Immunochaperone-based gene therapy targeting prostate cancer

描述（由申请人提供）：虽然手术是前列腺癌的重要治疗方法，但切除原发性肿瘤可能会排除产生有效的长期保护以防止肿瘤复发的机会。这里测试的原理证明概念是，前列腺癌在切除之前，可以被设计成自毁并刺激有效和持续的免疫反应。我们假设，死亡和垂死的肿瘤细胞的微环境，包含能够产生高度特异性免疫反应的分子，将减少局部和/或转移性肿瘤复发的可能性。前列腺癌细胞在整合了mda-7基因后，会在体内自我毁灭，mda-7是一种新型的肿瘤抑制细胞因子，能诱导癌细胞凋亡和细胞死亡，而不会伤害正常细胞。与此同时，前列腺癌细胞将被工程化以产生一种有效的免疫刺激剂grp 170，其作为诱导抗原特异性免疫的“疫苗”。利用临床相关模型，我们将确定肿瘤内递送表达分泌型grp 170和mda-7的基因根除前列腺癌和转移的治疗效果（目的1）。我们将确定和表征参与长期抗肿瘤反应发展的潜在免疫机制（目的2）。该提案将提供第一个实验证据，测试系统性抗肿瘤免疫应答可以通过靶向肿瘤和免疫系统的2种治疗分子原位联合递送产生的概念。Mda-7已经在临床上进行了评估，并已显示出安全性以及对晚期癌症的抗肿瘤活性。这项拟议中的研究可能会在不久的将来为前列腺癌患者设计一项临床试验。

DESCRIPTION (provided by applicant: While surgery is an important treatment for prostate cancer, it is possible that removal of the primary tumor may preclude an opportunity for generating effective long-term protection against tumor recurrence. The proof-of principle concept tested here is that prostate cancer, prior to removal, can be engineered to self destruct and stimulate a potent and sustained immune response. We hypothesize that the microenvironment of dead and dying tumor cells, containing molecules capable of generating highly specific immune responses will diminish the potential for local and/or metastatic tumor recurrence. Prostate cancer cells following their incorporation of the gene for mda-7, a novel tumor suppressing cytokine that induces apoptosis and cell death in cancer cells without harming normal cells, will self-destruct in vivo. Simultaneously, the prostate cancer cells will have been engineered to produce a potent immunostimulatory agent, grp170, that serves as a "vaccine" inducing antigen specific immunity. Using clinically relevant models, we will determine the therapeutic efficacy of intratumor delivery of genes expressing secretable grp170 and mda-7 to eradicate prostate cancer and metastasis (aim 1). We will identify and characterize the underlying immune mechanisms involved in development of long-term antitumor responses (aim 2). The proposal will provide the first experimental evidence testing the concept that systemic antitumor immune responses can be generated by combined delivery of 2 therapeutic molecules in situ that target both the tumor and the immune system. Mda-7 is already being evaluated in the clinic and has shown safety as well as antitumor activity against advanced cancer. The proposed research could lead to the design of a clinical trial for patients with prostate cancer in the very near future.