Abstract
The aim of this study was to determine the immunogenicity and antitumor activity of autologous, tumor-derived heat shock protein gp96-peptide complex vaccine (HSPPC-96; Oncophage®) given with GM-CSF and IFN-α in pre-treated metastatic (AJCC stage IV) melanoma patients. Patients underwent surgical resection of metastatic lesions for HSPPC-96 production. HSPPC-96 was administered subcutaneously (s.c.) in four weekly intervals (first cycle). Patients with more available vaccine and absence of progressive disease received four additional injections in 2-week intervals (second cycle) or more. GM-CSF was given s.c. at the same site at days –1, 0 and +1, while IFN-α (3 MU) was administered s.c. at a different site at days +4 and +6. Antigen-specific anti-melanoma T and NK lymphocyte response was assessed by enzyme-linked immunospot assay on peripheral blood mononuclear cells obtained before and after vaccination. Thirty-eight patients were enrolled, 20 received at least four injections (one cycle) of HSPPC-96 and were considered assessable. Toxicity was mild and most treatment-related adverse events were local erythema and induration at the injection site. Patients receiving at least four injections of HSPPC-96 were considered evaluable for clinical response: of the 18 patients with measurable disease post surgery, 11 showed stable disease (SD). The ELISPOT assay revealed an increased class I HLA-restricted T and NK cell-mediated post-vaccination response in 5 out of 17 and 12 out of the 18 patients tested, respectively. Four of the five class I HLA-restricted T cell responses fall in the group of SD patients. Vaccination with autologous HSPPC-96 together with GM-CSF and IFN-α is feasible and accompanied by mild local and systemic toxicity. Both tumor-specific T cell-mediated and NK cell responses were generated in a proportion of patients. Clinical activity was limited to SD. However, both immunological and clinical responses were not improved as compared with those recorded in a previous study investigating HSPPC-96 monotherapy.
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Abbreviations
- AEs:
-
adverse events
- DTH:
-
delayed-type hypersensitivity
- ELISPOT:
-
enzyme-linked immunospot
- GM-CSF:
-
granulocyte/macrophage-colony stimulating factor
- HSP:
-
heat shock proteins
- HSPPC-96:
-
heat shock proteins peptide complexes gp96
- IFN:
-
interferon
- IHC:
-
immunohistochemistry
- IL:
-
interleukin
- NK:
-
natural killer
- PBMC:
-
peripheral blood mononuclear cells
- RECIST:
-
response evaluation criteria in solid tumors
- s.c.:
-
subcutaneously
References
Belli F, Testori A, Rivoltini L, Maio M, Andreola G, Sertoli MR, Gallino P, Piris A, Cattelan A, Lazzari I, Carrabba M, Scita G et al (2002) Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: Clinical and immunologic findings. J Clin Oncol 20:4169–4180
Parmiani G, Testori A, Maio M, Castelli C, Rivoltini L, Pilla L, Belli F, Mazzaferro V, Coppa J, Patuzzo R, Sertoli MR, Hoos A et al (2004) Heat-shock proteins and their use as anti-cancer vaccines. Clin Cancer Res 10:8142–8146
Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman RM (1992) Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte-macrophage colony stimulating factor. J Exp Med 176:1693–1699
Soiffer R, Lynch T, Mihm M, Jung K, Rhuda C, Schmollinger JC, Hodi FS, Liebster L, Lam P, Mentzer S, Singer S, Tanabe KK et al (1998) Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage-colony stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc Natl Acad Sci USA 95:13141–13146
Weber J, Sondak VK, Scotland R, Phillip R, Wang F, Rubio V, Stuge TB, Groshen SG, Gee C, Jeffery GG, Sian S, Lee PP (2003) Granulocyte-macrophage-colony stimulating factor added to a multipeptide vaccine for resected stage II melanoma. Cancer 97:186–200
Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S (2000) Escape of human solid tumors from T cell recognition: molecular mechanisms and functional significance. Adv Immunol 74:181–273
Giacomini M, Fraioli R, Calabro AM, DiFilippo F, Natali PG (1991) Class I major histocompatibility complex enhancement by recombinant leukocyte interferon in the peripheral blood mononuclear cells and plasma of melanoma patients. Cancer Res 51:652–656
Therasse P, Arbuck SG, Eisenhauer EA (2000) 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 92:205–216
Mazzaferro V, Coppa J, Carrabba MG, Rivoltini L, Schiavo M, Regalia E, Mariani L, Camerini T, Marchianò A, Andreola S, Camerini R, Corsi M et al (2003) Vaccination with autologous tumor-derived heat-shock protein Gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 9:3235–3245
Pass HA, Schwarz SL, Wunderlich JR, Rosenberg SA (1998) Immunization of patients with melanoma peptide vaccines: Immunologic assessment using the ELISPOT assay. Cancer J Sci Am 4:316–323
