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Vaccine Detail
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pcDNA3/hMUC1 DNA Vaccine Combined with mANT2 shRNA-1 |
| Vaccine Information |
- Vaccine Name: pcDNA3/hMUC1 DNA Vaccine Combined with mANT2 shRNA-1
- Target Pathogen: Cancer
- Target Disease: Cancer
- Type: DNA vaccine
- Status: Research
- Host Species for Licensed Use: Mouse
- Antigen: MUC1 VNTR (20aa) (Choi et al., 2011)
- Immunization Route: Intramuscular injection (i.m.)
- Description: A DNA vaccine (pcDNA3/hMUC1) combined with intratumoral mANT2 shRNA-1 gene therapy tested in the B16F1 murine melanoma model in C57BL/6 mice bearing subcutaneous BMF tumors (B16F1 melanoma cells stably co-expressing hMUC1 and firefly luciferase). The mANT2 shRNA-1 component silences ANT2, a mitochondrial inner membrane antiapoptotic oncoprotein overexpressed in proliferative cancer cells, inducing tumor cell apoptosis via reduced intracellular ATP synthesis, DNA fragmentation, and active caspase-3 activation, while upregulating MHC class I, Fas, and ICAM-I on tumor cell surfaces to render BMF cells more susceptible to MUC1-associated CTL lysis. Combined treatment induced 57-fold more apoptotic tumor cells versus controls (1,760 ± 60 vs. 31 ± 9 per 3×10⁴ BMF cells, p<0.0005), 5.7-fold more MUC1-associated IFN-γ-secreting CD8+ T cells in splenocytes (206 ± 17 vs. 36 ± 9 per 3×10⁴, p<0.01), and 7.6-fold more tumor-infiltrating MUC1-associated CD8+ T cells (144 ± 21 vs. 19 ± 4 per 3×10⁴, p<0.01). CTL killing activity was significantly greater versus all monotherapy arms at day 33 (45.8 vs. 8.5–25.5% specific lysis) and day 54 (33.2 vs. 4.0–18.1% specific lysis), demonstrating durable long-term cytotoxicity. CD11c+CD86+ dendritic cells were over eightfold higher versus controls (236 ± 19 vs. 27 ± 4), and hMUC1-loaded CD11c+ cells from draining lymph nodes generated over 40-fold more IFN-γ-secreting CD8+ T cells versus controls (1,227 ± 155 vs. 30 ± 10). Pulmonary metastasis was suppressed 15-fold versus controls (0.6 ± 0.5 vs. 8.8 ± 1.3 lung nodules, p<0.00005), tumor growth was significantly inhibited versus all monotherapy arms (p<0.0001), and overall survival was improved (p<0.05). Cured animals rejected MUC1-expressing BMF rechallenge but not antigen-negative B16F1-Fluc cells, confirming durable MUC1-specific immunological memory and synergistic antitumor effects exceeding either monotherapy alone. MUC1 is a membrane-bound glycoprotein overexpressed in an aberrant or incompletely glycosylated form in various human cancers including melanoma, breast, colon, and pancreatic cancers (Choi et al., 2011).
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| Host Response |
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| References |
Choi et al., 2011: Choi Y, Jeon YH, Jang JY, Chung JK, Kim CW. Treatment with mANT2 shRNA enhances antitumor therapeutic effects induced by MUC1 DNA vaccination. Molecular therapy : the journal of the American Society of Gene Therapy. 2011; 19(5); 979-989. [PubMed: 21063392].
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