Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 2/2011

Open Access 01-02-2011 | Original Article

Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909

Authors: Jürgen Kuball, Karin de Boer, Eva Wagner, Mohammed Wattad, Edite Antunes, Risini D. Weeratna, Alain P. Vicari, Carina Lotz, Suzanne van Dorp, Samantha Hol, Philip D. Greenberg, Wolfgang Heit, Heather L. Davis, Matthias Theobald

Published in: Cancer Immunology, Immunotherapy | Issue 2/2011

Login to get access

Abstract

T cells with specificity for antigens derived from Wilms Tumor gene (WT1), Proteinase3 (Pr3), and mucin1 (MUC1) have been demonstrated to lyse acute myeloid leukemia (AML) blasts and multiple-myeloma (MM) cells, and strategies to enhance or induce such tumor-specific T cells by vaccination are currently being explored in multiple clinical trials. To test safety and immunogenicity of a vaccine composed of WT1-, Pr3-, and MUC1-derived Class I-restricted peptides and the pan HLA-DR T helper cell epitope (PADRE) or MUC1-helper epitopes in combination with CpG7909 and MontanideISA51, four patients with AML and five with MM were repetitively vaccinated. No clinical responses were observed. Neither pre-existing nor naive WT1-/Pr3-/MUC1-specific CD8+ T cells expanded in vivo by vaccination. In contrast, a significant decline in vaccine-specific CD8+ T cells was observed. An increase in PADRE-specific CD4+ T helper cells was observed after vaccination but these appeared unable to produce IL2, and CD4+ T cells with a regulatory phenotype increased. Taken into considerations that multiple clinical trials with identical antigens but different adjuvants induced vaccine-specific T cell responses, our data caution that a vaccination with leukemia-associated antigens can be detrimental when combined with MontanideISA51 and CpG7909. Reflecting the time-consuming efforts of clinical trials and the fact that 1/3 of ongoing peptide vaccination trails use CpG and/or Montanide, our data need to be taken into consideration.
Appendix
Available only for authorised users
Literature
1.
Molldrem J, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N, Fukushima P, Barrett AJ (1996) Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood 88:2450–2457PubMed
2.
Molldrem JJ, Clave E, Jiang YZ, Mavroudis D, Raptis A, Hensel N, Agarwala V, Barrett AJ (1997) Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units. Blood 90:2529–2534PubMed
3.
Bellantuono I, Gao L, Parry S, Marley S, Dazzi F, Apperley J, Goldman JM, Stauss HJ (2002) Two distinct HLA-A0201-presented epitopes of the Wilms tumor antigen 1 can function as targets for leukemia-reactive CTL. Blood 100:3835–3837CrossRefPubMed
4.
Kuball J, Dossett ML, Wolfl M, Ho WY, Voss RH, Fowler C, Greenberg PD (2007) Facilitating matched pairing and expression of TCR chains introduced into human T cells. Blood 109:2331–2338CrossRefPubMed
5.
Wolfl M, Kuball J, Ho WY, Nguyen H, Manley TJ, Bleakley M, Greenberg PD (2007) Activation-induced expression of CD137 permits detection, isolation, and expansion of the full repertoire of CD8+ T cells responding to antigen without requiring knowledge of epitope specificities. Blood 110:201–210CrossRefPubMed
6.
Oka Y, Tsuboi A, Taguchi T, Osaki T, Kyo T, Nakajima H, Elisseeva OA, Oji Y, Kawakami M, Ikegame K, Hosen N, Yoshihara S, Wu F, Fujiki F, Murakami M, Masuda T, Nishida S, Shirakata T, Nakatsuka S, Sasaki A, Udaka K, Dohy H, Aozasa K, Noguchi S, Kawase I, Sugiyama H (2004) Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci USA 101:13885–13890CrossRefPubMed
7.
Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Blau IW, Hofmann WK, Uharek L, Thiel E, Scheibenbogen C (2009) A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood 113:6541–6548CrossRefPubMed
8.
Rezvani K, Yong AS, Mielke S, Savani BN, Musse L, Superata J, Jafarpour B, Boss C, Barrett AJ (2008) Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood 111:236–242CrossRefPubMed
