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.

抽象的。该补充剂将评估我们高度选择性免疫治疗平台在HIV阳性癌症患者中的有效性。这个新型的生物制剂平台被称为“用于T细胞激活的人工免疫突触”的Santac，它概述了免疫突触中经历的抗原特异性和costimulation信号的元素。 SNTTAC由共价束缚的肽MHC模块（C-PMHC）和与FC结构域支架相关的共刺激分子组成，SNTTAC指导了特定于表位的特定于靶向T细胞群体的cost量刺激信号。 SC-PMHC结构域是针对特定T细胞克隆的“地址”，用于传递一系列的商品域（例如IL-2、4-1BBL，CD28激动剂），从而导致抗原选择性调节疾病相关的T体体内和体内的T细胞，从而消除当前免疫原性的副作用，从而消除当前的免疫原理，从而消除全球范围的全球范围，从而消除了全球范围。最初的努力将利用MAC/WIHS联合队列研究（MWCCS）的布朗克斯站点的基础设施，该研究先前命名为Einstein/Montefiore的妇女间艾滋病毒研究（WIHS）。这些研究将定义Santac平台扩展和激活SARS-COV-2特异性T细胞的能力，这些细胞在HIV阳性患者和健康个体中广泛代表，这是自然感染和疫苗接种的结果。接下来，我们将使用选择性靶向HPV E7特异性CD8 T细胞的Santacs在HIV阳性癌症患者中调节癌症特异性CD8 T细胞的能力。这样的语法是HPV阳性头颈癌的多臂临床试验的主题。重要的是，在纽约布朗克斯市的蒙特菲奥雷爱因斯坦癌症中心集水区中发现的许多与HIV相关的癌症（例如肛门癌，宫颈癌）中实施了HPV； MWCC可以提供额外的未来机会，MWCC已收集了PBMC，并在所有参与者的多个时间点上对HPV感染进行了串行测试。将评估T细胞反应的多功能性，TCR库多样性和单细胞 - rnaseq。传递不同共刺激信号的语法的影响将与临床参数有关，包括病毒载荷，性别，疾病阶段以及种族和种族。 Syntacs激活HPV E7特异性T细胞的能力也将与肿瘤免疫微环境的特征相关，包括对新鲜收获肿瘤的E7特异性T细胞的定量和分析，评估病毒基因和免疫基因表达以及对肿瘤炎性T细胞的定量和表型的评估。总之，这些研究将定义与艾滋病毒相关的恶性肿瘤对抗原特异性语法的反应性，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械差异，并定义了族对种族多样性HIV+ HIV+患者种群中对Syntacs的反应的生物标志物。这些结果将直接影响我们对HIV状态和对尖端免疫疗法的反应性之间关系的理解，并为将来的翻译和临床机会奠定了基础。 叙述。由于人们认为对免疫疗法的反应，并且一般不愿将严重合并医学问题的患者纳入治疗试验的治疗试验，因此将艾滋病毒患者排除在行业进行的大多数临床试验之外。为了超越这种做法，我们将研究实验室中开发的新生物学的有效性，用于调节来自HIV+患者和HIV+癌症患者的受保护的免疫细胞。