Synergistic tumoricidal effect of combined hMUC1 vaccination and hNIS radioiodine gene therapy

Yong Hyun Jeon,Chul Woo Kim,Sun Och Yoon,Yun Choi,June-Key Chung

doi:10.1158/1535-7163.mct-08-0277

Abstract

We examined the merits of combinatorial hMUC1 vaccination and hNIS radioiodine gene therapy and evaluated its tumoricidal effects in an animal tumor model. CMNF (CT26 expressing hMUC1, hNIS, and firefly luciferase) cells were transplanted into 28 mice, and 4 and 11 days after tumor challenge, tumor-bearing mice were immunized i.m. with pcDNA3.1 or pcDNA-hMUC1 vaccine and subsequently administered PBS or (131)I i.p. [four groups (7 mice per group): pcDNA3.1 + PBS, phMUC1 + PBS, pcDNA3.1 + (131)I, and phMUC1 + (131)I groups]. Thirty-two days after tumor challenge, we rechallenged mice in the pcDNA3.1 + (131)I and phMUC1 + (131)I groups with CMNF cells. Tumor progression and tumor-free mice (%) were monitored by bioluminescence. We investigated hMUC1-associated immune response generated by combination therapy. Marked tumor growth inhibition was observed in the phMUC1 + (131)I group by bioluminescence at 32 days after tumor challenge. Mice in phMUC1 + (131)I group showed complete hMUC1-expressing tumor suppression after tumor rechallenge, whereas mice in the pcDNA3.1 + (131)I group did not. The tumor-free mice (%) were much higher in the phMUC1 + (131)I group than in the other three groups. Levels of hMUC1-associated CD8(+)IFN-gamma(+) T cells were higher in the phMUC1 + (131)I group than in the other three groups. hMUC1-loaded CD11(+) cells in the phMUC1 + (131)I group were found to be most effective at generating hMUC1-associated CD8(+)IFN-gamma(+) T cells. The activities of hMUC1-associated cytotoxic T cells in the phMUC1 + (131)I group were higher than in the other three groups. Our data suggest that phMUC1 + (131)I combination therapy synergistically generates marked tumoricidal effects against established hMUC1-expressing cancers.

Highlights

Radiation destroys both cancer cells and other cells within tumor stroma, such as endothelial cells and intratumoral lymphocytes [1]
On the other hand, irradiated cancer or stroma cells show increased expressions of cell surface proteins, such as Fas, MHC class I molecules, and intracellular adhesion molecule-1 (5 – 7). These microenvironmental modifications could provide therapeutic advantages: (a) antigen-presenting cells might detect antigenic proteins derived from dying cancer cells and stimulate T cells in a MHC class-restricted manner and (b) activated T cells could migrate to cancer cells or immune-related organs through adhesion molecules in vascular lumen [8]
Cancer vaccinations using cancer DNA, tumor-derived cell, or dendritic cell vaccines have been applied to preclinical/ clinical disease models (22 – 28)

Summary

Introduction

Radiation destroys both cancer cells and other cells within tumor stroma, such as endothelial cells and intratumoral lymphocytes [1]. On the other hand, irradiated cancer or stroma cells show increased expressions of cell surface proteins, such as Fas, MHC class I molecules, and intracellular adhesion molecule-1 (5 – 7). These microenvironmental modifications could provide therapeutic advantages: (a) antigen-presenting cells might detect antigenic proteins derived from dying cancer cells and stimulate T cells in a MHC class-restricted manner and (b) activated T cells could migrate to cancer cells or immune-related organs through adhesion molecules in vascular lumen [8]. When other therapeutic modalities (e.g., immunotherapy and chemotherapy) are combined with radiotherapy, this radiation-induced immune response may be enhanced

Methods

Results

Conclusion