Enhancing HSV-1 as an Antitumor Gene Therapy Vector

描述(申请人提供)：恶性胶质瘤已经挑战了传统疗法的进步，并引发了对新治疗方式研究的深入探索，包括使用病毒载体进行基因治疗。HSV-1中Gamma134.5基因的突变使其成为一种有希望的有条件复制的病毒载体，其成功复制和溶瘤仅限于肿瘤细胞。建议的研究将通过增强HSV的内在抗肿瘤能力和优化其重组免疫刺激治疗基因的外在武库来提高HSV作为基因治疗剂的潜力。第一种方法是增强其在肿瘤环境中发挥作用的“内在”能力。通过在SCID小鼠侧翼生长的人类恶性胶质瘤(D54和U87)中连续传代Gamma134.5缺陷的HSV，将允许体内选择压力产生具有增强的抗胶质瘤活性的突变体。第二种“外源性”方法将通过优化其促进肿瘤靶向免疫反应的能力来增强病毒的细胞还原和治疗能力。构建表达IL-18的HSV-1载体有望诱导更多针对肿瘤细胞的免疫细胞渗透以破坏肿瘤细胞。此外，使用表达IL-18的HSV和M002(表达IL-12的HSV)的组合，或者同时表达IL-12和IL-18的HSV，应该会因为IL-12和IL-18之间的协同作用而产生更强的抗肿瘤效果。最后，我们预计，通过连续传代选择具有不同免疫刺激基因的Oncolytics Gamma134.5(-)HSV-1载体的联合将对这些顽固性和几乎普遍致命的恶性胶质瘤产生治疗性“双重打击”。

DESCRIPTION (provided by applicant): Malignant gliomas have defied advances in traditional therapies and have engendered intensive exploration into the study of novel treatment modalities, including the use of viral vectors for gene therapy. Mutation of the gamma134.5 gene in HSV-1 has made it a promising therapeutic candidate as a conditionally replicating viral vector whose successful replication and oncolysis is limited to tumor cells. The proposed studies will improve the potential of HSV as a gene therapy agent by both enhancing its intrinsic anti-tumor capabilities and optimizing its extrinsic arsenal of recombinant immunostimulatory therapeutic genes. The first approach will be to enhance its "intrinsic" ability to function within the tumor environment. Serially passaging gamma134.5-deficient HSVs through human malignant gliomas (D54 and U87) grown in the flanks of SCID mice will allow in vivo selective pressures to produce mutants possessing enhanced anti-glioma activity. The second "extrinsic" approach will augment the cytoreductive and curative ability of the virus by optimizing its ability to promote tumor-targeted immune responses. Construction of an HSV-1 vector expressing IL-18 is expected to elicit increased immune cell infiltrates targeting tumor cells for destruction. Furthermore, using a combination of IL- 18-expressing HSV with M002 (IL-12-expressing HSV), or an HSV expressing both IL-12 & IL-18, should lead to greater anti-tumor effects due to the proven synergy between IL-12 and IL-18. Finally, we anticipate that unifaction of oncolytics gamma134.5(-) HSV-1 vectors selected through serial passaging with different immunostimulatory genes will deliver a therapeutic "double hit" against these recalcitrant and nearly universally fatal malignant gliomas.