Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy

项目概要/摘要-项目2 免疫检查点抑制剂（ICI）的免疫疗法正在彻底改变许多癌症的治疗， 包括非小细胞肺癌（NSCLC），其中一小部分患有转移性疾病的患者 重要的回应。ICI的抗肿瘤活性被认为部分由CD 4+和CD 8 + T细胞介导 其识别新抗原，所述新抗原是源自肿瘤细胞中表达基因的突变的肽， 由I类或II类MHC分子呈递。因此，大多数患者对ICI的反应失败可能是由于 预先存在的肿瘤特异性T细胞应答不足，先前活化的T细胞不可逆功能障碍， 细胞或局部免疫抑制机制。一种能够加强或诱导新生的治疗性疫苗， 对新抗原的功能性T细胞应答可以单独或与ICI或其他免疫抑制剂组合是有益的。 克服肿瘤微环境中的免疫抑制的模式。推定的新抗原是 由于高突变负荷，在NSCLC中普遍存在，并且作为疫苗靶点可能上级自身抗原 因为能够应答的T细胞库不受中枢耐受机制的影响。 此外，理论上，疫苗可以靶向多种新抗原，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 可以使用肿瘤的全外显子组测序来鉴定候选新抗原以检测编码突变， 以及预测可能与MHC分子结合的肽的算法。治疗的初步临床应用 黑色素瘤中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抗原疫苗接种的新方法，其利用全身施用 工程化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，表达转基因的人T细胞的过继转移， 外源蛋白诱导了对转基因产物特异的有效的CD 8+和CD 4 + T细胞应答， 即使在免疫力严重受损的患者中，也可以通过随后的输注来增强。T细胞提供了 个性化药物的多功能平台，包括基于细胞的疫苗，因为它们可以很容易地 在cGMP条件下进行基因修饰和扩增，安全地全身给药，并有效地运输 到淋巴结部位以递送引发免疫应答的抗原。这个项目将把这个 在临床前模型和NSCLC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.