Overcoming the immune-suppressive tumor microenvironment through in situ vaccination nanotechnology.

摘要 肿瘤产生的免疫抑制微环境是免疫清除的关键障碍。 从而使癌症得以显现。我们建议使用一种类似植物病毒的纳米粒子来克服这一障碍- TILECT(VLP)平台技术用于原位接种，消除局部免疫抑制，产生有效的免疫抑制。 有效的局部和全身抗肿瘤免疫。我们最近展示了植物生产、工程设计的 基于VLP的纳米技术在转移性小鼠模型中激发强大的抗肿瘤免疫反应 黑色素瘤、卵巢癌和乳腺癌。数据表明，这种影响是系统性和持久性的，结果 在免疫记忆和防止复发方面。伴犬转移性疾病的初步研究 黑色素瘤表明，其强大的抗肿瘤功效可在犬类动物模型中复制，具有较高的 与人类黑色素瘤的相关性。原位疫苗接种提供了一种个性化的治疗方法，通过缓解 肿瘤介导的免疫抑制和增强抗肿瘤免疫抗原性。 被自己的肿瘤压迫着。拟议的使用植物VLP的纳米工程方法将改善 在几个方面的护理标准。首先，原位接种将增加抗原特异性T细胞的频率 细胞，导致持久的免疫记忆；这与检查点抑制剂不同，后者不是一种 Tigen特异性，激活所有经历过抗原的T细胞，并导致非靶标免疫毒性。其次，FDA- 经批准的使用T-VEC的原位疫苗接种证明了这种方法，但由于使用了AT-VEC，因此受到限制。 弱毒疱疹病毒具有传染性，稳定性差，每剂的价格也很高。而当 我们的支持数据表明在各种肿瘤模型中具有强大的疗效，其潜在的免疫学是 非常独特，还没有完全被理解。因此，这一提议的实质是解密 强大的纳米技术的工程设计空间，并勾勒出潜在的机械-- 行动的NISM。因此，这项提议旨在实现以下目标：1)破译VLP的分子-- LAR特征触发了强大的疗效。2)阐明免疫激活的潜在机制 由贵宾们准备好。3)进一步深入了解其作用机制和功效。 患有口腔黑色素瘤的伴侣犬。多PI伙伴关系和合作调查人员将有助于 节目的成功。总之，数据将提供抗肿瘤免疫激活的详细机制 并将向纳米工程学提供信息，以进一步改进方法和 开始在人类患者身上测试它的努力。

Summary The immune-suppressive microenvironment generated by tumors is a key barrier to immune clearance and thereby, enables cancer to manifest. We propose to overcome this barrier using a plant virus-like nanopar- ticle (VLP) platform technology for in situ vaccination, to eliminate local immunosuppression and generate ef- fective local and systemic anti-tumor immunity. We recently demonstrated that plant-produced, engineered VLP-based nanotechnologies stimulate a potent anti-tumor immune response in mouse models of metastatic melanoma, ovarian cancer, and breast cancer. Data indicate that the effect is systemic and durable, resulting in immune-memory and protection from recurrence. Preliminary studies in companion dogs with metastatic melanoma indicate that the potent anti-tumor efficacy can be replicated in the canine model, which has high relevance to human melanoma. In situ vaccination provides a personalized treatment approach by relieving the patient's tumor-mediated immunosuppression and potentiating anti-tumor immunity against antigens ex- pressed by their own tumor. The proposed nanoengineering approach using plant VLPs would improve the standard of care in several ways. First, in situ vaccination will increase the frequency of antigen-specific T cells, leading to long-lasting immunologic memory; this is in contrast to checkpoint inhibitors, which are not an- tigen specific, activate all antigen-experienced T cells and result in off-target immune toxicities. Second, FDA- approved in situ vaccination using T-VEC demonstrates the approach but is limited because of the use of at- tenuated herpes virus, which can be infectious, has poor stability and an extraordinary price per dose. While our supporting data indicate potent efficacy in various tumor models, the underlying immunology is quite unique and not yet completely understood. Therefore, the essence of this proposal is to decipher the engineering design space of the potent nanotechnology and to delineated the underlying mecha- nism of action. Therefore, this proposal sets out to fulfill the following aims: 1) To decipher the VLP's molecu- lar features triggering the potent efficacy. 2) To delineate the underlying mechanisms of immune activation primed by the VLPs. 3) To gain further insights into the mechanism of action and efficacy through study of companion dogs with oral melanoma. A multi-PI partnership and collaborating investigators will contribute to the success of the program. Together, data will provide detailed mechanisms of anti-tumor immune activation by engineered VLP nanotechnologies and will inform nanoengineering to further improve the approach and begin the effort to test it in human patients.