Varghese Susan, Rabkin Samuel D, Nielsen Petur G, Wang Wenzheng, Martuza Robert L
Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
Clin Cancer Res. 2006 May 1;12(9):2919-27. doi: 10.1158/1078-0432.CCR-05-1187.
Our goal was to evaluate whether systemic administration of NV1042, an interleukin-12 (IL-12)-expressing oncolytic herpes simplex virus, and its noncytokine parental vector NV1023 are effective against preexisting metastatic prostate cancer in an immunocompetent mice model.
Metastatic TRAMP-C2 lung tumors established in C57Bl/6 or nude mice were treated on day 21 with four i.v. administrations of NV1042 or NV1023 and sacrificed on day 42 to assess virus efficacy and the potential mechanism of efficacy.
NV1042 or NV1023 treatment was similarly effective in eliminating extrapleural and hemorrhagic tumors present in mock-treated mice. However, NV1042 was further effective compared with NV1023 in controlling the growth of lung tumors (as determined by mean surface tumor nodule number, lung weights, and surface tumor burden) and in extending survival. NV1042-treated mice exhibited a transient increase of serum IL-12 1 day posttreatment, whereas IL-12 levels in tumor bearing lungs persisted a further 2 days at least. Only splenocytes from NV1042-treated mice secreted IFN-gamma in response to TRAMP-C2 stimulation and displayed natural killer activity. The IL-12-mediated enhancement observed with NV1042 in the syngeneic model was abrogated in athymic mice treated in a similar manner, thus indicating a role for T cells in the augmented efficacy of NV1042 virus.
Systemic administration of the IL-12-expressing NV1042 virus is more effective than its noncytokine parent, NV1023, against preestablished metastatic lung tumors. Given the clinical safety profile of NV1020, the parental vector of NV1023, and NV1042's enhanced efficacy and ability to activate the host immune system, NV1042 merits clinical consideration for treating metastatic prostate cancers.
我们的目标是评估全身性给予NV1042（一种表达白细胞介素-12（IL-12）的溶瘤单纯疱疹病毒）及其非细胞因子亲本载体NV1023，在具有免疫活性的小鼠模型中对已存在的转移性前列腺癌是否有效。
在C57Bl/6或裸鼠中建立的转移性TRAMP-C2肺肿瘤在第21天接受四次静脉注射NV1042或NV1023治疗，并在第42天处死以评估病毒疗效和潜在的疗效机制。
NV1042或NV1023治疗在消除未处理小鼠中存在的胸膜外和出血性肿瘤方面同样有效。然而，与NV1023相比，NV1042在控制肺肿瘤生长（通过平均表面肿瘤结节数、肺重量和表面肿瘤负荷确定）和延长生存期方面更有效。接受NV1042治疗的小鼠在治疗后1天血清IL-12出现短暂升高，而荷瘤肺中的IL-12水平至少再持续2天。只有来自接受NV1042治疗的小鼠的脾细胞在受到TRAMP-C2刺激时分泌干扰素-γ并表现出自然杀伤活性。在同基因模型中用NV1042观察到的IL-12介导的增强作用在以类似方式治疗的无胸腺小鼠中被消除，因此表明T细胞在NV1042病毒增强的疗效中起作用。
全身性给予表达IL-12的NV1042病毒在对抗预先存在的转移性肺肿瘤方面比其非细胞因子亲本NV1023更有效。鉴于NV1023的亲本载体NV1020的临床安全性概况以及NV1042增强的疗效和激活宿主免疫系统的能力，NV1042值得在治疗转移性前列腺癌方面进行临床考虑。
