Cancer Immunotherapy

项目总结 癌症免疫治疗计划(CIM)的首要目标是加强对癌症的了解 免疫系统与癌症之间的相互作用，以及开发新的、有效的癌症免疫疗法。 这些目标将通过(一)促进协作研究，(二)开发和应用技术来实现 以高维度探测免疫系统，以及(Iii)支持和支持床到床 翻译以同时提供新的免疫疗法和发现生物标记物和机制 对免疫疗法的抵抗力。在当前资助期间由计划成员领导的基础研究 时期加深了对T细胞受体(TCR)的理解：多肽相互作用并发现了意想不到的 全身对肿瘤微环境(TME)局部免疫反应的贡献。计划成员 (I)产生了新技术，极大地增强了从下一代TCR收集的信息 测序；(2)创建了第一个能够识别孤儿TCR靶标的平台；以及(3)开发了 多重离子束成像(MIBI)，使FFPE组织中的蛋白质分析具有无与伦比的维度。 CIM成员的翻译研究(I)创造了“免疫刺激性抗体结合物”(ISACs)来诱导 抗肿瘤免疫；(Ii)确定了T细胞耗竭的基本特性，并创建了抗耗竭能力 和过继细胞疗法的耗竭逆转平台；(3)发现抗原密度阈值是主要的 汽车功能调节器并创造了调整这种阈值的方法；(4)翻译设计合理 CAR-T细胞疗法进入临床试验，为难治性癌症患者提供了好处；以及(V) 创建了一个强大的反向翻译计划，该计划正在识别新的反应生物标志物和途径 对汽车疗法的抗拒。由医学博士克里斯托·麦考尔和医学博士埃德加·恩格曼共同领导的27名成员 该计划代表了医学院(SOM)的11个部门。计划成员主要是 许多NCI R01和P01、两个U54、一个R21、一个R35和一个NIH T32奖助金的参与者。同辈- 审查的资金包括来自NCI的430万美元，来自其他NIH的310万美元，以及来自其他同行审查的360万美元 来源，总计110万美元。自2015年以来，发表了442篇论文，其中11%是方案内论文，42%是方案间论文 计划性，以及94%的多机构合作。今后的主要努力将寻求：(一)界定机制 导致癌症转移的系统免疫耐受性；(Ii)利用先进的算法审问 TCR序列的大数据集；(Iii)扩大单细胞技术的使用，以提高对TCR序列的理解 癌症的免疫生物学和免疫疗法的预测/预防毒性；(Iv)开发下一代细胞 治疗平台，并进行临床试验，以提高过继细胞疗法的疗效；及(V) 扩展已经强大的反向翻译计划，以定义响应的生物标记物和途径 对CAR-T细胞疗法的抵抗。

PROJECT SUMMARY The overarching goals of the Cancer Immunotherapy Program (CIM) are to enhance understanding of the interaction between the immune system and cancer and to develop novel, effective cancer immunotherapies. These goals will be achieved by (i) fostering collaborative research, (ii) developing and applying technologies to probe the immune system with high dimensionality, and (iii) enabling and supporting bench-to-bedside-to-bench translation to simultaneously deliver novel immunotherapies and discover biomarkers and mechanisms of resistance to immunotherapies. Fundamental research led by program members during the current funding period has enhanced understanding of T cell receptor (TCR):peptide interactions and identified unexpected systemic contributions to local immune responses in the tumor microenvironment (TME). Program members have (i) generated new technologies that greatly enhance the information gleaned from next-generation TCR sequencing; (ii) created the first platform capable of identifying targets of orphan TCRs; and (iii) developed multiplex ion beam imaging (MIBI), which enables unparalleled dimensionality of protein analysis in FFPE tissue. Translational research by CIM members (i) created “immune stimulating antibody conjugates” (ISACs) to induce antitumor immunity; (ii) defined fundamental properties of T cell exhaustion and created exhaustion-resistance and exhaustion-reversal platforms for adoptive cell therapy; (iii) discovered antigen density thresholds as a major regulator of CAR functionality and created approaches to tune such thresholds; (iv) translated rationally designed CAR-T cell therapies into clinical trials, which have provided benefit for patients with refractory cancers; and (v) created a robust reverse translation program that is identifying novel biomarkers of response and pathways of resistance to CAR therapeutics. Co-led by Crystal Mackall, MD, and Edgar Engleman, MD, the 27 members of the program represent 11 departments in the School of Medicine (SOM). Program members are major participants in a number of NCI R01s and P01s, two U54s, an R21, an R35, and one NIH T32 grant. Peer- reviewed funding consists of $4.3M from the NCI, $3.1M from other NIH, and $3.6M from other peer-reviewed sources, totaling $11.0M. Since 2015, 442 papers have been published, with 11% intra-programmatic, 42% inter- programmatic, and 94% multi-institutional collaborations. Major future efforts will seek to (i) define mechanisms of systemic immune tolerance that enable cancer metastasis; (ii) leverage advanced algorithms to interrogate large datasets of TCR sequences; (iii) expand the use of single-cell technologies to improve understanding of the immunobiology of cancer and predict/prevent toxicity of immunotherapies; (iv) develop next-generation cell therapy platforms and conduct clinical trials aimed at improving the efficacy of adoptive cell therapies; and (v) expand an already robust reverse translational program to define biomarkers of response and pathways of resistance to CAR-T cell therapies.