Immunochaperone-based gene therapy targeting prostate cancer

描述(申请人提供：虽然手术是前列腺癌的一种重要治疗方法，但切除原发肿瘤可能会排除产生针对肿瘤复发的有效长期保护的机会。这里测试的原则验证概念是，前列腺癌在切除之前，可以被改造成自我摧毁并刺激强大和持续的免疫反应。我们假设，死亡和濒临死亡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，将降低局部和/或转移性肿瘤复发的可能性。前列腺癌细胞在加入MDA-7基因后，将在体内自毁。MDA-7是一种新的肿瘤抑制细胞因子，可在不损害正常细胞的情况下诱导癌细胞的凋亡和细胞死亡。同时，前列腺癌细胞将被改造成产生一种有效的免疫刺激剂Grp170，作为一种诱导抗原特异性免疫的“疫苗”。利用临床相关模型，我们将确定瘤内注射表达分泌Grp170和MDA-7的基因以根除前列腺癌和转移的治疗效果(目标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(目标2)。该提案将提供第一个实验证据，检验通过联合原位输送两种针对肿瘤和免疫系统的治疗分子可以产生系统性抗肿瘤免疫反应的概念。丙二醛-7已经在临床上进行了评估，并显示出对晚期癌症的安全性和抗肿瘤活性。这项拟议的研究可能会在不久的将来导致设计一项针对前列腺癌患者的临床试验。

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.