Cancer Immunotherapy

项目摘要 癌症免疫治疗计划（CIM）的首要目标是提高对癌症的认识。 免疫系统和癌症之间的相互作用，并开发新的，有效的癌症免疫疗法。 这些目标将通过以下方式实现：（i）促进合作研究，（ii）开发和应用技术， 用高维度探测免疫系统，以及（iii）实现和支持实验室到床边到实验室 翻译，同时提供新的免疫疗法，并发现生物标志物和机制， 对免疫疗法的抵抗。在当前资助期间由项目成员领导的基础研究 一段时间以来，加强了对T细胞受体（TCR）：肽相互作用的理解，并发现了意想不到的 在肿瘤微环境（TME）中对局部免疫应答的全身性贡献。计划会员 （i）产生了新技术，大大增强了从下一代TCR收集的信息 测序;（ii）创建了第一个能够识别孤儿TCR靶点的平台;以及（iii）开发了 多路离子束成像（MIBI），其能够在FFPE组织中实现无与伦比的蛋白质分析维度。 CIM成员的转化研究（i）创建了“免疫刺激抗体缀合物”（ISAC），以诱导 抗肿瘤免疫;（ii）定义T细胞耗竭的基本特性，并产生耗竭抗性 和过继性细胞治疗的耗竭逆转平台;（iii）发现抗原密度阈值作为主要的 CAR功能的调节器，并创建了调整这些阈值的方法;（iv）合理设计的 CAR-T细胞疗法进入临床试验，为难治性癌症患者提供了益处;以及（v） 创建了一个强大的反向翻译程序，该程序正在识别新的生物标志物的反应和途径， 对CAR疗法的抗性。由Crystal Mackall医学博士和埃德加恩格尔曼医学博士共同领导，27名成员 该计划的代表11个部门在医学院（SOM）。节目组成员主要 参与了一些NCI R 01和P01，两个U 54，一个R21，一个R35和一个NIH T32资助。同行- 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，以及来自其他同行评审的360万美元。 来源，总计1100万美元。自2015年以来，共发表了442篇论文，其中11%是计划内的，42%是跨计划的。 94%是多机构合作。今后的主要努力将力求：㈠确定机制 系统免疫耐受，使癌症转移;（ii）利用先进的算法来询问 TCR序列的大型数据集;（iii）扩大单细胞技术的使用，以提高对 癌症免疫生物学和预测/预防免疫疗法毒性;（iv）开发下一代细胞 治疗平台，并进行旨在提高过继细胞疗法疗效的临床试验;以及（v） 扩大已经强大的反向翻译程序，以确定生物标志物的反应和途径， 对CAR-T细胞疗法的耐药性。

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.