Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers
Enhanced therapeutic efficacy of IL-12, but not GM-CSF, expressing oncolytic herpes simplex virus for transgenic mouse derived prostate cancers
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DOI：
10.1038/sj.cgt.7700900
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Martuza, RL
中科院分区：
文献类型：
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作者：
Varghese, S;Rabkin, SD;Martuza, RL
具有复制能力的溶瘤性单纯疱疹病毒（HSV）具有针对各种癌症（包括前列腺癌）的广谱活性，通过其直接杀细胞作用和通过引发肿瘤特异性免疫而发挥双重作用。这些病毒可以将免疫调节分子递送到肿瘤，从而增强累积的抗肿瘤应答。这对于通常免疫原性差的前列腺癌是特别期望的。本文所述的比较三种不同溶瘤HSV（G207、G47 Delta和NV 1023）抑制免疫原性差的TRAMP-C2小鼠前列腺肿瘤生长的功效的初始研究表明，NV 1023在治疗已建立的肿瘤中最有效。在NV 1023背景（NV 1042）上IL-12的表达，而不是GM-CSF（NV 1034）的表达，进一步增强了NV 1023在具有高度可变的MHC I类水平的两种鼠前列腺癌模型中的功效，Pr 14 -2具有91%的细胞染色，TRAMP-C2具有2%的细胞染色。NV 1042还抑制两种前列腺癌模型中远处未接种肿瘤的生长。NV 1042处理的肿瘤表现出增加的免疫细胞浸润和降低的血管生成水平。因此，表达IL-12的溶瘤性疱疹病毒能够直接产生细胞毒性，并且可以通过在肿瘤破坏部位同时表达细胞因子来调节否则次优的免疫应答，可以作为寻找显性和隐性前列腺癌的有价值的临床试剂。
Replication competent oncolytic herpes simplex viruses (HSV) with broad-spectrum activity against various cancers, including prostate cancer, exert a dual effect by their direct cytocidal action and by eliciting tumor-specific immunity. These viruses can deliver immunoregulatory molecules to tumors so as to enhance the cumulative antitumor response. This is particularly desirable for prostate cancers, which are usually poorly immunogenic. Initial studies described herein comparing the efficacy of three different oncolytic HSVs (G207, G47 Delta, and NV1023) to inhibit the growth of the poorly immunogenic TRAMP-C2 mouse prostate tumors demonstrated that NV1023 was most effective in treating established tumors. The expression of IL-12 on an NV1023 background (NV1042), but not the expression of GM-CSF (NV1034), further enhanced the efficacy of NV1023 in two murine prostate cancer models with highly variable MHC class I levels, Pr14-2 with 91% and TRAMP-C2 with 2% of cells staining. NV1042 also inhibited the growth of distant noninoculated tumors in both prostate cancer models. NV1042 treated tumors exhibited increased immune cell infiltration and decreased levels of angiogenesis. Thus, an IL-12 expressing oncolytic herpes virus, which is capable of direct cytotoxicity and can modulate the otherwise suboptimal immune response through concomitant expression of the cytokine at the site of tumor destruction, could serve as a valuable clinical agent to seek out both overt and occult prostate cancers.