PHASE I STUDY OF COMBINED VIRAL & SUICIDE GENE THERAPIES

尽管前列腺癌的传统治疗方法（手术和放射治疗）对早期疾病患者的治愈率很高，但这些癌症中有很大一部分会复发，每种治疗方法都会导致高发病率。雄激素非依赖性前列腺癌的预后要差得多，因为没有有效的治疗方法，而且绝大多数患者最终死于这种疾病。我们确实需要开发新的治疗方法，以降低与传统治疗相关的发病率，降低局部肿瘤复发率，并改善复发性和雄激素非依赖性癌症的前景。在接受放射治疗作为主要治疗的前列腺癌患者中，高达80%的人在5年内生化失败（PSA上升），65%的人在10年内死亡。不幸的是，针对此类患者的治疗选择有限。我们的研究项目开发了一种新的三模基因治疗前列腺癌的方法。我们的方法利用一种具有裂解性、复制能力的腺病毒（Ad5-CD/TKrep）选择性地、有效地向前列腺肿瘤传递一对治疗性“自杀”基因。动物临床前研究表明，Ad5-CD/TKrep病毒本身具有强大的抗肿瘤作用。通过激活两种自杀基因系统（CD/5-FC和HSV-1 TK/GCV），可显著提高Ad5- CD/TKrep病毒治疗的疗效，这两种自杀基因系统使恶性细胞对特定药物敏感，并使其对辐射敏感。我们的研究工作目前正处于临床前/ I期临床研究的风口浪尖。一项I期研究将评估Ad5-CD/TKrep病毒治疗联合双重前药治疗前列腺癌放疗后局部复发男性的毒性和疗效，该研究已获得美国机构审查委员会（IRB）的批准，并已向美国食品和药物管理局（FDA）提交了一份新药研究（IND）申请。本提案的具体目的是评估Ad5-CD/TKrep病毒治疗联合双重前药治疗对放射治疗后前列腺癌局部复发患者的毒性和疗效。将对12名患者（4名患者/剂量）进行剂量递增研究，每剂量使用10e9至10e12病毒颗粒（vp），以确定可安全给人的最大耐受剂量（MTD）。临床反应将在随访期间通过血清PSA水平的一系列测量，以及通过直肠指检（DRE）、经直肠超声（TRUS）和前列腺穿刺活检评估肿瘤的存在来评估。这项研究可能会为男性局限性前列腺癌提供安全有效的治疗方法。

Although conventional therapies for prostate cancer (surgery and radiation therapy) produce a high rate of cure for patients with early stage disease, a significant fraction of these cancers recur and each therapy results in high morbidity. The prognosis for androgen-independent prostate cancer is much worse, as there is no effective treatment and a vast majority of these patients eventually succumb to the disease. There is a real need to develop new therapies that would reduce the morbidity associated with conventional therapies, decrease the incidence of local tumor recurrence, and improve the outlook for recurrent and androgen-independent cancer. Up to 80 percent of prostate cancer patients who received radiation therapy as their primary treatment will fail biochemically (develop a rising PSA) within 5 years and 65 percent will die within 10 years. Unfortunately, limited therapeutic options exist for such patients. Our research program has developed a novel, trimodal gene therapy approach for the treatment of prostate cancer. Our approach utilizes a lytic, replication-competent adenovirus (Ad5-CD/TKrep) to selectively and efficiently deliver a pair of therapeutic "suicide" genes to prostate tumors. Preclinical studies in animals have demonstrated that the Ad5-CD/TKrep virus itself generates a potent anti-tumor effect. The therapeutic efficacy of Ad5- CD/TKrep viral therapy can be enhanced significantly by invoking two suicide gene systems (CD/5-FC and HSV-1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents and sensitizes them to radiation. Our research efforts are currently at the cusp of preclinical/phase I clinical studies. A phase I study that will evaluate the toxicity and efficacy of Ad5-CD/TKrep viral therapy concomitant with double prodrug therapy in men with local recurrence of prostate cancer following radiotherapy has been approved by our Institutional Review Boards (IRB), and an Investigational New Drug (IND) application has been submitted to the U.S. Food and Drug Administration (FDA). The specific aims of this proposal are to evaluate the toxicity and efficacy of Ad5-CD/TKrep viral therapy concomitant with double prodrug therapy in patients with local recurrence of prostate cancer following radiation therapy. A dose escalation study will be performed on 12 patients (4 patients/dose) using 10e9 to 10e12 viral particles (vp) per dose to determine the maximum tolerable dose (MTD) that can be safely administered to humans. Clinical response will be assessed during follow-up by serial measurements of serum PSA levels, and by assessing the presence of tumor by digital rectal exam (DRE), transrectal ultrasound (TRUS), and needle biopsy of the prostate. This research may lead to a safe and effective therapy for men with localized prostate cancer.