AUTOLOGOUS LMI VACCINE FOR MELANOMA AND RENAL CELL CARCINOMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。转移性黑色素瘤和肾细胞癌是无法治愈的恶性肿瘤，平均生存期不到一年。免疫刺激与白细胞介素(IL)-2已证明在治疗这些癌症的一些疗效。疫苗接种也被认为是一种治疗黑色素瘤和肾细胞癌的增强抗肿瘤T细胞反应的方法。肿瘤免疫治疗的一种新形式是在细胞大小（直径5微米）的微球表面施用肿瘤抗原。抗原，以蛋白质或细胞膜的形式，移位在二氧化硅微球上，为抗原特异性细胞毒性T淋巴细胞（CTL）激活提供了有效的刺激，从而导致肿瘤细胞死亡。这种形式的抗原呈递称为大多价免疫原（LMI）。用包被肿瘤膜的LMI接种荷瘤小鼠，恶性病变明显消退。本研究的主要目的是测试自体肿瘤膜包被LMI治疗转移性黑色素瘤和肾细胞癌患者的安全性。为诊断和分期或缓解症状而接受手术切除肿瘤或受影响淋巴结的患者将有资格参加。肿瘤细胞的膜从切除的组织中分离出来，附着在5微米的硅珠上。在第1天给予单剂量化疗药物环磷酰胺，它可以抑制抑制性T细胞，从而阻止疫苗接种产生足够的免疫反应。在第8天和第36天给予LMI。第1周每日皮下给予IL-2。LMI给药后5天（第13-20天和第41-48天）。前6名患者单独接受环环磷酰胺和LMI治疗，以评估这种联合治疗的安全性。随后的患者（最多30名）将接受环环磷酰胺、疫苗和四种剂量水平中的一种IL-2治疗，以确定这些药物的安全性。次要目的是确定接种疫苗后是否产生免疫应答，尽管本研究的目的不是确定这种应答的统计学意义。细胞因子产生循环CTL和延迟型超敏反应（DTH）反应将决定免疫反应前后的疫苗接种。这些数据将为晚期黑色素瘤和肾细胞癌患者的肿瘤免疫学机制提供见解。GCRC将注射环磷酰胺、疫苗和白介素-2注射，并将从患者身上提取研究血液样本。此外，将在GCRC中进行DTH反应的皮肤试验。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Metastic melanoma and renal cell carconoma are incurable malignancies with an average survival of less than one year. Immune stimulation with interleukin (IL)-2 has demonstrated some efficacy in the treatment of these cancers. Vaccination has also been explored as a treatment that boosts antitumor T cell responses in melanoma, as well as renal cell carcinoma. A novel form of tumor immunotherapy involves the administration of tumor antigen on the surface of cell-sized (5 micron diameter) microspheres. Antigen, in the form of proteins or cell membranes, displaced on silica microspheres provide an effective stimulus for antigen-specific cytotoxic T lymphocytes (CTL) activation that results in tumor cell killing. This form of antigen presentation is termed Large Multivalent Immunogen (LMI). Vaccination of tumor-bearing mice with tumor membrane-coated LMI resulted in significant regression of malignant lesions. The primary objective of this study is to test the safety of autologous tumor membrane-coated LMI in the treatment of patients with metastic melanoma and renal cell carcinoma. Patients undergoing surgical resection of a tumor or affected lymph nodes for diagnosis and staging or for palliation of symptoms will be eligible to participate. Membranes from tumor cells are siloated from the resected tissue and attached to 5-micron silica beads. A single dose of the chemotherapy drug Cytoxan, which inhibits suppressor T cells that may prevent an adequate immune response to vaccination is given on day 1. LMI is administered on day 8 and 36. Daily subcutaneous IL-2 is given for week 1. 5 days after the LMI doses on days 13-20 and 41-48. The first 6 patients receive Cytoxan and LMI alone to evaluate the safety of this combination. Subsequent patients (up to 30) will be treated with Cytoxan, vaccine, and one of four dose levels of IL-2 in order to determine the safety of these agents together. The secondary objective is to determine whether an immune response is generated following vaccination, although this study is not designed to determine the statistical significance of such a response. Cytokine production by circulating CTL and the delayed-type hypersensitivity (DTH) reaction will determine immune response before and after vaccine administration. These data will provide insight into the mechanisms of tumor immunology in those patients with advanced melanoma and renal cell carcinoma. The GCRC will administer Cytoxan, the vaccine and IL-2 injections, and will draw research blood samples from patients. Further, skin test for DTH reactions will be performed in the GCRC.