Grinshtein N, Ventresca M, Margl R, Bernard D, Yang T-C, Millar J B, Hummel J, Beermann F, Wan Y, Bramson J L
Department of Pathology and Molecular Medicine, McMaster University, ON, Canada.
Cancer Gene Ther. 2009 Apr;16(4):338-50. doi: 10.1038/cgt.2008.89. Epub 2008 Nov 7.
We have investigated the therapeutic potential of a prototypic melanoma vaccine based on recombinant adenovirus expressing human dopachrome tautomerase in the B16F10 murine melanoma model. We found that in the presence of a tumor, the magnitude of T-cell immunity evoked by the vaccine was significantly reduced. This impairment was compounded by defects in cytokine production and degranulation within the tumor-infiltrating lymphocytes (TILs). We showed that the combination of vaccination with high-dose cyclophosphamide was able to skew the response toward the target antigen and enhanced both the quantity and quality of antigen-specific CD8+ and CD4+ T-cell responses in tumor-bearing mice, which resulted in the inhibition of tumor growth. Furthermore, when tumor-specific antigens were targeted by the vaccine, the combination therapy could actually produce tumor regression, which appeared to result from the high frequency of antigen-specific T cells. These data show that recombinant adenovirus vaccines are compatible with conventional high-dose chemotherapy and that the combined treatment results in improved therapeutic outcomes relative to either agent individually.
我们在B16F10小鼠黑色素瘤模型中研究了基于表达人多巴色素互变异构酶的重组腺病毒的原型黑色素瘤疫苗的治疗潜力。我们发现，在存在肿瘤的情况下，疫苗诱发的T细胞免疫强度显著降低。肿瘤浸润淋巴细胞（TILs）内细胞因子产生和脱颗粒的缺陷使这种损害更加严重。我们表明，高剂量环磷酰胺与疫苗联合使用能够使反应偏向靶抗原，并增强荷瘤小鼠中抗原特异性CD8+和CD4+ T细胞反应的数量和质量，从而导致肿瘤生长受到抑制。此外，当疫苗靶向肿瘤特异性抗原时，联合治疗实际上可以使肿瘤消退，这似乎是由于抗原特异性T细胞的高频率所致。这些数据表明，重组腺病毒疫苗与传统高剂量化疗兼容，并且联合治疗相对于单独使用任何一种药物都能产生更好的治疗效果。
