MHC CLASS II BASED TUMOR VACCINE

基于 MHC II 类的肿瘤疫苗

• 批准号: 6144491
• 负责人: MINZHEN XU
• 金额: $ 17.33万
• 依托单位: ANTIGEN EXPRESS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-14 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6144491
• 关键词: Adenoviridae; MHC class II antigen; antisense nucleic acid; cell line; colon neoplasms; drug screening /evaluation; gene expression; gene therapy; genetic polymorphism; invariant chain; laboratory mouse; molecular cloning; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; neoplastic cell; transcription factor; transfection /expression vector; tumor antigens; vaccine development; vector vaccine

Presentation of endogenous tumor antigens by MHC class Il molecules in tumor cells lacking the inhibitory li protein generates an effective anti- tumor response. Tumor cells can be either MHC class Il positive or negative. We have demonstrated potent anti-tumor immunity in mice by selective inhibition of the li protein in MHC class Il positive tumor cells. Others have demonstrated similar results in MHC class Il negative tumor cells by simply expressing exogenous MHC class Il genes (without li gene expression). To produce a universal anti-tumor immunotherapy strategy, we are now developing a gene therapy approach to induce appropriate MHC class II gene expression using the MHC class Il transactivator gene (CIITA) concomitant with inhibition of li gene expression. The CIITA gene has the advantage of inducing the endogenous MHC class Il genes, which is important as these genes are highly polymorphic. However, Ii gene expression is also induced by CIITA, requiring the use of our previously established methodology for li inhibition. We are focussing initially on colon cancer because treatment for recurrent disease is limited and initial clinical trials using broadly immunostimulatory mechanisms have shown promise. During the Phase I portion of this study, we will establish the optimal dosing conditions for MHC class Il induction and li inhibition using recombinant CIITA containing adenovirus and li antisense to achieve in vivo tumor immunity using a murine colon cancer cell line (MC-38). Success will trigger phase Il studies, wherein we will develop appropriate constructs using human gene sequences, demonstrate activity in primary human tumor samples, establish the broad range applicability of our approach and complete all necessary studies requisite to an IND filing. PROPOSED COMMERCIAL APPLICATIONS: There is a significant unmet need for cancer therapy. The immunotherapy approach we are developing will be applicable to nearly all types of cancer. As our technology is based on a specific anti-tumor strategy (i.e., as opposed to classical cytotoxic chemotherapeutic agents) it can be readily dovetailed with current treatment modalities.

在缺乏抑制性li蛋白的肿瘤细胞中通过MHC II类分子呈递内源性肿瘤抗原产生有效的抗肿瘤应答。肿瘤细胞可以是MHC II类阳性或阴性。我们已经通过选择性抑制MHC II类阳性肿瘤细胞中的li蛋白在小鼠中证明了有效的抗肿瘤免疫。其他人通过简单地表达外源性MHC II类基因（没有li基因表达）在MHC II类阴性肿瘤细胞中证明了类似的结果。为了产生一种通用的抗肿瘤免疫治疗策略，我们现在正在开发一种基因治疗方法，以诱导适当的MHC II类基因的表达，使用MHC II类反式激活基因（CIITA）伴随着抑制li基因的表达。CIITA基因具有诱导内源性MHC II类基因的优点，这是重要的，因为这些基因是高度多态性的。然而，Ii基因表达也诱导CIITA，需要使用我们以前建立的方法抑制。我们最初将重点放在结肠癌上，因为复发性疾病的治疗是有限的，并且使用广泛的免疫刺激机制的初步临床试验已经显示出希望。在本研究的I期部分，我们将使用含有腺病毒和li反义的重组CIITA建立用于MHC II类诱导和li抑制的最佳给药条件，以使用鼠结肠癌细胞系（MC-38）实现体内肿瘤免疫。成功将触发II期研究，其中我们将使用人类基因序列开发适当的构建体，在原发性人类肿瘤样品中证明活性，建立我们方法的广泛适用性，并完成IND申请所需的所有必要研究。拟议的商业应用：癌症治疗存在显著的未满足需求。我们正在开发的免疫治疗方法将适用于几乎所有类型的癌症。由于我们的技术是基于特定的抗肿瘤策略（即，与经典的细胞毒性化疗剂相反），其可以容易地用当前的治疗方式来替代。