9.
Hiltbold EM, Ciborowski P, Finn OJ (1998) Naturally processed class II epitope from the tumor antigen MUC1 primes human CD4 + T cells. Cancer Res 58:5066–5070PubMed
10.
Domenech N, Henderson RA, Finn OJ (1995) Identification of an HLA-A11-restricted epitope from the tandem repeat domain of the epithelial tumor antigen mucin. J Immunol 155:4766–4774PubMed
11.
Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W (2000) Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 96:3102–3108PubMed
12.
Brossart P, Schneider A, Dill P, Schammann T, Grunebach F, Wirths S, Kanz L, Buhring HJ, Brugger W (2001) The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes. Cancer Res 61:6846–6850PubMed
13.
Gulley JL, Arlen PM, Tsang KY, Yokokawa J, Palena C, Poole DJ, Remondo C, Cereda V, Jones JL, Pazdur MP, Higgins JP, Hodge JW, Steinberg SM, Kotz H, Dahut WL, Schlom J (2008) Pilot study of vaccination with recombinant CEA-MUC-1-TRICOM poxviral-based vaccines in patients with metastatic carcinoma. Clin Cancer Res 14:3060–3069CrossRefPubMed
14.
Smith JW, Walker EB, Fox BA, Haley D, Wisner KP, Doran T, Fisher B, Justice L, Wood W, Vetto J, Maecker H, Dols A, Meijer S, Hu HM, Romero P, Alvord WG, Urba WJ (2003) Adjuvant immunization of HLA-A2-positive melanoma patients with a modified gp100 peptide induces peptide-specific CD8+ T-cell responses. J Clin Oncol 21:1562–1573CrossRefPubMed
15.
van Driel WJ, Ressing ME, Kenter GG, Brandt RM, Krul EJ, van Rossum AB, Schuuring E, Offringa R, Bauknecht T, Tamm-Hermelink A, van Dam PA, Fleuren GJ, Kast WM, Melief CJ, Trimbos JB (1999) Vaccination with HPV16 peptides of patients with advanced cervical carcinoma: clinical evaluation of a phase I-II trial. Eur J Cancer 35:946–952CrossRefPubMed
16.
Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327CrossRefPubMed
17.
Speiser DE, Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F, Krieg AM, Cerottini JC, Romero P (2005) Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115:739–746PubMed
18.
Pashenkov M, Goess G, Wagner C, Hormann M, Jandl T, Moser A, Britten CM, Smolle J, Koller S, Mauch C, Tantcheva-Poor I, Grabbe S, Loquai C, Esser S, Franckson T, Schneeberger A, Haarmann C, Krieg AM, Stingl G, Wagner SN (2006) Phase II trial of a toll-like receptor 9-activating oligonucleotide in patients with metastatic melanoma. J Clin Oncol 24:5716–5724CrossRefPubMed
19.
Valmori D, Souleimanian NE, Tosello V, Bhardwaj N, Adams S, O’Neill D, Pavlick A, Escalon JB, Cruz CM, Angiulli A, Angiulli F, Mears G, Vogel SM, Pan L, Jungbluth AA, Hoffmann EW, Venhaus R, Ritter G, Old LJ, Ayyoub M (2007) Vaccination with NY-ESO-1 protein and CpG in Montanide induces integrated antibody/Th1 responses and CD8 T cells through cross-priming. Proc Natl Acad Sci USA 104:8947–8952CrossRefPubMed
20.
Speiser DE, Baumgaertner P, Voelter V, Devevre E, Barbey C, Rufer N, Romero P (2008) Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc Natl Acad Sci USA 105:3849–3854CrossRefPubMed
21.
Molenkamp BG, Sluijter BJ, van Leeuwen PA, Santegoets SJ, Meijer S, Wijnands PG, Haanen JB, van den Eertwegh AJ, Scheper RJ, de Gruijl TD (2008) Local administration of PF-3512676 CpG-B instigates tumor-specific CD8+ T-cell reactivity in melanoma patients. Clin Cancer Res 14:4532–4542CrossRefPubMed
22.
Huber C, Bobek N, Kuball J, Thaler S, Hoffarth S, Huber C, Theobald M, Schuler M (2005) Inhibitors of apoptosis confer resistance to tumour suppression by adoptively transplanted cytotoxic T-lymphocytes in vitro and in vivo. Cell Death Differ 12:317–325CrossRefPubMed
23.
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 310:40–52CrossRefPubMed
24.
Pepperl-Klindworth S, Besold K, Frankenberg N, Farkas M, Kuball J, Theobald M, Plachter B (2006) Cytomegalovirus interleukin-10 expression in infected cells does not impair MHC class I restricted Peptide presentation on bystanding antigen-presenting cells. Viral Immunol 19:92–101CrossRefPubMed
