Skip to main content
Top
Published in: Cancer Immunology, Immunotherapy 6/2011

Open Access 01-06-2011 | Original article

hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes

Authors: Else M. Inderberg Suso, Svein Dueland, Anne-Marie Rasmussen, Turid Vetrhus, Steinar Aamdal, Gunnar Kvalheim, Gustav Gaudernack

Published in: Cancer Immunology, Immunotherapy | Issue 6/2011

Login to get access

Abstract

Immunotherapy targeting the hTERT subunit of telomerase has been shown to induce robust immune responses in cancer patients after vaccination with single hTERT peptides. Vaccination with dendritic cells (DCs) transfected with hTERT mRNA has the potential to induce strong immune responses to multiple hTERT epitopes and is therefore an attractive approach to more potent immunotherapy. Blood samples from such patients provide an opportunity for identification of new, in vivo processed T-cell epitopes that may be clinically relevant. A 62-year-old female patient underwent radical surgery for a pancreatic adenocarcinoma. After relapse, she obtained stable disease on gemcitabine treatment. Due to severe neutropenia, the chemotherapy was terminated. The patient has subsequently been treated with autologous DCs loaded with hTERT mRNA for 3 years. Immunomonitoring was performed at regular intervals following start of vaccination and clinical outcome measured by CT and PET/CT evaluation. The patient developed an immune response against several hTERT-derived Th and CTL epitopes. She presently shows no evidence of active disease based on PET/CT scans. No serious adverse events were experienced and the patient continues to receive regular booster injections. We here provide evidence for the induction of hTERT-specific immune responses following vaccination of a pancreas cancer patient with DCs loaded with hTERT mRNA. These responses are associated with complete remission. A thorough analysis of this patient immune response has provided a unique opportunity to identify novel epitopes, associated with clinical effects. These will be included in future hTERT vaccines.
Literature
1.
go back to reference Philip PA, Mooney M, Jaffe D, Eckhardt G, Moore M, Meropol N, Emens L, O’Reilly E, Korc M, Ellis L, Benedetti J, Rothenberg M, Willett C, Tempero M, Lowy A, Abbruzzese J, Simeone D, Hingorani S, Berlin J, Tepper J (2009) Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol 27(33):5660–5669PubMedCrossRef Philip PA, Mooney M, Jaffe D, Eckhardt G, Moore M, Meropol N, Emens L, O’Reilly E, Korc M, Ellis L, Benedetti J, Rothenberg M, Willett C, Tempero M, Lowy A, Abbruzzese J, Simeone D, Hingorani S, Berlin J, Tepper J (2009) Consensus report of the national cancer institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol 27(33):5660–5669PubMedCrossRef
2.
go back to reference Wong HH, Lemoine NR (2008) Biological approaches to therapy of pancreatic cancer. Pancreatology 8(4–5):431–461PubMedCrossRef Wong HH, Lemoine NR (2008) Biological approaches to therapy of pancreatic cancer. Pancreatology 8(4–5):431–461PubMedCrossRef
3.
go back to reference Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, Buanes T, Gaudernack G (2006) Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer 95(11):1474–1482PubMedCrossRef Bernhardt SL, Gjertsen MK, Trachsel S, Moller M, Eriksen JA, Meo M, Buanes T, Gaudernack G (2006) Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer 95(11):1474–1482PubMedCrossRef
4.
go back to reference Bhagwandin VJ, Shay JW (2009) Pancreatic cancer stem cells: fact or fiction? Biochim Biophys Acta 1792(4):248–259PubMed Bhagwandin VJ, Shay JW (2009) Pancreatic cancer stem cells: fact or fiction? Biochim Biophys Acta 1792(4):248–259PubMed
5.
