Intravesical BCG is a highly effective treatment for high-grade nonmuscle invasive bladder cancer and carcinoma in situ (CIS); however, for patients who are either resistant or become unresponsive to BCG therapy there is a need for alternative treatment approaches. This study examined the safety and feasibility of intravesically administered recombinant fowlpox virus encoding GM-CSF (Arm A) or TRICOM (Arm B); and the local and systemic immunologic responses generated to the vector(s). Twenty bladder cancer patients scheduled for cystectomy as their standard of care received preoperatively four weekly doses of intravesical recombinant fowlpox. Treatment was well tolerated, however, three patients experienced transient elevations of liver transaminases, with one rising to the level of a DLT. Cystectomy derived tumor and normal bladder mucosa demonstrated mRNA for the virally encoded LacZ gene supporting effective infection/transfection. Detected serum antibody to the LacZ encoding β-galactosidase indicated successful expression of vector-encoding gene products and the ability to immunize via the bladder site. H&E and IHC using a panel of immune cell specific antigens demonstrated immune cell infiltration of the bladder wall. These findings demonstrate good safety profile, successful infection/transfection, ability to generate systemic immune response, and local recruitment of immune cell populations with intravesical administration of fowlpox-based constructs encoding for GM-CSF(rF-GM-CSF) or TRICOM (rF-TRICOM), and support further evaluation of this treatment modality for bladder cancer.

中文翻译：

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膀胱癌患者膀胱内注射重组禽痘-GM-CSF（rF-GM-CSF）或fowlpox-TRICOM（rF-TRICOM）的I期新辅助研究。

膀胱内注射 BCG 是一种非常有效的治疗高级别非肌肉浸润性膀胱癌和原位癌 (CIS) 的方法；然而，对于对卡介苗治疗耐药或无反应的患者，需要其他治疗方法。该研究检查了膀胱内注射编码 GM-CSF（A 组）或 TRICOM（B 组）的重组禽痘病毒的安全性和可行性；以及对载体产生的局部和全身免疫反应。20 名计划接受膀胱切除术作为其标准护理的膀胱癌患者在术前每周接受四次膀胱内重组鸡痘。治疗耐受性良好，但是，3 名患者出现肝转氨酶短暂升高，其中 1 人升至 DLT 水平。膀胱切除术衍生的肿瘤和正常膀胱黏膜证明病毒编码的 LacZ 基因的 mRNA 支持有效感染/转染。检测到的针对 LacZ 编码 β-半乳糖苷酶的血清抗体表明载体编码基因产物的成功表达和通过膀胱部位进行免疫的能力。H&E 和 IHC 使用一组免疫细胞特异性抗原证明了膀胱壁的免疫细胞浸润。这些发现证明了良好的安全性、成功的感染/转染、产生全身免疫反应的能力，以及通过膀胱内施用编码 GM-CSF（rF-GM-CSF）或 TRICOM（rF -TRICOM），并支持进一步评估这种膀胱癌的治疗方式。