Project 2: Targeting Neoantigens for Lung Cancer Immunotherapy

项目总结/摘要 – 项目 2 使用免疫检查点抑制剂（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患有 显着的反应。 ICI 的抗肿瘤活性被认为部分是由 CD4 和 CD8 T 细胞介导的 识别新抗原，新抗原是源自肿瘤细胞表达基因突变的肽， 由 I 类或 II 类 MHC 分子呈递。因此，大多数患者对 ICI 没有反应可能是由于 预先存在的肿瘤特异性 T 细胞反应不足，先前激活的 T 细胞出现不可逆功能障碍 细胞或局部免疫抑制机制。能够增强或诱导从头开始的治疗性疫苗 功能性 T 细胞对新抗原的反应单独或与 ICI 或其他药物联合使用可能是有益的 克服肿瘤微环境中的免疫抑制的方法。假定的新抗原是 由于突变负荷高，在非小细胞肺癌中普遍存在，作为疫苗靶点可能优于自身抗原 因为能够做出反应的 T 细胞库不受中枢耐受机制的影响。 此外，理论上，疫苗可以针对多种新抗原，这可以克服 肿瘤上抗原和 MHC 表达以及单一新抗原质量的异质性。多个 可以使用肿瘤的全外显子组测序来检测编码突变来识别候选新抗原， 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 黑色素瘤新抗原疫苗最近提供了原理证明，并揭示了这种疫苗的潜力 癌症免疫治疗的个性化方法。 我们开发了一种新抗原疫苗接种的新方法，该方法利用全身给药 经改造可表达癌症特异性突变的自体 T 细胞 (Tvax)。该策略是由 我们实验室的临床数据表明，表达转基因编码的人类 T 细胞的过继转移 外源蛋白诱导针对转基因产物的有效 CD8 和 CD4 T 细胞特异性反应 即使对于免疫力严重受损的患者，后续输注也会增强疗效。 T 细胞提供 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 条件下进行基因改造和扩增，系统安全管理，交通高效 到淋巴结部位，将抗原递送到引发免疫反应的地方。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.