Antigen specific strategies for treatment of HIV+ cancer patients in the Montefiore/Einstein Cancer Center Catchment Area (Immuno/microenvironment)

蒙特菲奥里/爱因斯坦癌症中心流域地区治疗 HIV 癌症患者的抗原特异性策略（免疫/微环境）

• 批准号: 10710266
• 负责人: EDWARD CHU
• 金额: $ 25万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10710266
• 关键词: 2019-nCoV; AIDS related cancer; Address; Affect; Aging; Agonist; Albert Einstein Cancer Center; Antigens; Biological; Biological Products; Biology; CD28 gene; CD8-Positive T-Lymphocytes; Cancer Burden; Cancer Center; Cancer Center Support Grant; Cancer Etiology; Cancer Patient; Catchment Area; Cells; Chromatin; Clinical; Clinical Informatics; Clinical Trials; Clone Cells; Cohort Studies; Colon Carcinoma; Colorectal Cancer; Community Outreach; Conduct Clinical Trials; Development; Diagnostic; Disease; Education and Outreach; Effectiveness; Elements; Enrollment; Epigenetic Process; Epitopes; Ethnic Origin; Evaluation; Evolution; Fc domain; Funding; Future; Gender; Gene Expression; Genetic; Genetic Transcription; HIV; HIV Seronegativity; HIV Seropositivity; HPV E7; Harvest; Health system; Hematologic Neoplasms; Home; Hormonal; Human; Human Papillomavirus; Human papilloma virus infection; Imaging technology; Immune; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Industry; Infection; Infrastructure; Interleukin-2; Intestines; Investigational Therapies; Link; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Medical; Medicine; Metabolic; Minority; Minority Groups; NCI Center for Cancer Research; Names; Neoplasm Metastasis; New York City; Normal Cell; Obesity; Participant; Pathogenesis; Patients; Peptide/MHC Complex; Perception; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Population; Population Research; Prevention; Prevention program; Prevention strategy; Provider; Race; Research; Research Activity; Research Personnel; Resource Sharing; Resources; Role; Science; Services; Signal Transduction; Site; T cell response; T-Cell Activation; T-Lymphocyte; T-cell receptor repertoire; Technology; Testing; Therapeutic Studies; Therapeutic Trials; Translating; Translations; Vaccination; Villus; Viral; Viral Load result; Women' s Interagency HIV Study; arm; cancer care; cancer cell; cancer diagnosis; cancer epidemiology; cancer health disparity; cancer prevention; cancer therapy; community engagement; comorbidity; dietary; efficacy evaluation; epidemiology study; ethnic diversity; experience; human cancer mouse model; human stem cells; immunological synapse; immunoregulation; in vivo; innovation; microbiome; mouse model; novel; oral HPV-positive head and neck cancers; patient population; pre-clinical; preclinical study; programs; response biomarker; scaffold; side effect; single-cell RNA sequencing; small molecule inhibitor; socioeconomics; stem cell differentiation; stem cells; study characteristics; treatment strategy; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

ABSTRACT. This supplement will evaluate the efficacy of our highly selective immunotherapeutic platform in HIV-positive cancer patients. This novel biologics platform, termed synTac for “artificial immunological synapse for T-cell activation”, recapitulates elements of the antigen-specific and costimulatory signals experienced at the immunological synapse. Composed of covalently tethered peptide-MHC modules (c-pMHC) and costimulatory molecules linked to an Fc domain scaffold, synTac directs epitope-specific delivery of a wide range of costimulatory signals to targeted T cell populations. The sc-pMHC domain acts as an “address” to target specific T cell clones for delivery of a range of comodulatory domains (e.g., IL-2, 4-1BBL, CD28 agonists), resulting in antigen-selective modulation of disease relevant T cells in vitro and in vivo, thus eliminating the side effects of current immunotherapeutics, which elicit global immune modulation. Initial efforts will leverage the infrastructure of the Bronx site of the MACS/WIHS Combined Cohort Study (MWCCS), previously named the Women's Interagency HIV Study (WIHS) at Einstein/Montefiore. These studies will define the ability of the synTac platform to expand and activate SARS-CoV-2 specific T cells that are broadly represented across HIV-positive patients and healthy individuals as the consequence of natural infection and vaccination. Next we will examine the ability of our platform to modulate cancer specific CD8 T cells in HIV-positive cancer patients using synTacs that selectively target HPV E7-specific CD8 T cells. One such synTac is the subject of a multi-arm clinical trial for HPV-positive head and neck cancer. Importantly, HPV is implicated in a number of HIV-associated cancers (e.g., anal cancer, cervical cancer) found within the Montefiore Einstein Cancer Center catchment area in the Bronx in New York City; additional future opportunities may be provided by the MWCCS, which has collected PBMCs and has performed serial testing for HPV infection at multiple timepoints for all participants. T cell responses will be evaluated for polyfunctionality, TCR repertoire diversity and by single cell-RNAseq. The impact of synTacs delivering different costimulatory signals will be correlated with clinical parameters including viral load, gender, stage of disease, and race and ethnicity. The ability of synTacs to activate HPV E7-specific T cells will also be correlated with features of the tumor immune micro-environment, including quantification and analysis of E7- specific T cells from fresh harvested tumors, evaluation of viral and immune gene expression as well as quantification and phenotyping of tumor infiltrating T cells. Together, these studies will define the responsiveness of HIV-associated malignancies to the antigen-specific synTacs, identify the mechanistic differences between HIV-positive cancer patients, HIV-negative cancer patients and healthy individuals, and define biomarkers of response to synTacs in ethnically diverse HIV+ patient populations. These results will directly impact our understanding of the relationship between HIV-status and responsiveness to a cutting-edge immunotherapy, and set the stage for future translational and clinical opportunities. NARRATIVE. People with HIV are excluded from most clinical trials conducted by industry due to the perception that they would not respond to immunotherapies and a general reluctance to enroll patients with serious co-morbid medical problems onto therapeutic trials for cancer diagnosis. In an effort to move beyond this practice, we will examine the effectiveness of a novel biologic developed in our lab for modulating protective immune cells from HIV+ patients and HIV+ cancer patients.

