The Landscape of Tumor intrinsic Genetic Resistance to T cell Therapy

项目摘要/摘要 上皮癌是一种常见的恶性肿瘤，占人类癌症的80%到90%。 尽管在化疗、靶向治疗和免疫治疗方面取得了突破，但他们总体上 在晚期是无法治愈的。细胞疗法在某些方面显示出显著的疗效 晚期血液病，但应用该方法治疗上皮癌 变得更加困难。这个项目的短期目标是阐明细胞治疗的原理。 使用人类乳头瘤病毒(HPV)相关癌症作为疾病模型的上皮性癌症。 该项目的长期目标是发现和开发针对hpv相关的细胞疗法。 癌症和其他常见的恶性肿瘤。对Si2期的研究表明，肿瘤- 浸润性淋巴细胞可导致HPV相关的持久、完整的肿瘤反应 癌症；针对HPV癌蛋白的基因工程T细胞可以诱导强大的肿瘤 HPV相关癌症的消退--包括免疫检查点阻断耐药肿瘤； 和肿瘤固有的抗原处理机制(APM)和干扰素(干扰素)的遗传缺陷 反应通路控制着对工程化TCR-T细胞疗法的抵抗。 R00阶段的研究将建立在Si2发现的基础上，目标是1)阐明HPV- 相关癌症肿瘤固有免疫相关基因的多维图景 耐药(IRGR)和2)研究细胞治疗和免疫压力对IRGR的影响 以及IRGR对肿瘤细胞治疗反应的影响。将对与HPV相关的癌症进行概况分析 T细胞识别和杀伤肿瘤的特定功能基因的改变。此外, 将进行探索性分析，以确定候选免疫逃避基因 以高于预期的频率改变或驱动基于空间克隆的克隆进化 架构映射。细胞疗法对IRGR的影响，反之亦然，将通过 肿瘤浸润性淋巴细胞治疗患者HPV相关性肿瘤的研究 以及改良的TCR-T细胞疗法。免疫压力对IRGR的纵向影响将是 通过比较原发肿瘤和转移性肿瘤并通过分析连续的患者内部分析进行调查， 异时性肿瘤切除。这项研究将提供一个完整的理解 HPV相关癌症中免疫反应和IRGR的交互作用。这项工作至关重要 在细胞治疗的背景下理解免疫编辑和肿瘤耐药性 有必要指导预测性生物标志物的发现和下一步的合理设计 世代治疗策略。

PROJECT SUMMARY/ABSTRACT Epithelial cancers are common malignancies that account for 80 to 90 percent of human cancers. Despite breakthroughs in chemotherapy, targeted therapy, and immunotherapy, they generally are incurable in advanced stages. Cell therapy has shown remarkable efficacy in certain advanced stage hematologic cancers, but application of the approach to epithelial cancers has been more difficult. The short-term goal of this project is to elucidate principles of cell therapy in epithelial cancers using human papillomavirus (HPV)-associated cancers as a disease model. The long-term goal of this project is to discover and develop cellular therapy for HPV-associated cancers and other common malignancies. Research in the Si2 phase demonstrated that tumor- infiltrating lymphocytes can cause durable, complete tumor responses in HPV-associated cancers; genetically engineered T cells targeting an HPV oncoprotein can induce robust tumor regression in HPV-associated cancers – including immune checkpoint blockade resistant tumors; and tumor-intrinsic genetic defects in antigen processing machinery (APM) and interferon (IFN) response pathways control resistance to engineered TCR-T cell therapy. Research in the R00 phase will build on the Si2 findings with the goals to 1) elucidate in HPV- associated cancers a multidimensional picture of tumor-intrinsic immune related genetic resistance (IRGR) and 2) investigate the impact of cell therapy and immune pressure on IRGR and of IRGR on tumor response to cell therapy. HPV-associated cancers will be profiled for alterations in genes with defined function in tumor recognition and killing by T cells. In addition, exploratory analyses will be conducted to identify candidate immune evasion genes that are altered at frequencies greater than expected or that drive clonal evolution based on spatial clonal architecture mapping. The impact of cell therapy on IRGR and vice versa will be investigated by study of HPV-associated cancers from patients treated with tumor-infiltrating lymphocyte therapy and engineered TCR-T cell therapy. The longitudinal impact of immune pressure on IRGR will be investigated by comparing primary versus metastatic tumors and by analyzing serial intra-patient, metachronous tumor resections. This research will provide an integrated understanding of the reciprocal effects of immune response and IRGR in HPV-associated cancers. The work is critical to understanding immune editing and tumor resistance in the context of cell therapy and is necessary to guide the discovery of predictive biomarkers and the rational design of next- generation treatment strategies.