Generation of cytotoxic T‐cell responses with synthetic melanoma‐associated peptides in vivo: Implications for tumor vaccines with melanoma‐associated antigens

Jaeger, E.; Bernhard, Helga; Romero, Pedro; Ringhoffer, Mark; Arand, Michael; Karbach, Julia; Ilsemann, Christiane; Hagedorn, Manfred

doi:10.1002/(sici)1097-0215(19960410)66:2<162::aid-ijc4>3.3.co;2-k

Cited by 65 publications

(89 citation statements)

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“…Synthetic peptide plus adjuvant vaccines have been shown to induce only low frequencies of circulating antigen-specific T cells, despite administration of 8 or more injections (34,35). Moreover, in the majority of cancer patient studies reported so far, T cell responses could not be detected ex vivo but rather only after 1 or more rounds of in vitro T cell stimulation and proliferation (21,24,36,37). A small number of studies (using 0.5-1 mg peptide per vaccination plus adjuvants or cytokines) described ex vivo detectable T cell responses (22,25), but T cell frequencies were still 10-100 times lower than what we observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909

Speiser¹,

Líénard²,

Rufer³

et al. 2005

J. Clin. Invest.

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128

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Section: Discussionmentioning

confidence: 99%

Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909

Speiser¹,

Líénard²,

Rufer³

et al. 2005

J. Clin. Invest.

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128

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“…Furthermore, advanced stage tumour patients frequently present ill-defined impairments of immune responsiveness. A number of reports indicate that, irrespective of discrete vaccination procedures, repeated immunisation courses are required in order to obtain detectable specific stimulation, and such responsiveness is frequently not sustained in time (Jaeger et al, 1996;Marchand et al, 1999;Thurner et al, 1999). Most active specific immunotherapies currently rely on the in vivo administration (Jaeger et al, 1996;Rosenberg et al, 1998;Marchand et al, 1999) or the ex vivo pulsing of APC prior to reinfusion, with synthetic peptides (Nestle et al, 1998;Thurner et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Immunogenic class I restricted peptides are usually injected intradermally for vaccination purposes (Jaeger et al, 1996;Rosenberg et al, 1998;Marchand et al, 1999). The main APC type in this tissue is represented by Langerhans cells (LC), iDC that, upon antigen uptake and maturation traffick to lymph nodes, are able to activate both naive and memory T cells (Bell et al, 1999;Lanzavecchia and Sallusto, 2001) (Figures 1, 2).…”

Section: As Presenters Of Antigens Encapsulated In Sslmentioning

confidence: 99%

“…Synthetic peptides have been used in the presence or absence of cytokines or adjuvants in a number of protocols, and their administration has been shown to result in clinical responses (Jaeger et al, 1996;Rosenberg et al, 1998;Marchand et al, 1999).…”

mentioning

confidence: 99%

“…Still, peptides are poor immunogens, characterised by short halflives 'in vitro' and 'in vivo', possibly due to the effects of serum and cellular peptidases (Amoscato et al, 1998;Brinckerhoff et al, 1999;Blanchet et al, 2001;Albo et al, 2003), and long immunisation courses are required before specific responsiveness eventually becomes evident (Jaeger et al, 1996;Marchand et al, 1999, Coulie andvan der Bruggen, 2003).…”

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confidence: 99%

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Encapsulation into sterically stabilised liposomes enhances the immunogenicity of melanoma-associated Melan-A/MART-1 epitopes

