Immunotherapy with Dendritic-Allogeneic Tumor Cells

树突状同种异体肿瘤细胞的免疫治疗

• 批准号: 7252652
• 负责人: SUYU SHU
• 金额: $ 29.74万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7252652
• 关键词: Active Immunotherapy; Allogenic; Anatomic Sites; Animals; Antigens; Autologous Dendritic Cells; Breast Carcinoma; CD8B1 gene; Cancer Vaccines; Cell Line; Cell fusion; Cell hybridization; Characteristics; Chemicals; Clinical Treatment; Clinical Trials; Dendritic Cells; Development; Disease regression; Haplotypes; Histocompatibility; Hybrid Cells; Hybrids; Immune; Immune response; Immunotherapy; Interferons; Laboratories; Melanoma Cell; Metastatic Melanoma; Molecular; Mus; Numbers; Plague; Polyethylene Glycols; Polyvalent Melanoma Vaccine; Protocols documentation; Rate; Reproducibility; Research Personnel; Source; System; T-Lymphocyte; Therapeutic Effect; Toxic effect; Transcriptional Activation; Treatment Efficacy; Up-Regulation; Vaccination; Vaccines; Virus; base; beta-Galactosidase; cancer immunotherapy; design; heterokaryon; immunogenicity; melanoma; neoplastic cell; preclinical study; programs; response; tumor

DESCRIPTION (provided by applicant): Dendritic cells (DCs) induce primary T cell responses and are being extensively evaluated as vehicles for antigen (Ag) delivery in cancer immunotherapy. One strategy employs the use of hybrid cells generated by fusing DCs with tumor cells. Technically, fusion using chemical fusogens such as polyethylene glycol (PEG) or viruses has been plagued by low efficiency, toxicity and poor reproducibility. We recently developed an electrofusion protocol with which heterokaryons are generated with high fusion rates. In pre-clinical studies, fusion cells stimulated IFN? secretion from both CD4 and CD8 immune T cells, and for immunotherapy, a single vaccination resulted in tumor regression. Based on these observations, we have recently designed a clinical trial for the treatment of metastatic melanoma by vaccination with fusion of autologous DCs and allogeneic melanoma cell lines (PMCV or CanvaxinTU). In this protocol, 3 selected allogeneic tumor cells provide a source of tumor-associated Ags. However, little laboratory analysis has focused on defining the immunogenicity and potential therapeutic effects of this approach. Because of the immune response to histo-incompatible allo-Ags on allogeneic tumor cells, immune responses to tumor Ags may be subjected to down- or up-regulation. The mechanisms of allogeneic tumor vaccine need to be analyzed. In this proposal, two animal tumor systems will be used for the development of allogeneic vaccine. The first system will utilize beta-galactosidase (beta-gal) as a surrogate tumor rejection Ag that has been introduced into the B16/F10 (H-2b) melanoma and 4T1 (H-2d) breast carcinoma. The second system consists of three murine melanomas [B16 (H-2b), K1735 (H-2k) and cloudman S91 (H-2d)] of different haplotypes but sharing a number of natural tumor-associated Ags. These allogeneic tumors will be electrofused with syngeneic DCs. Their molecular characteristics, immunogenicities, and therapeutic effects will be analyzed against syngeneic tumors. The specific aims are: 1) To determine the immunogenicity and therapeutic efficacy of syngeneic DC-allogeneic tumor (allo-DC-tumor) hybrids generated by electrofusion; 2) To characterize and analyze immune responses to tumor-associated Ags and to allogeneic histocompatibility Ags; 3) Active immunotherapy against advanced tumors; and 4) To generate tumor-immune T cells from mice immunized with allo-DC-tumor hybrid cells for adoptive immunotherapy.

描述（由申请人提供）：树突状细胞（DC）诱导原代T细胞反应，并被广泛评估为癌症免疫疗法中抗原（AG）递送的车辆。一种策略采用通过将DC与肿瘤细胞融合而产生的杂化细胞的使用。从技术上讲，使用化学融合剂（例如聚乙烯乙二醇（PEG））或病毒的融合因低效率，毒性和可重复性差而受到困扰。我们最近开发了一种电渗渗；通过该方案产生高融合速率。在临床前研究中，融合细胞刺激了IFN？ CD4和CD8免疫T细胞的分泌，对于免疫疗法，一次疫苗接种导致肿瘤消退。基于这些观察结果，我们最近设计了一项临床试验，用于通过与自体DC和同种异体黑色素瘤细胞系（PMCV或Canvaxintu）融合进行疫苗接种来治疗转移性黑色素瘤。在该方案中，3个选定的同种异体肿瘤细胞提供了与肿瘤相关的AG的来源。但是，很少的实验室分析重点是定义这种方法的免疫原性和潜在的治疗作用。由于对同种异体肿瘤细胞的组织不兼容的同异质反应的免疫反应，对肿瘤AG的免疫反应可能会受到下调或上调的影响。需要分析同种异性肿瘤疫苗的机制。在该提案中，将使用两个动物肿瘤系统用于同种异体疫苗的开发。第一个系统将利用β-半乳糖苷酶（β-GAL）作为替代肿瘤排斥AG，已引入B16/F10（H-2B）黑色素瘤和4T1（H-2D）乳腺癌中。第二个系统由不同的单倍型的三种鼠黑色素瘤[B16（H-2B），K1735（H-2K）和Cloudman S91（H-2D）]组成，但共享许多与自然肿瘤相关的AG。这些同种异体肿瘤将用合元DC电控。它们的分子特征，免疫原性和治疗作用将针对合成性肿瘤进行分析。具体目的是：1）确定合成性DC - 合成性肿瘤（Allo-DC-tumor）杂种的免疫原性和治疗功效； 2）表征和分析对肿瘤相关的AG和对同种异体组织相容性AG的免疫反应； 3）对晚期肿瘤的主动免疫疗法； 4）从用Allo-DC肿瘤杂化细胞免疫的小鼠产生肿瘤 - 免疫T细胞进行过养免疫疗法。