Mode-of-action, efficacy, and safety of a homologous multi-epitope vaccine in a murine model for adjuvant treatment of renal cell carcinoma.
OBJECTIVE
In a phase-III trial it was recently shown that an adjuvant renal cell carcinoma (RCC) vaccine (Reniale) reduces the risk of tumour progression following nephrectomy. This clinical trial focused on efficacy and did not investigate end-points relating to mode-of-action of the vaccine. In a murine model we investigated mode-of-action, efficacy, and safety of a homologous RENCA cell-based vaccine.


METHODS
Six groups with 12 BALB/c mice per group received five vaccinations (lysate of 1x10(6)-1x10(7) RENCA cells, manufactured with or without prior IFN-gamma incubation) at 3-wk intervals before tumour transplantation and one vaccination 14 d afterwards. Controls (12 mice) received only solvent. All mice were sacrificed 21 d after tumour transplantation.


METHODS
Animal welfare, tumour growth, number of metastases, and the presence of cytotoxic T-lymphocytes as determined by a (51)chromium-release assay. Adoptive immune transfer experiments (vaccination of nine mice with the RENCA vaccine or saline and transfer of serum, spleen cells, and CD4 and/or CD8 depleted spleen cells into five recipient mice each) were carried out to demonstrate involvement of different immune mechanisms.


RESULTS
All controls developed a renal tumour, compared to 7/72 animals (9.7%) in the vaccine groups. The mean number of lung metastases was 100 (range 3-750) in controls and 4 (range 0-196) in the vaccine groups, respectively. Tumour uptake and number of metastases were not related to the vaccine dose. The (51)chromium-release assay confirmed a significant tumour-specific cytolytic activity and marginally increased NK activity of splenocytes from vaccinated mice against RENCA cells compared to controls. Adoptive immune transfer experiments showed that the antitumoural effective immune mechanisms are cell-based.


CONCLUSIONS
We could demonstrate the mode-of-action, efficacy, and safety of a homologous tumour vaccine in a RENCA model. These findings support the positive results from a phase-III trial with Reniale.
Department of Urology, University of Lübeck Medical School, Lübeck, Germany. doehn@medinf.mu-luebeck.de
Christian
C
Doehn
Norbert
N
Esser
Hans-Gerd
HG
Pauels
Stephan T
ST
Kiessig
Matthias
M
Stelljes
Armin
A
Grossmann
Dieter
D
Jocham
Joachim
J
Drevs
D056704:Adaptive Immunity; D019264:Adoptive Transfer; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary / Q000601:surgery; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D009392:Nephrectomy; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D047368:Tumor Burden / Q000276:immunology
D019496:Cancer Vaccines; C548299:reniale