MHC CLASS II BASED TUMOR VACCINE

MHC类Il分子在缺乏抑制li蛋白的肿瘤细胞中呈递内源性肿瘤抗原可产生有效的抗肿瘤反应。肿瘤细胞可以是MHC Il阳性或阴性。我们通过选择性抑制MHC类Il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。其他人通过简单表达外源性MHC Il类基因（不表达li基因）在MHC Il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，利用MHC类Il反激活基因（CIITA）诱导适当的MHC II类基因表达，同时抑制li基因表达。CIITA基因具有诱导内源性MHC Il类基因的优势，这一点很重要，因为这些基因是高度多态性的。然而，Ii基因的表达也会被CIITA诱导，因此需要使用我们之前建立的li抑制方法。我们最初专注于结肠癌，因为对复发性疾病的治疗是有限的，使用广泛免疫刺激机制的初步临床试验显示出希望。在本研究的I期部分，我们将利用含有腺病毒和li反义的重组CIITA建立MHC Il诱导和li抑制的最佳剂量条件，以实现小鼠结肠癌细胞系（MC-38）的体内肿瘤免疫。成功将触发i期研究，其中我们将使用人类基因序列开发适当的构建物，在原发性人类肿瘤样本中证明活性，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。建议的商业应用：在癌症治疗方面有显著的未满足的需求。我们正在开发的免疫疗法将适用于几乎所有类型的癌症。由于我们的技术是基于一种特定的抗肿瘤策略（即，与传统的细胞毒性化疗药物相反），它可以很容易地与当前的治疗方式相结合。

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.