Nasman-Glaser B, Eriksson I, Adamson L, Rossmann E, Widen K, Horvath R, Kokhaei P, Vertuani S, Mellstedt H, Osterborg A (2012) Vaccination with dendritic cells loaded with tumor apoptotic bodies (Apo-DC) in patients with chronic lymphocytic leukemia: effects of various adjuvants and definition of immune response criteria. Cancer Immunol Immunother 61(6):865–879

    Article  PubMed  CAS  Google Scholar 

  24. Adamson L, Palma M, Choudhury A, Eriksson I, Nasman-Glaser B, Hansson M, Hansson L, Kokhaei P, Osterborg A, Mellstedt H (2009) Generation of a dendritic cell-based vaccine in chronic lymphocytic leukaemia using CliniMACS platform for large-scale production. Scand J Immunol 69(6):529–536

    Article  PubMed  CAS  Google Scholar 

  25. Poschke I, Mao Y, Adamson L, Salazar-Onfray F, Masucci G, Kiessling R (2012) Myeloid-derived suppressor cells impair the quality of dendritic cell vaccines. Cancer Immunol Immunother 61(6):827–838

    Article  PubMed  CAS  Google Scholar 

  26. Koike N, Pilon-Thomas S, Mule JJ (2008) Nonmyeloablative chemotherapy followed by T cell adoptive transfer and dendritic cell-based vaccination results in rejection of established melanoma. J Immunother 31(4):402–412

    Article  PubMed  Google Scholar 

  27. Lutz-Nicoladoni C, Wallner S, Stoitzner P, Pircher M, Gruber T, Wolf AM, Gastl G, Penninger JM, Baier G, Wolf D (2012) Reinforcement of cancer immunotherapy by adoptive transfer of cblb-deficient CD8+ T cells combined with a DC vaccine. Immunol Cell Biol 90(1):130–134

    Article  PubMed  CAS  Google Scholar 

  28. Park MY, Kim CH, Sohn HJ, Oh ST, Kim SG, Kim TG (2007) The optimal interval for dendritic cell vaccination following adoptive T cell transfer is important for boosting potent anti-tumor immunity. Vaccine 25(42):7322–7330

    Article  PubMed  CAS  Google Scholar 

  29. Song S, Zhang K, You H, Wang J, Wang Z, Yan C, Liu F (2010) Significant anti-tumour activity of adoptively transferred T cells elicited by intratumoral dendritic cell vaccine injection through enhancing the ratio of CD8(+) T cell/regulatory T cells in tumour. Clin Exp Immunol 162(1):75–83

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Tamai H, Watanabe S, Zheng R, Deguchi K, Cohen PA, Koski GK, Shu S (2008) Effective treatment of spontaneous metastases derived from a poorly immunogenic murine mammary carcinoma by combined dendritic-tumor hybrid vaccination and adoptive transfer of sensitized T cells. Clin Immunol 127(1):66–77

    Article  PubMed  CAS  Google Scholar 

  31. Kandalaft LE, Powell DJ Jr, Chiang CL, Tanyi J, Kim S, Bosch M, Montone K, Mick R, Levine BL, Torigian DA, June CH, Coukos G (2013) Autologous lysate-pulsed dendritic cell vaccination followed by adoptive transfer of vaccine-primed ex vivo co-stimulated T cells in recurrent ovarian cancer. Oncoimmunology 2(1):e22664

    Article  PubMed  PubMed Central  Google Scholar 

  32. Goff SL, Smith FO, Klapper JA, Sherry R, Wunderlich JR, Steinberg SM, White D, Rosenberg SA, Dudley ME, Yang JC (2010) Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL. J Immunother 33(8):840–847

    Article  PubMed  Google Scholar 

  33. Rosenberg SA, Dudley ME (2009) Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21(2):233–240

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. 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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U, Robbins PF, Huang J, Citrin DE, Leitman SF, Wunderlich J, Restifo NP, Thomasian A, Downey SG, Smith FO, Klapper J, Morton K, Laurencot C, White DE, Rosenberg SA (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26(32):5233–5239

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. de Vries IJ, Castelli C, Huygens C, Jacobs JF, Stockis J, Schuler-Thurner B, Adema GJ, Punt CJ, Rivoltini L, Schuler G, Coulie PG, Lucas S (2011) Frequency of circulating Tregs with demethylated FOXP3 intron 1 in melanoma patients receiving tumor vaccines and potentially Treg-depleting agents. Clin Cancer Res 17(4):841–848

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank B. Näsman-Glaser and K. Heimersson for their expert technical assistance. R. Tell is supported by a 50 % research position from the Karolinska Institutet Thematic Network IMTAC. The study was supported by grants to R. Kiessling from the Swedish Cancer Society (120598 Cancerfonden), the Cancer Society of Stockholm (121103 Cancerföreningen, Radiumhemmets Forskningsfonder), Torsten Söderbergs stiftelse, the Swedish Medical Research Council (K2011-66X-15387-07-3 VR), an ALF-Project grant from Stockholm City Council (20110070 ALF Medicin 2012), the Knut and Alice Wallenberg Foundations and a grant from Magnus Bergvalls Foundation to T. Lövgren.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden

    Isabel Poschke, Tanja Lövgren, Lars Adamson, Maria Nyström, Emilia Andersson, Johan Hansson, Roger Tell, Giuseppe V. Masucci & Rolf Kiessling

  2. German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Isabel Poschke

Authors
  1. Isabel Poschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tanja Lövgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lars Adamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Nyström
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Emilia Andersson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Johan Hansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roger Tell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giuseppe V. Masucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rolf Kiessling
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isabel Poschke.

Additional information

Giuseppe V. Masucci and Rolf Kiessling have contributed equally to this study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 161 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Poschke, I., Lövgren, T., Adamson, L. et al. A phase I clinical trial combining dendritic cell vaccination with adoptive T cell transfer in patients with stage IV melanoma. Cancer Immunol Immunother 63, 1061–1071 (2014). https://doi.org/10.1007/s00262-014-1575-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1575-2

Keywords

Search

Navigation