25.
Alexander J, Fikes J, Hoffman S, Franke E, Sacci J, Appella E, Chisari FV, Guidotti LG, Chesnut RW, Livingston B, Sette A (1998) The optimization of helper T lymphocyte (HTL) function in vaccine development. Immunol Res 18:79–92CrossRefPubMed
26.
Alexander J, Sidney J, Southwood S, Ruppert J, Oseroff C, Maewal A, Snoke K, Serra HM, Kubo RT, Sette A et al (1994) Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1:751–761CrossRefPubMed
27.
Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Lowenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD (2003) Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 21:4642–4649CrossRefPubMed
28.
Blade J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G, Gertz M, Giralt S, Jagannath S, Vesole D (1998) Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 102:1115–1123CrossRefPubMed
29.
Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687CrossRefPubMed
30.
Teague RM, Sather BD, Sacks JA, Huang MZ, Dossett ML, Morimoto J, Tan X, Sutton SE, Cooke MP, Ohlen C, Greenberg PD (2006) Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors. Nat Med 12:335–341CrossRefPubMed
31.
Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W (2004) Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+ CD25+ regulatory T cells. J Immunol 173:4433–4442PubMed
32.
Jarnicki AG, Conroy H, Brereton C, Donnelly G, Toomey D, Walsh K, Sweeney C, Leavy O, Fletcher J, Lavelle EC, Dunne P, Mills KH (2008) Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J Immunol 180:3797–3806PubMed
33.
Gnjatic S, Altorki NK, Tang DN, Tu SM, Kundra V, Ritter G, Old LJ, Logothetis CJ, Sharma P (2009) NY-ESO-1 DNA vaccine induces T-cell responses that are suppressed by regulatory T cells. Clin Cancer Res 15:2130–2139CrossRefPubMed
34.
Molenkamp BG, van Leeuwen PA, Meijer S, Sluijter BJ, Wijnands PG, Baars A, van den Eertwegh AJ, Scheper RJ, de Gruijl TD (2007) Intradermal CpG-B activates both plasmacytoid and myeloid dendritic cells in the sentinel lymph node of melanoma patients. Clin Cancer Res 13:2961–2969CrossRefPubMed
35.
Dzionek A, Inagaki Y, Okawa K, Nagafune J, Rock J, Sohma Y, Winkels G, Zysk M, Yamaguchi Y, Schmitz J (2002) Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions. Hum Immunol 63:1133–1148CrossRefPubMed
36.
Maslak PG, Dao T, Krug LM, Chanel S, Korontsvit T, Zakhaleva V, Zhang R, Wolchok JD, Yuan J, Pinilla-Ibarz J, Berman E, Weiss M, Jurcic J, Frattini MG, Scheinberg DA (2010) Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia. Blood 116:171–179CrossRefPubMed
37.
Van Tendeloo VF, Van De Velde CJ, Van Driessche A, Cools N, Anguille S, Ladell K, Gostick E, Vermeulen K, Pieters K, Nijs G, Stein B, Smits EL, Schroyens WA, Gadisseur AP, Vrelust I, Jorens PG, Goossens H, de Vries I, Price DA, Oji Y, Oka Y, Sugiyama H, Berneman ZN (2010) Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci USA 107:13824–13829CrossRefPubMed
38.
Choi C, Witzens M, Bucur M, Feuerer M, Sommerfeldt N, Trojan A, Ho A, Schirrmacher V, Goldschmidt H, Beckhove P (2005) Enrichment of functional CD8 memory T cells specific for MUC1 in bone marrow of patients with multiple myeloma. Blood 105:2132–2134CrossRefPubMed
39.
Gajewski TF, Meng Y, Blank C, Brown I, Kacha A, Kline J, Harlin H (2006) Immune resistance orchestrated by the tumor microenvironment. Immunol Rev 213:131–145CrossRefPubMed
40.
Aichele P, Brduscha-Riem K, Zinkernagel RM, Hengartner H, Pircher H (1995) T cell priming versus T cell tolerance induced by synthetic peptides. J Exp Med 182:261–266CrossRefPubMed
41.
Toes RE, Blom RJ, Offringa R, Kast WM, Melief CJ (1996) Enhanced tumor outgrowth after peptide vaccination. Functional deletion of tumor-specific CTL induced by peptide vaccination can lead to the inability to reject tumors. J Immunol 156:3911–3918PubMed
42.