go back to reference Viatte S, Alves PM, Romero P (2006) Reverse immunology approach for the identification of CD8 T-cell-defined antigens: advantages and hurdles. Immunol Cell Biol 84(3):318–330PubMedCrossRef Viatte S, Alves PM, Romero P (2006) Reverse immunology approach for the identification of CD8 T-cell-defined antigens: advantages and hurdles. Immunol Cell Biol 84(3):318–330PubMedCrossRef
6.
go back to reference Saeboe-Larssen S, Fossberg E, Gaudernack G (2002) mRNA-based electrotransfection of human dendritic cells and induction of cytotoxic T lymphocyte responses against the telomerase catalytic subunit (hTERT). J Immunol Methods 259 (1–2):191–203 Saeboe-Larssen S, Fossberg E, Gaudernack G (2002) mRNA-based electrotransfection of human dendritic cells and induction of cytotoxic T lymphocyte responses against the telomerase catalytic subunit (hTERT). J Immunol Methods 259 (1–2):191–203
7.
go back to reference Su Z, Dannull J, Yang BK, Dahm P, Coleman D, Yancey D, Sichi S, Niedzwiecki D, Boczkowski D, Gilboa E, Vieweg J (2005) Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 174(6):3798–3807PubMed Su Z, Dannull J, Yang BK, Dahm P, Coleman D, Yancey D, Sichi S, Niedzwiecki D, Boczkowski D, Gilboa E, Vieweg J (2005) Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 174(6):3798–3807PubMed
8.
go back to reference Kyte JA, Mu L, Aamdal S, Kvalheim G, Dueland S, Hauser M, Gullestad HP, Ryder T, Lislerud K, Hammerstad H, Gaudernack G (2006) Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA. Cancer Gene Ther 13(10):905–918PubMedCrossRef Kyte JA, Mu L, Aamdal S, Kvalheim G, Dueland S, Hauser M, Gullestad HP, Ryder T, Lislerud K, Hammerstad H, Gaudernack G (2006) Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumor-mRNA. Cancer Gene Ther 13(10):905–918PubMedCrossRef
9.
go back to reference Alldawi L, Takahashi M, Narita M, Ayres F, Tsukada N, Osman Y, Furukawa T, Aizawa Y (2005) Effect of prostaglandin E2, lipopolysaccharide, IFN-gamma and cytokines on the generation and function of fast-DC. Cytotherapy 7(2):195–202PubMedCrossRef Alldawi L, Takahashi M, Narita M, Ayres F, Tsukada N, Osman Y, Furukawa T, Aizawa Y (2005) Effect of prostaglandin E2, lipopolysaccharide, IFN-gamma and cytokines on the generation and function of fast-DC. Cytotherapy 7(2):195–202PubMedCrossRef
10.
go back to reference Tanaka F, Yamaguchi H, Haraguchi N, Mashino K, Ohta M, Inoue H, Mori M (2006) Efficient induction of specific cytotoxic T lymphocytes to tumor rejection peptide using functional matured 2 day-cultured dendritic cells derived from human monocytes. Int J Oncol 29(5):1263–1268PubMed Tanaka F, Yamaguchi H, Haraguchi N, Mashino K, Ohta M, Inoue H, Mori M (2006) Efficient induction of specific cytotoxic T lymphocytes to tumor rejection peptide using functional matured 2 day-cultured dendritic cells derived from human monocytes. Int J Oncol 29(5):1263–1268PubMed
11.
go back to reference Ho WY, Nguyen HN, Wolfl M, Kuball J, Greenberg PD (2006) In vitro methods for generating CD8+ T-cell clones for immunotherapy from the naive repertoire. J Immunol Methods 310(1–2):40–52PubMedCrossRef Ho WY, Nguyen HN, Wolfl M, Kuball J, Greenberg PD (2006) In vitro methods for generating CD8+ T-cell clones for immunotherapy from the naive repertoire. J Immunol Methods 310(1–2):40–52PubMedCrossRef
12.
go back to reference Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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(3):205–216 Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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(3):205–216
13.
