Laust Amanda K, Sur Brandon W, Wang Kehui, Hubby Bolyn, Smith Jonathan F, Nelson Edward L
Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, CA 92697, USA.
Breast Cancer Res Treat. 2007 Dec;106(3):371-82. doi: 10.1007/s10549-007-9517-8. Epub 2007 Mar 10.
The ability to overcome intrinsic tolerance to a strict "self" tumor-associated antigen (TAA) and successfully treat pre-existing tumor is the most stringent test for anti-tumor immunotherapeutic strategies. Although this capacity has been demonstrated in various models using complicated strategies that may not be readily translated into the clinical arena, straightforward antigen-specific immunotherapeutic strategies in the most stringent models of common epithelial cancers have largely failed to meet this standard. We employed an immunotherapeutic strategy using an alphavirus-based, virus-like replicon particle (VRP), which has in vivo tropism for dendritic cells, to elicit immune responses to the non-mutated TAA rat neu in an aggressive rat mammary tumor model. Using this VRP-based immunotherapeutic strategy targeting a single TAA, we generated effective anti-tumor immunity in the setting of pre-existing tumor resulting in the cure of 36% of rats over multiple experiments, P = 0.002. We also observed down-regulation of rat neu expression in tumors that showed initial responses followed by tumor escape with resumption of rapid tumor growth. These responses were accompanied by significant anti-tumor proliferative responses and CD8+ cellular tumor infiltrates, all of which were restricted to animals receiving the anti-neu immunotherapy. Together these data, obtained in a stringent "self" TAA model, indicate that the VRP-based antigen-specific immunotherapy elicits sufficiently potent immune responses to exert immunologic pressure, selection, and editing of the growing tumors, thus supporting the activity of this straightforward immunotherapy and suggesting that it is a promising platform upon which to build even more potent strategies.
克服对严格的“自身”肿瘤相关抗原（TAA）的内在耐受性并成功治疗已存在肿瘤的能力，是对抗肿瘤免疫治疗策略最严格的考验。尽管在各种模型中已通过复杂策略证明了这种能力，而这些策略可能难以直接转化到临床领域，但在常见上皮癌最严格的模型中，直接的抗原特异性免疫治疗策略在很大程度上未能达到这一标准。我们采用了一种基于甲病毒的病毒样复制子颗粒（VRP）的免疫治疗策略，该颗粒在体内对树突状细胞具有嗜性，以在侵袭性大鼠乳腺肿瘤模型中引发针对未突变TAA大鼠neu的免疫反应。使用这种针对单一TAA的基于VRP的免疫治疗策略，我们在已存在肿瘤的情况下产生了有效的抗肿瘤免疫力，在多个实验中使36%的大鼠得以治愈，P = 0.002。我们还观察到，在最初出现反应随后肿瘤逃逸并恢复快速生长的肿瘤中，大鼠neu表达下调。这些反应伴随着显著的抗肿瘤增殖反应和CD8 + 细胞肿瘤浸润，所有这些都仅限于接受抗neu免疫治疗的动物。在严格的“自身”TAA模型中获得的这些数据共同表明，基于VRP的抗原特异性免疫疗法引发了足够强大的免疫反应，从而对生长中的肿瘤施加免疫压力、进行选择和编辑，因此支持了这种直接免疫疗法的活性，并表明它是一个有前景的平台，可在此基础上构建更强大的策略。
