1672P - Novel strategy for designing and optimizing of dendritic - cell - based anticancer vaccine

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Cancer Immunology and Immunotherapy
Translational Research
Presenter Natalia Khranovska
Authors N. Khranovska1, G.P. Potebnia2, O. Skachkova1, O. Tanasienko2, N. Svergun1, V. Sitko1, O.G. Fedorchuk3, V.V. Niculina1
  • 1Experimental Oncology, National Cancer Institute of the MPH Ukraine, 03022 - Kiev/UA
  • 2Department Of Biotherapy Means Construction, R.E.Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kiev/UA
  • 3Department Of Medical Correction Of Oncogenesis, R.E.Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kiev/UA

Abstract

Background

Despite widely explore of DC based immunotherapy in cancer, optimal conditions for the generation of phenotypically and functionally mature DCs remain to be established. Maturation of DC can be achieved by several stimuli: pathogen-associated triggers or endogenous danger signals. In this study, we diversely explore the new approach for creating effective DC-vaccine employing the exogenous cytotoxic lectins (CLs) from Bacillus subtilis.

Methods

To study the effect of CLs on degree of DCs maturity and ability to produce IL-12 DCs of 10 healthy donors were used. DCs were generated from peripheral blood monocytes ex vivo in the presence of GM-CSF and IL-4 during 8 days. CLs from Bacillus subtilis (18,5 and 79 kDa) were added to immature DCs on day 6. Maturation state and functional activity of DCs were evaluated by the expression of cell surface markers CD83, CD86, HLA-DR and IL-10, 12 p35, p40 mRNA levels. For clinical trial DCs loaded with lysate of tumor cells (LTC) and treated with CLs were used. DC-vaccine has been tested in adjuvant regimen in 73 stage III-IV ovarian cancer (OC) patients. Patients of control group received the same treatment, except the DC-immunotherapy.

Results

IL-12 p40, p35 and IL-10 mRNA levels were strongly up-regulated by CLs. Exposure DCs to CLs caused 2-10 - fold increase in mRNA cytokine level expression in comparison with control DC incubated in the presence of grows factors only. The effect of CLs was dose dependent and was not due to a block of DCs maturation as determined by analysis of DC surface markers. CLs contributed to a simultaneously significant increasing in CD86/HLA-DR expression (up to 89,44 ±5.26 vs 55,94 ± 12,0 %) and slightly augmented CD83 expression. The most prominent changes in the expression of maturation-associated molecules was observed in DCs treated with CLs in the concentrations 0,04-0,1 mg/ml and thus appear to be the most suitable CLs concentrations for use in the DC-immunotherapy clinical trial. Kaplan-Meier analysis revealed prolonged 4 - year overall survival of OC patients treated with elaborated DC – vaccine compared with the control group (50 vs 39 %; F Cox test: P = 0,034).

Conclusion

Manipulation of DCs with CLs from B.subtilis may prove to be a particularly effective way to stimulate antitumor immunity in cancer patients which leads to a clinical benefit.

Disclosure

All authors have declared no conflicts of interest.