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.

Abstract

Recombinant plasmid DNA and attenuated poxviruses are under development as cancer and infectious disease vaccines. We present the results of a phase I clinical trial of recombinant plasmid DNA and modified vaccinia Ankara (MVA), both encoding 7 melanoma tumor antigen cytotoxic T lymphocyte (CTL) epitopes. HLA-A*0201-positive patients with surgically treated melanoma received either a "prime-boost" DNA/MVA or a homologous MVA-only regimen. Ex vivo tetramer analysis, performed at multiple time points, provided detailed kinetics of vaccine-driven CTL responses specific for the high-affinity melan-A(26-35) analogue epitope. Melan-A26-35-specific CTL were generated in 2/6 patients who received DNA/MVA (detectable only after the first MVA injection) and 4/7 patients who received MVA only. Ex vivo ELISPOT analysis and in vitro proliferation assays confirmed the effector function of these CTL. Responses were seen in smallpox-vaccinated as well as vaccinia-naive patients, as defined by anti-vaccinia antibody responses demonstrated by ELISA assay. The observations that 1) CTL responses were generated to only 1 of the recombinant epitopes and 2) that the magnitude of these responses (0.029-0.19% CD8(+) T cells) was below the levels usually seen in acute viral infections suggest that to ensure high numbers of CTL specific for multiple recombinant epitopes, a deeper understanding of the interplay between CTL responses specific for the viral vector and recombinant epitopes is required.

• Authors: Caroline L Smith, P Rod Dunbar, Fareed Mirza, Michael J Palmowski, Dawn Shepherd, Sarah C Gilbert, Pierre Coulie, Joerg Schneider, Eric Hoffman, Robert Hawkins, Adrian L Harris, Vincenzo Cerundolo
• Journal: International journal of cancer (Int J Cancer) Vol. 113 Issue 2 Pg. 259-66 (Jan 10 2005) ISSN: 0020-7136 [Print] United States
• PMID: 15386406 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Epitopes
• Vaccines, DNA
• Vaccines, Synthetic

Topics

• Adult
• Aged
• Antibody Formation
• Antigens, Neoplasm (immunology)
• Enzyme-Linked Immunosorbent Assay
• Epitopes
• Female
• Genetic Engineering
• Humans
• Immunotherapy (methods)
• Male
• Melanoma (immunology, pathology, therapy)
• Middle Aged
• Neoplasm Recurrence, Local (immunology, pathology)
• Plasmids (genetics)
• Skin Neoplasms (immunology, pathology, therapy)
• T-Lymphocytes, Cytotoxic (immunology)
• Vaccines, DNA
• Vaccines, Synthetic (immunology)
• Vaccinia virus (genetics)