Intravesical rF-GMCSF and rF-TRICOM in the treatment of advanced bladder cancer

描述（由申请人提供）：该拟定治疗策略的总体目标是在合理设计的膀胱微环境操作后，对膀胱癌产生有效的全身免疫。多年来，我们一直专注于表征肿瘤微环境中的免疫参数，作为识别操纵靶点的一种手段，最终目标是诱导肿瘤特异性免疫。我们的新假设，即通过使用痘病毒重组体的基因转移来操纵肿瘤微环境，使我们在黑色素瘤中进行了一系列病灶内野生型牛痘和编码GM-CSF的重组牛痘的I期研究，并随后在膀胱癌中进行了膀胱内野生型牛痘的I期研究。我们目前对膀胱癌膀胱内基因转移的研究是我们临床前研究和早期临床试验的直接翻译。这项研究是FDA要求的，因为它代表了重组痘病毒的首次人体膀胱内给药，为我们提供了一个独特的机会来评估关键问题，即调节膀胱微环境的能力，最终目标是产生积极的免疫应答。我们选择了药物rF-GM-CSF和rF-TRICOM，这是基于我们的临床前研究，这些研究表明与肿瘤相关细胞因子谱相关的抗原呈递抑制。此外，我们正在使用重组报告基因B-半乳糖苷酶（B-gal），不仅定量转染效率，但也作为一种抗原，研究通过膀胱隔室免疫的能力，这是以前没有做过的。这些研究将为后续使用重组痘病毒重组体作为膀胱癌的局部/全身治疗提供关键数据。具体而言，我们建议：1.确定与膀胱内滴注rF-GM-CSF和/或TRICOM相关的局部和全身毒性，并确定MTD/II期剂量。2.确定膀胱内注射rF-GM-CSF和/或rF-TRICOM 3后尿路上皮和肿瘤的感染/转染效率。定义膀胱内注射rF-GM-CSF和/或rF-TRICOM后膀胱中的局部免疫应答，以及4.评估通过膀胱隔室免疫膀胱癌患者的能力。我们相信，这些研究的结果将提供关键的见解，以使用膀胱内基因转移作为膀胱癌的治疗方式的能力，并使我们能够提高设计关键的II期试验的能力。

DESCRIPTION (provided by applicant): The overall goal of this proposed treatment strategy is the development of effective systemic immunity to bladder cancer following the rationally designed manipulation of the bladder microenvironment. For a number of years, we have focused on characterizing immune parameters at the tumor microenvironment as a means of identifying targets for manipulation with the ultimate goal of inducing tumor-specific immunity. Our novel hypothesis that manipulation of the tumor microenvironment via gene transfer using poxvirus recombinants led us to perform a series of Phase I studies of intralesional wild type vaccinia and recombinant vaccinia encoding GM-CSF in melanoma and subsequently intravesical wild type vaccinia in bladder cancer. Our current study of intravesical gene transfer in bladder cancer is a direct translation of our preclinical studies and early clinical trials. This study, required by the FDA as it represents a first-in-man intravesical administration of recombinant poxvirus, provides us a unique opportunity to assess critical questions as to the ability to modulate the bladder microenvironment with the ultimate goal of engendering a positive immune response. We have chosen agents, rF-GM-CSF and rF-TRICOM, based on our preclinical studies demonstrating depressed antigen presentation associated with the tumor-associated cytokine profile. In addition, we are using recombinants with the reporter gene B-galactosidase (B-gal) to not only quantitate efficiency of transfection but also as an antigen with which to study the ability to immunize via the bladder compartment which has not been done previously. These studies will provide critical data for subsequent use of recombinant poxvirus recombinants as local/systemic therapy for bladder cancer. More specifically, we propose to: 1. Determine local and systemic toxicity associated with the intravesical instillation of rF-GM-CSF and/or TRICOM and establish an MTD/Phase II dose. 2. Determine the efficiency of infection/transfection of the urothelium arid tumor following intravesical rF-GM-CSF and/or rF-TRICOM 3. Define the localized immune response in the bladder following intravesical rF-GM-CSF and/or rF-TRICOM and 4. Assess the ability to immunize bladder cancer patients via the bladder compartment. We believe that the results of these studies will provide critical insights as to the ability to use intravesical gene transfer as a therapeutic modality for bladder cancer and allow us an enhanced ability to design critical Phase II trials.