go back to reference Kyte JA, Kvalheim G, Aamdal S, Saeboe-Larssen S, Gaudernack G (2005) Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. Cancer Gene Ther 12(6):579–591PubMedCrossRef Kyte JA, Kvalheim G, Aamdal S, Saeboe-Larssen S, Gaudernack G (2005) Preclinical full-scale evaluation of dendritic cells transfected with autologous tumor-mRNA for melanoma vaccination. Cancer Gene Ther 12(6):579–591PubMedCrossRef
14.
go back to reference Schroers R, Huang XF, Hammer J, Zhang J, Chen SY (2002) Identification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4+ T-helper cells. Cancer Res 62(9):2600–2605PubMed Schroers R, Huang XF, Hammer J, Zhang J, Chen SY (2002) Identification of HLA DR7-restricted epitopes from human telomerase reverse transcriptase recognized by CD4+ T-helper cells. Cancer Res 62(9):2600–2605PubMed
15.
go back to reference Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358(25):2698–2703PubMedCrossRef Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, Jungbluth A, Gnjatic S, Thompson JA, Yee C (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358(25):2698–2703PubMedCrossRef
16.
go back to reference Welters MJ, Kenter GG, Piersma SJ, Vloon AP, Lowik MJ, Berends-van der Meer DM, Drijfhout JW, Valentijn AR, Wafelman AR, Oostendorp J, Fleuren GJ, Offringa R, Melief CJ, van der Burg SH (2008) Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res 14(1):178–187PubMedCrossRef Welters MJ, Kenter GG, Piersma SJ, Vloon AP, Lowik MJ, Berends-van der Meer DM, Drijfhout JW, Valentijn AR, Wafelman AR, Oostendorp J, Fleuren GJ, Offringa R, Melief CJ, van der Burg SH (2008) Induction of tumor-specific CD4+ and CD8+ T-cell immunity in cervical cancer patients by a human papillomavirus type 16 E6 and E7 long peptides vaccine. Clin Cancer Res 14(1):178–187PubMedCrossRef
17.
go back to reference Xie Y, Akpinarli A, Maris C, Hipkiss EL, Lane M, Kwon EK, Muranski P, Restifo NP, Antony PA (2010) Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J Exp Med 207(3):651–667 Xie Y, Akpinarli A, Maris C, Hipkiss EL, Lane M, Kwon EK, Muranski P, Restifo NP, Antony PA (2010) Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma. J Exp Med 207(3):651–667
18.
go back to reference Nakanishi Y, Lu B, Gerard C, Iwasaki A (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462(7272):510–513PubMedCrossRef Nakanishi Y, Lu B, Gerard C, Iwasaki A (2009) CD8(+) T lymphocyte mobilization to virus-infected tissue requires CD4(+) T-cell help. Nature 462(7272):510–513PubMedCrossRef
19.
go back to reference Faure F, Mantegazza A, Sadaka C, Sedlik C, Jotereau F, Amigorena S (2009) Long-lasting cross-presentation of tumor antigen in human DC. Eur J Immunol 39(2):380–390PubMedCrossRef Faure F, Mantegazza A, Sadaka C, Sedlik C, Jotereau F, Amigorena S (2009) Long-lasting cross-presentation of tumor antigen in human DC. Eur J Immunol 39(2):380–390PubMedCrossRef
20.
go back to reference Toes RE, Offringa R, Blom RJ, Melief CJ, Kast WM (1996) Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction. Proc Natl Acad Sci USA 93(15):7855–7860PubMedCrossRef Toes RE, Offringa R, Blom RJ, Melief CJ, Kast WM (1996) Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction. Proc Natl Acad Sci USA 93(15):7855–7860PubMedCrossRef
21.
go back to reference Toes RE, van der Voort EI, Schoenberger SP, Drijfhout JW, van Bloois L, Storm G, Kast WM, Offringa R, Melief CJ (1998) Enhancement of tumor outgrowth through CTL tolerization after peptide vaccination is avoided by peptide presentation on dendritic cells. J Immunol 160(9):4449–4456PubMed Toes RE, van der Voort EI, Schoenberger SP, Drijfhout JW, van Bloois L, Storm G, Kast WM, Offringa R, Melief CJ (1998) Enhancement of tumor outgrowth through CTL tolerization after peptide vaccination is avoided by peptide presentation on dendritic cells. J Immunol 160(9):4449–4456PubMed