et al. 2004

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Tumour-associated antigens (TAA)-specific vaccination requires highly immunogenic reagents capable of inducing cytotoxic T cells (CTL). Soluble peptides are currently used in clinical applications despite an acknowledged poor immunogenicity. Encapsulation into liposomes has been suggested to improve the immunogenicity of discrete antigen formulations. We comparatively evaluated the capacity of HLA-A2.1 restricted Melan-A/MART-1 epitopes in soluble form (S) or following inclusion into sterically stabilised liposomes (SSL) to be recognised by specific CTL, to stimulate their proliferation and to induce them in healthy donors' peripheral blood mononuclear cells (PBMC), as well as in melanoma-derived tumour-infiltrating lymphocytes (TIL). HLA-A2.1 þ , Melan-A/ MART-1-NA-8 melanoma cells served as targets of specific CTL in 51Cr release assays upon pulsing by untreated or human plasmatreated soluble or SSL-encapsulated Melan-A/MART-1 27 -35 (M27 -35) or 26 -35 (M26 -35) epitopes. These reagents were also used to stimulate CTL proliferation, measured as 3H-thymidine incorporation, in the presence of immature dendritic cells (iDC), as antigen-presenting cells (APC). Induction of specific CTL upon stimulation with soluble or SSL-encapsulated peptides was attempted in healthy donors' PBMC or melanoma-derived TIL, and monitored by 51Cr release assays and tetramer staining. Na-8 cells pulsing with SSL M27 -35 resulted in a five-fold more effective killing by specific CTL as compared with equal amounts of S M27 -35. Encapsulation into SSL also provided a partial (50%) protection of M27 -35 from plasma hydrolysis. No specific advantages regarding M26 -35 were detectable in these assays. However, at low epitope concentrations (p100 ng ml À1 ), SSL M26 -35 was significantly more effective in inducing CTL proliferation than S M26 -35, in the presence of iDC, as APC. Preincubation with iDC for 6 h virtually abolished the capacity of S M26 -35 to stimulate specific CTL proliferation, but only partially affected that of SSL M26 -35. Most importantly, SSL M26 -35 was able to enhance the induction of specific CTL in healthy donors PBMC and in melanoma-derived TIL as compared to S M26 -35. Taken together, our data indicate that encapsulation of TAA epitopes into SSL results in effective immunogenic formulations suitable for clinical use in active specific tumour immunotherapy.

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Construction and characterization of a recombinant adenovirus directing expression of the MAGE-1 tumor-specific antigen

et al. 1997

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The finding that many human melanomas express distinct antigens that can be recognised by specific cytolytic T lymphocytes (CTL) implies that immunotherapeutic strategies against this cancer might prove effective. The ex vivo delivery of a tumour‐associated antigen to autologous cells and the subsequent re‐administration of these cells to the patient might prove effective in boosting the T cell immune response. Recombinant human adenoviral vectors provide an efficient delivery system and have many advantages over other viral and non‐viral delivery vehicles. Infection of a panel of human melanoma cell lines by AdCMVMAGE‐1, a novel recombinant adenovirus which incorporates the full‐length MAGE‐1 cDNA, was shown to induce production of high levels of MAGE‐1 protein. Incubation of transduced HLA‐A1 expressing melanoma cell lines with 2 anti‐MAGE‐1.A1 CTL clones resulted in specific recognition and lysis of target cells, indicating that the exogenous MAGE‐1 protein was processed and presented in a normal manner. Furthermore, quantitative analyses demonstrated a correlation between the efficiency of transduction and the proportion of cells lysed. Importantly for future clinical trials, stimulation of peripheral blood lymphocytes (PBLs) from a melanoma patient by AdCMVMAGE‐1‐transduced autologous cells resulted in the generation of specific CTLs against the MAGE‐1 antigen. Together, our data emphasize the utility of adenoviruses as vaccination vehicles and highlight the potential efficacy of this approach for the treatment of melanoma. Int. J. Cancer 72:1045–1055, 1997. © 1997 Wiley‐Liss, Inc.

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Generation of cytotoxic T‐cell responses with synthetic melanoma‐associated peptides in vivo: Implications for tumor vaccines with melanoma‐associated antigens

Cited by 65 publications

References 1 publication

Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909

Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909

Encapsulation into sterically stabilised liposomes enhances the immunogenicity of melanoma-associated Melan-A/MART-1 epitopes

Construction and characterization of a recombinant adenovirus directing expression of the MAGE-1 tumor-specific antigen

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