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: 10020925
• 负责人: Mark Cobbold
• 金额: $ 40.82万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020925
• 关键词: Address; Antibodies; Antibody-drug conjugates; Antigens; Antiviral Agents; 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; 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 Antigens; Virus; Woman; Work; Xenograft Model; anti-PD1 therapy; antibody libraries; antigen processing; antitumor effect; antiviral immunity; base; cancer cell; cancer type; cell mediated immune response; clinical 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.

项目摘要 总结 头颈部癌症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）。最近，免疫疗法，以免疫的形式， 检查点阻断（ICB）被证明在恢复T细胞介导的免疫应答方面是有效的， 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，部分原因是免疫系统的异质性。 但主要是由于突变数量的变化，肿瘤突变负荷（TMB） 与反应的可能性密切相关。现在有压倒性的证据表明， 肿瘤控制中T细胞靶向新抗原，但不幸的是，大多数（> 80%）头部肿瘤患者 并且颈部癌缺乏足够的新抗原来响应ICB。 一个复合率限制因素是肿瘤特异性免疫的低频率，即使在肿瘤特异性免疫中也难以检测到。 ICB应答患者中。相比之下，我们发现HNSCC患者具有极高水平的 对持久性病毒的免疫力可以超过50%的CD8 + T细胞。然而，这种免疫力无法 由于T细胞受体（TCR）的高度特异性，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的 递送高免疫原性肽抗原，我们可以重新编程肿瘤细胞， 预先存在的细胞毒性T细胞。 在我们实验室最近的一项进展中，我们已经能够通过以下方法选择性地重编程肿瘤抗原性： 使用抗体递送的MHC I类限制性肽抗原的释放。我们已经研制出抗体 肽-表位缀合物（APEC）可以选择性地将肽递送至细胞表面， 表面装载到空MHC I类分子中而不被内化。根据初步结果，我们 我建议开发一种能够调节HNSCC上展示的抗原的生物素，以匹配肿瘤 抗原性与预先存在的CTL库。 在P01赠款的支持下，我们的目标是开发和测试一种新的免疫治疗方法， 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，并设计APEC 有效地和选择性地重编程MHC I类分子以呈递主要病毒抗原;（2）了解 抗原重编程的体内限制和与ICB的测试协同作用以及通过 5 '氮杂胞苷在体内重定向针对人HNSCC的人抗病毒免疫。