Gene Therapy and Radiation Therapy for Prostate Cancer

描述（由申请人提供）：在过去的15年里，我们的转化研究项目一直在开发一种多模式、基于基因治疗的癌症治疗方法。我们已经在五项非转移性前列腺癌的临床试验中评估了我们的研究方法的毒性和初步疗效。我们的早期结果表明，我们的方法是安全的，并有可能改善局部肿瘤控制。虽然局部肿瘤控制是重要的，但高风险前列腺癌的新疗法如果要对生存产生影响，就必须针对转移性疾病。因此，我们在我们的研究方法中增加了第四种模式，即产生带有白细胞介素12 （IL-12）的第三代腺病毒，该病毒具有根除局部和转移性疾病的潜力。这种新的腺病毒在临床前研究中产生了令人鼓舞的初步结果，我们计划将其用于临床治疗高危前列腺癌。在特定的目标1中，我们将在免疫功能正常的前列腺癌模型中验证IL-12将提高复制能力腺病毒介导的自杀基因治疗和放射治疗的功效。患有前列腺内TRAMP-C2肿瘤的C57BL/6雄性小鼠将接受瘤内注射Ad5-yCD/mutTKSR39rep-mIL12，随后进行2周的5-氟胞嘧啶(5-FC) +更昔洛韦（GCV）前药治疗和盆腔放疗。主要终点是局部和转移性肿瘤的控制。次要终点包括T细胞活化、NK和CTL活性、血清和肿瘤细胞因子水平以及抗肿瘤免疫的发展。在特定目标2中，我们将验证环磷酰胺（CP）可以安全地与复制能力腺病毒介导的自杀和IL-12基因治疗联合使用，并且联合治疗在体内表现出协同作用的假设。疗效将在没有和有CP的免疫功能正常的原位trump - c2肿瘤模型中进行检验。疗效终点与特异性目标1相同。将对C57BL/6雄性小鼠和叙利亚仓鼠进行毒性检查，后者允许人类腺病毒复制。在特定的目标3中，我们将验证复制能力腺病毒介导的自杀和IL-12基因治疗可以安全地与强度调节放疗（IMRT）和雄激素抑制治疗（AST）联合用于新诊断的高危前列腺癌男性的假设。15名高风险前列腺癌（分期e T3或Gleason e 8或PSA > 20 ng/mL）的男性（5组，每组3名患者）将接受5个剂量水平的单次注射Ad5- yCD/mutTKSR39rep-hIL12 （1 × 1010vp至1 × 1012vp，以半对数增量）。腺病毒将在经直肠超声引导下经前列腺内注射。两天后，男性将接受2周的5-FC +缬更昔洛韦（vGCV）前药治疗，同时接受80 Gy IMRT和2年AST治疗。主要终点是到第90天的毒性。次要终点是：1)2年前列腺活检，2)无生化/临床失败（FFF）， 3)疾病特异性生存，4)总生存，5)血清细胞因子水平。我们相信这项研究将会产生很大的影响，因为它可能会导致更好的治疗侵袭性前列腺癌。

DESCRIPTION (provided by applicant): For the past 15 years our translational research program has been developing a multi-modal, gene therapy- based approach for the treatment of cancer. We have evaluated the toxicity and preliminary efficacy of our investigational approach in five clinical trials of non-metastatic prostate cancer. Our early stage results indicate that our approach is safe and has the potential to improve local tumor control. Although local tumor control is important, new therapies for high-risk prostate cancer must also target metastatic disease if they are to have an impact on survival. Hence, we have added a fourth modality to our investigational approach by generating a third-generation adenovirus armed with interleukin 12 (IL-12) that has the potential to eradicate both local and metastatic disease. This new adenovirus has generated encouraging preliminary results in preclinical studies, and we plan to move it into the clinic targeting high-risk prostate cancer. In specific aim 1, we will test the hypothesis that IL-12 will improve the efficacy of replication-competent adenovirus-mediated suicide gene therapy and radiation in an immune-competent, orthotopic model of prostate cancer. C57BL/6 male mice bearing intraprostatic TRAMP-C2 tumors will receive an intratumoral injection of Ad5-yCD/mutTKSR39rep-mIL12 followed by 2 weeks of 5-fluorocytosine (5-FC) + ganciclovir (GCV) prodrug therapy and pelvic radiation. Primary endpoints are local and metastatic tumor control. Secondary endpoints include T cell activation, NK and CTL activity, serum and tumor cytokine levels, and development of anti-tumor immunity. In specific aim 2, we will test the hypothesis that cyclophosphamide (CP) can be combined safely with replication-competent adenovirus-mediated suicide and IL-12 gene therapy and that the combined therapies exhibit synergy in vivo. Efficacy will be examined in the immune-competent, orthotopic TRAMP-C2 tumor model without and with CP. Efficacy endpoints are identical to those in specific aim 1. Toxicity will be examined in C57BL/6 male mice and Syrian hamsters, the latter of which are permissive for human adenovirus replication. In specific aim 3, we will test the hypothesis that replication-competent adenovirus-mediated suicide and IL-12 gene therapy can be combined safely with intensity modulated radiation therapy (IMRT) and androgen suppression therapy (AST) in men with newly-diagnosed, high-risk prostate cancer. Fifteen men (5 cohorts, 3 patients each) with high-risk prostate cancer (Stage e T3 or Gleason e 8 or PSA > 20 ng/mL) will receive a single injection of Ad5- yCD/mutTKSR39rep-hIL12 at five dose levels (1 x 1010 vp to 1 x 1012 vp in half-log increments). The adenovirus will be injected intraprostatically under transrectal ultrasound-guidance. Two days later, men will receive 2 weeks of 5-FC + valganciclovir (vGCV) prodrug therapy concomitant with 80 Gy IMRT and e 2 years of AST. The primary endpoint is toxicity through day 90. Secondary endpoints are: 1) prostate biopsy at 2 years, 2) freedom from biochemical/clinical failure (FFF), 3) disease-specific survival, 4) overall survival, and 5) serum cytokine levels. We believe this research will have high impact because it may lead to better treatments for aggressive forms of prostate cancer.