摘要：本补充品将评估我们的高选择性免疫治疗平台对 HIV 阳性癌症患者的疗效。这种新型生物制剂平台被称为“用于 T 细胞激活的人工免疫突触”，概括了抗原特异性和共刺激信号的要素。由共价连接的肽-MHC 模块 (c-pMHC) 和与 Fc 结构域支架连接的共刺激分子组成， synTac 引导多种共刺激信号的表位特异性递送至目标 T 细胞群。 sc-pMHC 结构域充当靶向特定 T 细胞克隆的“地址”，以递送一系列共调节结构域（例如 IL-2）。 、4-1BBL、CD28 激动剂），从而在体外和体内对疾病相关 T 细胞进行抗原选择性调节，从而消除当前免疫治疗的副作用，从而引起全球性的关注。最初的工作将利用 MACS/WIHS 联合队列研究 (MWCCS) 的布朗克斯站点的基础设施，该研究以前称为爱因斯坦/蒙蒂菲奥里的女性机构间艾滋病毒研究 (WIHS)。这些研究将定义 synTac 平台的能力。扩大和激活 SARS-CoV-2 特异性 T 细胞，这些 T 细胞在 HIV 阳性患者和健康个体中广泛存在，是自然感染和疫苗接种的结果。 接下来，我们将检查我们的平台的能力。使用选择性靶向 HPV E7 特异性 CD8 T 细胞的 synTac 来调节 HIV 阳性癌症患者的癌症特异性 CD8 T 细胞，其中一种 synTac 是针对 HPV 阳性头颈癌的多臂临床试验的主题。与纽约市布朗克斯蒙特菲奥里爱因斯坦癌症中心服务区内发现的许多与艾滋病毒相关的癌症（例如肛门癌、宫颈癌）有关；未来可能有更多机会； MWCCS 收集了 PBMC，并在多个时间点对所有参与者进行了 HPV 感染的连续测试，将评估 T 细胞反应的多功能性、TCR 库多样性以及单细胞 RNAseq 提供不同的影响。共刺激信号将与临床参数相关，包括病毒载量、性别、疾病阶段以及种族和民族。synTacs 激活 HPV E7 特异性 T 细胞的能力也将与特征相关。肿瘤免疫微环境，包括来自新鲜收获的肿瘤的E7特异性T细胞的定量和分析、病毒和免疫基因表达的评估以及肿瘤浸润T细胞的定量和表型分析，这些研究将共同​​定义肿瘤免疫微环境的反应性。 HIV 相关恶性肿瘤针对抗原特异性 synTacs，确定 HIV 阳性癌症患者、HIV 阴性癌症患者和健康个体之间的机制差异，并定义不同种族 HIV+ 中对 synTacs 反应的生物标志物这些结果将直接影响我们对艾滋病毒状况和对尖端免疫疗法的反应之间关系的理解，并为未来的转化和临床机会奠定基础。 叙述：艾滋病毒感染者被排除在工业界进行的大多数临床试验之外，因为人们认为他们对免疫疗法没有反应，并且普遍不愿意将患有严重共病的患者纳入癌症诊断的治疗试验。除了这种做法之外，我们将检查我们实验室开发的一种新型生物制剂用于调节 HIV+ 患者和 HIV+ 癌症患者的保护性免疫细胞的有效性。