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.
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.
Smith
Caroline L
CL
Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, OX3 9DS, UK.
Dunbar
P Rod
PR
Mirza
Fareed
F
Palmowski
Michael J
MJ
Shepherd
Dawn
D
Gilbert
Sarah C
SC
Coulie
Pierre
P
Schneider
Joerg
J
Hoffman
Eric
E
Hawkins
Robert
R
Harris
Adrian L
AL
Cerundolo
Vincenzo
V
D000328:Adult; D000368:Aged; D000917:Antibody Formation; D000951:Antigens, Neoplasm / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000473:pathology; D010957:Plasmids / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics
D000951:Antigens, Neoplasm; D000939:Epitopes; D019444:Vaccines, DNA; D014614:Vaccines, Synthetic