Lewis JJ, Janetzki S, Schaed S, Panageas KS, Wang S, Williams L, Meyers M, Butterworth L, Livingston PO, Chapman PB, Houghton AN (2000) Evaluation of CD8+ T-cell frequency by the ELISPOT assay in healthy individuals and in patients with metastatic melanoma immunized with tyrosinase peptide. Int J Cancer 87:391–398
Scheibenbogen C, Romero P, Rivoltini L, Herr W, Schmittel A, Cerottini JC, Woelfel T, Eggermont AMM, Keilholz U (2000) Quantification of antigen-reactive T cells in peripheral blood by IFN-γ-ELISPOT and chromium release assay: a four centre comparative trial. J Immunol Methods 244:81–89
Rivoltini L, Castelli C, Carrabba M, Mazzaferro V, Pilla L, Huber V, Coppa J, Gallino G, Scheibenbogen C, Squarcina P, Cova A, Camerini R et al (2003) Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma-and colon carcinoma-specific T cells. J Immunol 171:3467–3474
Kawakami Y, Eliyahu S, Delgado CH, Robbins PF, Rivoltini L, Topalian SL, Miki T, Rosenbergs SA (1994) Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T cells infiltrating into tumor. Proc Natl Acad Sci USA 91:3515–3519
Mihm MC Jr, Clemente CG, Cascinelli N (1996) Tumor infiltrating lymphocytes in lymph node melanoma metastases: a histopathologic prognostic indicator and an expression of local immune response. Lab Invest 74:43–47
Moretta L, Bottino C, Pende D, Mingari MC, Biassoni R, Moretta A (2002) Human natural killer cells: their origin, receptors and function. Eur J Immunol 32:1205–1211
Tamura Y, Peng P, Liu K, Srivastava PK (1997) Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278:117–120
Pilla L, Squarcina P, Coppa J, Mazzaferro V, Huber V, Pende D, Maccalli C, Sovena G, Mariani L, Castelli C, Parmiani G, Rivoltini L (2005) Natural killer and NK-Like T-cell activation in colorectal carcinoma patients treated with autologous tumor-derived heat shock protein 96. Cancer Res 65:3942–3949
Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK (2000) Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 88:232–238
Gastpar R, Gross C, Rossbacher L, Ellwart J, Riegger J, Multhoff G (2004) The cell surface-localized heat shock protein 70 epitope TKD induces migration and cytolytic activity selectively in human NK cells. J Immunol 172:972–980
Scheibenbogen C, Schmittel A, Keilhjolz U, Allgauer T, Hofmann U, Max R, Thiel E, Schadendorf D (2000) Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. J Immunother 23:275–281
Slingluff CL, Petroni GR, Yamshikov GV, Barnd DL, Eastham S, Galavotti H, Patterson JW, Deacon DH, Hibbitts S, Teates D, Neese PY, Grosh WW et al (2003) Clinical and immunological results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony stimulating factor in adjuvant or pulsed on dendritic cells. J Clin Oncol 21:4016–4026
Ullenhag GJ, Frodin J-E, Mosolitis S, Kiaii S, Hassan M, Bonnet MC, Moingeon P, Mellstedt H, Rabbani H (2003) Immunization of colorectal carcinoma patients with a recombinant canarypox virus expressing the tumor antigen Ep-CAM/KSA (ALVAC-KSA) and granulocyte macrophage colony-stimulating factor induced a tumor-specific cellular immune response. Clin Cancer Res 9:2447–2456
Von Meheren M, Arlen P, Gulley J, Rogatko A, Cooper HS, Meropol NJ, Alpaugh RK, Davey M, McLaughlin S, Beard MT, Tsang KY, Schlom J, Weiner LM (2001) The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. Clin Cancer Res 7:1181–1191
Dillman RO, Wiemann M, Nayak SK, deLeon C, Hood K, DePriest C (2003) Interferon-gamma or granulocyte-macrophage colony-stimulating factor administered as adjuvants with a vaccine of irradiated autologous tumor cells from short-term cell line cultures: a randomized phase 2 trial of the cancer biotherapy research group. J Immunother 26:367–373
Pansky A, Hildebrand P, Fasler-Kan E, Beglinger C, Heim MH (2000) Defective JAK-STAT signal transduction pathway in melanoma cell resistant to growth inhibition by interferon-α. Int J Cancer 85:720–725
Acknowledgements
This study was supported by Antigenics Inc. (Lexington, MA, USA). The authors wish to thanks Drs Claudia Lombardo and Fernando Ravagnani for HLA typing, Mr Giulio Pezzaglia and Mr Gianluigi Rigamonti for excellent nursing work, and Ms Grazia Barp for editorial assistance.
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L.P. and R.P. have equally contributed to the work.
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Pilla, L., Patuzzo, R., Rivoltini, L. et al. A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-α in metastatic melanoma patients. Cancer Immunol Immunother 55, 958–968 (2006). https://doi.org/10.1007/s00262-005-0084-8
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DOI: https://doi.org/10.1007/s00262-005-0084-8