Bonifaz L, Bonnyay D, Mahnke K, Rivera M, Nussenzweig MC, Steinman RM (2002) Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 196:1627–1638CrossRefPubMed
43.
Orleans-Lindsay JK, Barber LD, Prentice HG, Lowdell MW (2001) Acute myeloid leukaemia cells secrete a soluble factor that inhibits T and NK cell proliferation but not cytolytic function–implications for the adoptive immunotherapy of leukaemia. Clin Exp Immunol 126:403–411CrossRefPubMed
44.
Chamuleau ME, van de Loosdrecht AA, Hess CJ, Janssen JJ, Zevenbergen A, Delwel R, Valk PJ, Lowenberg B, Ossenkoppele GJ (2008) High INDO (indoleamine 2, 3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome. Haematologica 93:1894–1898CrossRefPubMed
45.
Kedl RM, Rees WA, Hildeman DA, Schaefer B, Mitchell T, Kappler J, Marrack P (2000) T cells compete for access to antigen-bearing antigen-presenting cells. J Exp Med 192:1105–1113CrossRefPubMed
46.
Seder RA, Darrah PA, Roederer M (2008) T-cell quality in memory and protection: implications for vaccine design. Nat Rev Immunol 8:247–258CrossRefPubMed
47.
Kim D, Monie A, He L, Tsai YC, Hung CF, Wu TC (2008) Role of IL-2 secreted by PADRE-specific CD4+ T cells in enhancing E7-specific CD8+ T-cell immune responses. Gene Ther 15:677–687CrossRefPubMed
48.
49.
Karan D, Krieg AM, Lubaroff DM (2007) Paradoxical enhancement of CD8 T cell-dependent anti-tumor protection despite reduced CD8 T cell responses with addition of a TLR9 agonist to a tumor vaccine. Int J Cancer 121:1520–1528CrossRefPubMed
50.
Nicholaou T, Ebert LM, Davis ID, McArthur GA, Jackson H, Dimopoulos N, Tan B, Maraskovsky E, Miloradovic L, Hopkins W, Pan L, Venhaus R, Hoffman EW, Chen W, Cebon J (2009) Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma. Clin Cancer Res 15:2166–2173CrossRefPubMed
51.
Kordasti SY, Ingram W, Hayden J, Darling D, Barber L, Afzali B, Lombardi G, Wlodarski MW, Maciejewski JP, Farzaneh F, Mufti GJ (2007) CD4+ CD25high Foxp3 + regulatory T cells in myelodysplastic syndrome (MDS). Blood 110:847–850CrossRefPubMed
52.
Giannopoulos K, Dmoszynska A, Kowal M, Rolinski J, Gostick E, Price DA, Greiner J, Rojewski M, Stilgenbauer S, Dohner H, Schmitt M (2010) Peptide vaccination elicits leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients with chronic lymphocytic leukemia. Leukemia 24:798–805CrossRefPubMed
53.
Greiner J, Schmitt A, Giannopoulos K, Rojewski MT, Gotz M, Funk I, Ringhoffer M, Bunjes D, Hofmann S, Ritter G, Dohner H, Schmitt M (2010) High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. Haematologica 95:1191–1197CrossRefPubMed
Metadata
Title
Pitfalls of vaccinations with WT1-, Proteinase3- and MUC1-derived peptides in combination with MontanideISA51 and CpG7909
Authors
Jürgen Kuball
Karin de Boer
Eva Wagner
Mohammed Wattad
Edite Antunes
Risini D. Weeratna
Alain P. Vicari
Carina Lotz
Suzanne van Dorp
Samantha Hol
Philip D. Greenberg
Wolfgang Heit
Heather L. Davis
Matthias Theobald
Publication date
01-02-2011
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 2/2011
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-010-0929-7

Other articles of this Issue 2/2011

Cancer Immunology, Immunotherapy 2/2011 Go to the issue

Original Article

Primed tumor-reactive multifunctional CD62L+ human CD8+ T cells for immunotherapy

Original Article

Natural antibodies against nerve growth factor inhibit in vitro prostate cancer cell metastasis

Short Communication

CD8 Co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-β (TGF-β)-mediated suppression

Original Article

A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal clear-cell carcinoma: clinical and immunological findings

Original Article

Development of a successful antitumor therapeutic model combining in vivo dendritic cell vaccination with tumor irradiation and intratumoral GM-CSF delivery

Original Article

Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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
Image Credits