Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence

Smith, Caroline L.; Dunbar, P. Rod; Mirza, Fareed; Palmowski, Michael J.; Shepherd, Dawn; Gilbert, Sarah C.; Coulie, Pierre G.; Schneider, J; Hoffman, Eric W.; Hawkins, Robert E.; Harris, Adrian L.; Cerundolo, Vincenzo

doi:10.1002/ijc.20569

Cited by 84 publications

(55 citation statements)

References 52 publications

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“…In only a few cases, a partial regression of the tumor burden and stabilization of disease was observed (14 -21). By combining the recombinant viral vectors in heterologous prime-boost regimens, the specific T cell precursor frequencies could be elevated, yet clinical benefits remained elusive (22)(23)(24)(25)(26). Thus, improving immunogenicity of existing viral vectors, testing of new vector combinations, and tailoring the ultimate memory responses are of importance.…”

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confidence: 99%

Comparative Prime-Boost Vaccinations Using Semliki Forest Virus, Adenovirus, and ALVAC Vectors Demonstrate Differences in the Generation of a Protective Central Memory CTL Response against the P815 Tumor

Näslund

Uyttenhove

Nordström

et al. 2007

The Journal of Immunology

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Tumor-specific Ags are potential target molecules in the therapeutic treatment of cancer. One way to elicit potent immune responses against these Ags is to use recombinant viruses, which activate both the innate and the adaptive arms of the immune system. In this study, we have compared Semliki Forest virus (SFV), adenovirus, and ALVAC (poxvirus) vectors for their capacity to induce CD8+ T cell responses against the P1A tumor Ag and to elicit protection against subsequent challenge injection of P1A-expressing P815 tumor cells in DBA/2 mice. Both homologous and heterologous prime-boost regimens were studied. In most cases, both higher CD8+ T cell responses and better tumor protections were observed in mice immunized with heterologous prime-boost regimens, suggesting that the combination of different viral vectors is beneficial for the induction of an effective immune response. However, homologous immunization with SFV provided potent tumor protection despite a rather moderate primary CD8+ T cell response as compared with mice immunized with recombinant adenovirus. SFV-immunized mice showed a rapid and more extensive expansion of P1A-specific CD8+ T cells in the tumor-draining lymph node after tumor challenge and had a higher frequency of CD62L+ P1A-specific T cells in the blood, spleen, and lymph nodes as compared with adenoimmunized mice. Our results indicate that not only the magnitude but in particular the quality of the CD8+ T cell response correlates with tumor protection.

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confidence: 99%

Comparative Prime-Boost Vaccinations Using Semliki Forest Virus, Adenovirus, and ALVAC Vectors Demonstrate Differences in the Generation of a Protective Central Memory CTL Response against the P815 Tumor

Näslund

Uyttenhove

Nordström

et al. 2007

The Journal of Immunology

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“…8,9 Thus, to boost DNA-primed Her-2/neu-specific immune responses, we also constructed an adenoviral vaccine expressing the extracellular and transmembrane domain of human Her-2/neu using nonreplicating adenovirus vector. The expression of Her-2/neu and/or hGM-CSF by the genetic vaccine constructs was confirmed by fluorescence-activated cell sorting (FACS) and immunoblot analysis after in vitro transduction of CT26 or 293T cells with pHM-hGM-CSF or AdHM (Figure 1).…”

Section: Construction Of Genetic Vaccines Expressing Human Her-2/neumentioning

confidence: 99%

“…9 To increase the limited immunogenicity of plasmid DNA vaccines, several investigators have used recombinant viruses as a boost for DNA vaccines. 23 Although adenoviruses are widely used as vectors in clinical gene therapy trials, their use was limited because they induced adenovirus-specific innate and adaptive immune responses 24 that could be detrimental to the generation of tumor antigen-specific immune responses.…”

Section: Non-human Primate Study Against Human Her-2/neu H-j Ko Et Almentioning

confidence: 99%

“…23 Although adenoviruses are widely used as vectors in clinical gene therapy trials, their use was limited because they induced adenovirus-specific innate and adaptive immune responses 24 that could be detrimental to the generation of tumor antigen-specific immune responses. 9 To reduce these adenovirus-specific responses, we designed prior immunizations with plasmid DNA vaccine. Subsequent DNA vaccination can also boost antigen-specific memory responses induced by DNA and/or adenovirus immunization.…”

Section: Non-human Primate Study Against Human Her-2/neu H-j Ko Et Almentioning

confidence: 99%

“…We used human granulocyte-macrophage colony-stimulating factor (GM-CSF) as a genetic adjuvant for the DNA vaccine to enhance immune responses against Her-2/neu. On the basis of previous reports of the limited efficacy of DNA vaccines in patients, 8,9 we combined adenoviral vaccine with DNA immunization to increase the immunogenicity of the DNA vaccine. The preclinical data obtained from our study suggest that Her-2/neu genetic vaccines might be both immunogenic and safe in humans.…”

Section: Introductionmentioning

confidence: 99%

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Immunogenicity and safety profiles of genetic vaccines against human Her-2/neu in cynomolgus monkeys

Kim

et al. 2008

Gene Ther

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MHC‐peptide‐specific antibodies reveal inefficient presentation of an HLA‐A*0201‐restricted, Melan‐A‐derived peptide after active intracellular processing

Held

Wadle²,

Dauth

et al. 2007

Eur J Immunol

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MHC-peptide-specific Fab antibodies binding to HLA-A*0201 complexes presenting the wild-type EAAGIGILTV (EAA) or analogue Melan-A 10-mer ELAGIGILTV (ELA) peptide were generated to study efficacy of peptide processing and presentation. None of the selected Fab antibodies detected the naturally processed EAA/HLA-A*0201 complex on melanoma tumor cells, confirming the known low peptide number on the cell surface. To study the effect of peptide presentation and processing in more detail, genes coding for the A27L-mutated Melan-A protein or the processed ELA peptide were introduced into HLA-A*0201 + B cells by infection with the respective recombinant vaccinia virus construct producing equimolar amounts of GFP-ubiquitin directly linked to the fragment of interest. Correlating GFP expression to actual numbers of peptide presented, 110-260 ELA peptides had to be synthesized to be presented by a single MHC class I antigen-peptide complex. This number increased 10-to 20-fold when ELA peptide presentation from the A27L-mutated full length Melan-A protein was studied, since 1600-5200 GFP molecules needed to be synthesized for the detection of one ELA peptide. Our results indicate that peptide processing rather than presentation is the rate-limiting step in our experimental setting and is much more ineffective for Melan-A than has been previously shown for other MHC class I-restricted epitopes.

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Recombinant modified vaccinia Ankara primes functionally activated CTL specific for a melanoma tumor antigen epitope in melanoma patients with a high risk of disease recurrence

Cited by 84 publications

References 52 publications

Comparative Prime-Boost Vaccinations Using Semliki Forest Virus, Adenovirus, and ALVAC Vectors Demonstrate Differences in the Generation of a Protective Central Memory CTL Response against the P815 Tumor

Comparative Prime-Boost Vaccinations Using Semliki Forest Virus, Adenovirus, and ALVAC Vectors Demonstrate Differences in the Generation of a Protective Central Memory CTL Response against the P815 Tumor

Immunogenicity and safety profiles of genetic vaccines against human Her-2/neu in cynomolgus monkeys

MHC‐peptide‐specific antibodies reveal inefficient presentation of an HLA‐A*0201‐restricted, Melan‐A‐derived peptide after active intracellular processing

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