Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy

项目摘要/摘要-项目2 免疫检查点抑制剂(ICI)的免疫疗法正在给许多癌症的治疗带来革命性的变化， 包括非小细胞肺癌(NSCLC)，其中一小部分转移性疾病的患者 重要的回应。ICI的抗肿瘤活性被认为部分是由CD4和CD8T细胞介导的 识别新的抗原，这些新的抗原是从肿瘤细胞和 由I类或II类MHC分子呈递。因此，大多数患者对ICI反应失败的原因可能是 预先存在的肿瘤特异性T细胞反应不足，先前激活的T细胞不可逆转的功能障碍 细胞，或局部免疫抑制机制。一种能够促进或诱导新生的治疗性疫苗 功能性T细胞对新抗原的反应可能是单独有益的，或者与ICI或其他 克服肿瘤微环境中免疫抑制的方法。推定的新抗原是 由于高突变负荷而在非小细胞肺癌中流行，作为疫苗靶点可能优于自身抗原 因为具有反应能力的T细胞库不受中枢耐受机制的影响。 此外，从理论上讲，一种疫苗可以针对多种新抗原，这可以克服 肿瘤上抗原和MHC表达的异质性，以及单一新抗原的质量。多重 可以使用肿瘤的整个外显子组测序来识别候选新抗原以检测编码突变， 以及预测多肽可能与MHC分子结合的算法。治疗性药物的初步临床应用 黑色素瘤的新抗原疫苗最近提供了原理证明，并揭示了这一点的潜力。 癌症免疫治疗的个性化方法。 我们已经开发了一种新的新抗原疫苗接种方法，它利用系统地给药 经过改造以表达癌症特异性突变的自体T细胞(TVAX)。这一战略是由 我们实验室的临床数据显示，过继转移表达转基因编码基因的人T细胞 外源蛋白诱导针对转基因产物的CD8和CD4T细胞反应 即使在免疫力严重受损的患者中，随后的输液也会增强这种作用。T细胞提供了一种 个性化药物的通用平台，包括基于细胞的疫苗，因为它们可以很容易 转基因并在cGMP条件下扩展，系统安全管理，交通高效 到淋巴结处传递抗原，在那里启动免疫反应。这个项目将翻译这个 在临床前模型和非小细胞肺癌患者中接种新抗原的独特方法。

Project Summary/Abstract – Project 2 Immunotherapy with immune checkpoint inhibitors (ICI) is revolutionizing the treatment of many cancers, including non-small cell lung cancer (NSCLC) where a small subset of patients with metastatic disease have significant responses. The antitumor activity of ICI is thought in part to be mediated by CD4+ and CD8+ T cells that recognize neoantigens, which are peptides derived from mutations in expressed genes in tumor cells and presented by class I or II MHC molecules. Thus, the failure of most patients to respond to ICI may result from an insufficient pre-existing tumor-specific T cell response, irreversible dysfunction of previously activated T cells, or local immunosuppressive mechanisms. A therapeutic vaccine capable of boosting or inducing de novo functional T cell responses to neoantigens could be beneficial alone, or in combination with ICI or other modalities that overcome immunosuppression in the tumor microenvironment. Putative neoantigens are prevalent in NSCLC due to the high mutation burden, and may be superior to self-antigens as vaccine targets because the T cell repertoire capable of responding is not affected by central tolerance mechanisms. Moreover, multiple neoantigens can theoretically be targeted by a vaccine, which could overcome heterogeneity in antigen and MHC expression on tumors, and in the quality of a single neoantigen. Multiple candidate neoantigens can be identified using whole exome sequencing of tumors to detect coding mutations, and algorithms that predict peptides likely to bind to MHC molecules. Initial clinical applications of therapeutic neoantigen vaccines in melanoma have recently provided proof-of-principle, and revealed the potential of this personalized approach to cancer immunotherapy. We have developed a novel approach to neoantigen vaccination that utilizes the systemic administration of autologous T cells engineered to express cancer-specific mutations (Tvax). This strategy was suggested by clinical data from our lab showing that adoptive transfer of human T cells expressing transgenes encoding foreign proteins induced potent CD8+ and CD4+ T cell responses specific for the transgene product that were boosted by subsequent infusions, even in patients with severely compromised immunity. T cells provide a versatile platform for personalized medicines, including cell based vaccines because they can be easily genetically modified and expanded in cGMP conditions, safely administered systemically, and traffic efficiently to lymph node sites to deliver antigens where immune responses are initiated. This project will translate this unique approach for vaccination to neoantigens in preclinical models and patients with NSCLC.