Project 2: Redirecting pre-existing anti-viral immunity to HNSCCs with APECs

项目 2：利用 APEC 将已有的抗病毒免疫力重定向至 HNSCC

• 批准号: 10478896
• 负责人: Thorsten Roman Mempel
• 金额: $ 40.01万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478896
• 关键词: Address; Antibodies; Antibody-drug conjugates; Antigens; Azacitidine; Binding; Biological Response Modifier Therapy; Blood; CD8-Positive T-Lymphocytes; CDH3 gene; Cell Line; Cell surface; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Cytomegalovirus; Cytotoxic T-Lymphocytes; Data; Data Analyses; Defect; EPHB2 gene; Epidermal Growth Factor Receptor; Epigenetic Process; Epitopes; Frequencies; Future; Gene Expression; Grant; Head and Neck Cancer; Head and Neck Neoplasms; Head and Neck Squamous Cell Carcinoma; Herpesviridae; Heterogeneity; Histocompatibility; Histocompatibility Antigens Class I; Human; Human Herpesvirus 4; Human Papillomavirus; I-antigen; Immune; Immunity; Immunodeficient Mouse; Immunotherapeutic agent; Immunotherapy; In Vitro; Kinetics; Knowledge; Laboratories; Lead; MHC Class I Genes; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mediating; Memory; Mutation; New Agents; PD-1 inhibitors; Patients; Peptide Hydrolases; Peptide antibodies; Peptides; Persons; Pharmacodynamics; Population; Site; Specificity; Surface; Surface Antigens; T-Cell Activation; T-Cell Antigen Receptor Specificity; T-Lymphocyte; TACSTD1 gene; Technology; Testing; Therapeutic; Tumor Antigens; United States; Variant; Viral; Viral Antigens; Virus; Woman; Work; Xenograft Model; anti-PD1 therapy; antibody libraries; antibody test; antigen processing; antitumor effect; antiviral immunity; base; cancer cell; cancer type; cell mediated immune response; clinical trial implementation; cytotoxic; cytotoxic CD8 T cells; design; head and neck cancer patient; human disease; human model; immune checkpoint blockade; immune resistance; immunogenic; improved; in silico; in vivo; in vivo evaluation; men; neoantigens; neoplastic cell; novel strategies; novel therapeutics; peptide I; programmed cell death protein 1; reconstitution; response; success; synergism; tumor; tumor-immune system interactions

PROJECT SUMMARY Summary Head and neck cancer accounts for about 4% of all cancers in the United States with an estimated 64,690 people (47,650 men and 17,040 women) new cases this year. Recently immunotherapy, in the form of immune checkpoint blockade (ICB), is proving to be effective at restoring T cell mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients with cancer – particularly head and neck cancers. Patients respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition but mainly due to variation in the number of mutations, with the tumor mutational burden (TMB) strongly correlating with the likelihood of response. There is now overwhelming evidence that mutation-derived neoantigens are targeted by T-cells in tumor control but unfortunately the majority (>80%) of patients with head and neck cancer lack sufficient neoantigens to respond to ICB. A compounding rate limiting factor is the low frequency of tumor-specific immunity which is difficult to detect even in ICB responding patients. In contrast we have found patients with HNSCC have extremely high levels of immunity against persistent viruses which can be over 50% of CD8+ T-cells. Yet this immunity is unable to participate in targeting cancer cells due to the exquisite specificity of the T-cell receptor (TCR). Currently, there are no mechanisms to alter or increase antigens in cancer. We hypothesize that by selective delivery of highly immunogenic peptide antigens, we can reprogram tumor cells to strongly engage with pre-existing cytotoxic T-cells. In a recent advance from our laboratory, we have been able to selectively reprogram tumor antigenicity through the release of MHC class-I restricted peptide antigens, delivered using antibodies. We have developed antibody peptide-epitope conjugates (APECs) can selectively deliver peptides to the cell surface that then passively surface-load into empty MHC class-I molecules without becoming internalized. Based on preliminary results, we propose to develop a biotherapeutic that is able to modulate the antigens displayed on HNSCC, to match tumor antigenicity with preexisting CTL repertoire. With support through this P01 grant, we aim to develop and test a new immunotherapeutic approach for treating TMB low head and neck cancer. The specific aims of the study are:- (1) map anti-viral immunity in patients with HNSCC and then design APECs that efficiently and selectively reprogram MHC class-I molecules to present leading viral antigens; (2) Understand the in vivo constraints of antigenic reprogramming and test synergy with ICB and epigenetic modulation via 5'azacytidine to redirect human anti-viral immunity against human HNSCC in vivo.

项目总结 摘要 头颈癌约占美国所有癌症的4%，估计有64,690人 (47,650名男性和17,040名女性)今年的新病例。最近的免疫疗法，以免疫的形式 检查点阻断(ICB)，已被证明在恢复T细胞介导的免疫反应方面有效，可以 导致显著和持续的临床反应，但仅在一些癌症患者中-特别是头部和 颈部癌症。患者对免疫治疗的反应不可预测，部分原因是免疫的异质性 组成，但主要是由于突变数量的变化，与肿瘤突变负担(TMB) 与反应的可能性密切相关。现在有压倒性的证据表明，突变源于 在肿瘤控制中，新抗原是T细胞的靶点，但不幸的是，大多数(&gt；80%)头部患者 而宫颈癌缺乏足够的新抗原来对ICB产生反应。 一个限制复合率的因素是肿瘤特异性免疫的低频率，即使是很难检测到 在ICB反应的患者中。相比之下，我们发现HNSCC患者体内有极高水平的 对CD8+T细胞中50%以上的持续病毒具有免疫力。然而，这种豁免权无法 由于T细胞受体(TCR)的精致特异性，参与靶向癌细胞。 目前，还没有改变或增加癌症抗原的机制。我们假设通过选择性地 交付高免疫原性多肽抗原，我们可以重新编程肿瘤细胞，使其与 先前存在的细胞毒性T细胞。 在我们实验室的最新进展中，我们已经能够选择性地重新编程肿瘤的抗原性 MHC-I类限制性多肽抗原的释放，使用抗体传递。我们已经研制出抗体 多肽-表位偶联物(APECs)可以选择性地将多肽递送到细胞表面，然后被动地 表面负载到空的MHC-I类分子中，而不会内化。根据初步结果，我们 建议开发一种生物疗法，能够调节HNSCC上展示的抗原，以匹配肿瘤 与先前存在的CTL谱系的抗原性。 在这笔P01拨款的支持下，我们的目标是开发和测试一种新的免疫治疗方法来治疗 TMB低头颈癌。 本研究的具体目的是：(1)绘制HNSCC患者的抗病毒免疫图谱，然后设计APECS 高效和选择性地重新编程MHC-I类分子以呈现领先的病毒抗原；(2)了解 ICB和表观遗传调控对抗原重编程和试验协同作用的体内制约 5‘氮胞苷在体内重定向抗人HNSCC的抗病毒免疫。