22.
go back to reference Bijker MS, van den Eeden SJ, Franken KL, Melief CJ, Offringa R, van der Burg SH (2007) CD8+ CTL priming by exact peptide epitopes in incomplete Freund’s adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J Immunol 179(8):5033–5040PubMed Bijker MS, van den Eeden SJ, Franken KL, Melief CJ, Offringa R, van der Burg SH (2007) CD8+ CTL priming by exact peptide epitopes in incomplete Freund’s adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J Immunol 179(8):5033–5040PubMed
23.
go back to reference Zeng G, Li Y, El-Gamil M, Sidney J, Sette A, Wang RF, Rosenberg SA, Robbins PF (2002) Generation of NY-ESO-1-specific CD4+ and CD8+ T cells by a single peptide with dual MHC class I and class II specificities: a new strategy for vaccine design. Cancer Res 62(13):3630–3635PubMed Zeng G, Li Y, El-Gamil M, Sidney J, Sette A, Wang RF, Rosenberg SA, Robbins PF (2002) Generation of NY-ESO-1-specific CD4+ and CD8+ T cells by a single peptide with dual MHC class I and class II specificities: a new strategy for vaccine design. Cancer Res 62(13):3630–3635PubMed
24.
go back to reference Brunsvig PF, Aamdal S, Gjertsen MK, Kvalheim G, Markowski-Grimsrud CJ, Sve I, Dyrhaug M, Trachsel S, Moller M, Eriksen JA, Gaudernack G (2006) Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother 55(12):1553–1564PubMedCrossRef Brunsvig PF, Aamdal S, Gjertsen MK, Kvalheim G, Markowski-Grimsrud CJ, Sve I, Dyrhaug M, Trachsel S, Moller M, Eriksen JA, Gaudernack G (2006) Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother 55(12):1553–1564PubMedCrossRef
25.
go back to reference Nowak AK, Lake RA, Marzo AL, Scott B, Heath WR, Collins EJ, Frelinger JA, Robinson BW (2003) Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol 170(10):4905–4913PubMed Nowak AK, Lake RA, Marzo AL, Scott B, Heath WR, Collins EJ, Frelinger JA, Robinson BW (2003) Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells. J Immunol 170(10):4905–4913PubMed
26.
go back to reference Danet-Desnoyers GA, Luongo JL, Bonnet DA, Domchek SM, Vonderheide RH (2005) Telomerase vaccination has no detectable effect on SCID-repopulating and colony-forming activities in the bone marrow of cancer patients. Exp Hematol 33(11):1275–1280PubMedCrossRef Danet-Desnoyers GA, Luongo JL, Bonnet DA, Domchek SM, Vonderheide RH (2005) Telomerase vaccination has no detectable effect on SCID-repopulating and colony-forming activities in the bone marrow of cancer patients. Exp Hematol 33(11):1275–1280PubMedCrossRef
27.
go back to reference Liu JP, Chen W, Schwarer AP, Li H (2010) Telomerase in cancer immunotherapy. Biochim Biophys Acta 1805(1):35–42PubMed Liu JP, Chen W, Schwarer AP, Li H (2010) Telomerase in cancer immunotherapy. Biochim Biophys Acta 1805(1):35–42PubMed
28.
go back to reference Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, Hoff ST, Andersen P, Reed SG, Morris SL, Roederer M, Seder RA (2007) Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13(7):843–850PubMedCrossRef Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, Flynn BJ, Hoff ST, Andersen P, Reed SG, Morris SL, Roederer M, Seder RA (2007) Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13(7):843–850PubMedCrossRef
Metadata
Title
hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes
Authors
Else M. Inderberg Suso
Svein Dueland
Anne-Marie Rasmussen
Turid Vetrhus
Steinar Aamdal
Gunnar Kvalheim
Gustav Gaudernack
Publication date
01-06-2011
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 6/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-011-0991-9

Other articles of this Issue 6/2011

Cancer Immunology, Immunotherapy 6/2011 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine