Abramson Cancer Center Support Grant

艾布拉姆森癌症中心支持补助金

基本信息

批准号：
10362806
负责人：
ROBERT H VONDERHEIDE
金额：
$ 12.46万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10362806
关键词：
Abramson Cancer Center at the University of Pennsylvania Address Adult Area Automobile Driving Basic Science Beverages Breast Cancer Burden Cancer Center Cancer Center Support Grant Cancer Control Cancer Patient Capital Caring Catchment Area Cause of Death Cells Cellular biology Child Clinical Clinical Data Clinical Investigator Clinical Protocols Clinical Research Clinical Sciences Clinical Trials Collaborations Colorectal Community Outreach Comprehensive Cancer Center Country County DNA Damage Delaware Development Diagnosis Disease Early Diagnosis Ecosystem Enrollment Epigenetic Process Face Fostering Funding Genetic Geography Health Policy Health Services Research Health behavior Hospitals Human Papilloma Virus Vaccination Immunology Immunotherapy Incidence Intervention Trial Journals Laboratories Laboratory Research Leadership Lung Lymphoma Malignant Childhood Neoplasm Malignant Neoplasms Manuscripts Medicine Mission Modernization Monitor Nature New Jersey Oncogenes Paper Patients Pediatric Hospitals Pennsylvania Philadelphia Population Population Research Population Sciences Prevention Prostate Protocols documentation Proton Radiation Publications Publishing Recording of previous events Research Research Personnel Resource Sharing Resources Rest Risk Risk Assessment Risk Factors Science Scientist Smoking System T-Lymphocyte Training and Education Translating Translational Research Translations Underrepresented Populations United States United States National Institutes of Health Universities Vision anticancer research base behavioral economics brca gene cancer care cancer education cancer risk cancer surgery chimeric antigen receptor T cells clinical investigation clinical practice community engagement data management environmental toxicology ethnic diversity gene therapy health care delivery improved innovation melanoma member microbiome molecular imaging novel strategies novel therapeutic intervention outreach patient oriented population based prevent programs proton therapy public health relevance radiomics response smoking cessation survivorship targeted treatment tobacco control translational scientist treatment trial tumor metabolism tumor microenvironment

项目摘要

Cancer is the leading cause of death in people living with HIV (PLWH) on combination antiretroviral therapy (cART) in the United States and worldwide. As we approach the fourth decade of the HIV/AIDS epidemic, the burden of one such cancer, HIV-related lymphoma, remains substantial. Diffuse large B cell lymphoma (DLBCL) is one of the most common HIV-associated malignancies, and represents a significant medical need. Two landmark trials have led to the FDA approval of two different CD19 directed chimeric antigen receptor (CAR) T cell (CAR19) products in the United States for the treatment of relapsed or refractory (RR) large B cell lymphoma after two or more lines of systemic therapy: tisagenlecleucel (Kymriah™) and axicabtagene ciloleucel (Yescarta ®). Unfortunately, in both trials, patients with known HIV infection were excluded. Therefore, PLWH in the U.S. are not able to receive this potentially curative treatment. γδ T cells represent an important arm of the innate immune system known to be associated with a favorable prognosis in cancers including DLBCL and in fighting HIV infection, but are also known to be susceptible to HIV infection and to represent a latent viral reservoir. PLWH uniformly have depletion of the Vδ2 subset that highly expresses the CCR5 receptor, with associated decreased responsiveness to infection and tumor antigens. This project proposes to explore the concept of engineering γδ T cells, particularly the key Vγ9Vδ2 subset, to target DLBCL by knocking a CAR19 construct into the CCR5 gene. By engineering cells to have a new property we are combining the principles of genome editing with synthetic biology. The resulting γδCAR19-CCR5KO cells would have the potential to recognize and kill CD19 expressing lymphoma and normal CD19 cells via the CAR19 receptor, and to kill lymphoma and HIVinfected cells via the endogenous γδ TCR and innate cytotoxic properties of γδ T cells. They should proliferate in response to activation through the CAR19, and since they would be resistant to HIV infection they should not be killed by HIV, nor act as a future harbor for latent HIV. These proposed studies will address the feasibility of engineering and expanding γδCAR19-CCR5KO cells in culture, and then testing their ability to kill lymphoma cells and possibly clear HIV infection in cell culture and mouse tumor models. The results of these translational investigations would be used to support development of this concept to pilot manufacturing process development, serve as IND-enabling studies, and lead to a clinical trial.

癌症是美国和全球抗逆转录病毒疗法（CART）的HIV（PLWH）患者的主要死亡原因。当我们接近HIV/AIDS流行的第四个十年时，一种此类癌症的燃烧，与HIV相关的淋巴瘤的燃烧仍然很大。弥漫性大B细胞淋巴瘤（DLBCL）是最常见的HIV相关性恶性肿瘤之一，代表了巨大的医疗需求。两项具有里程碑意义的试验已导致FDA批准了两种不同的CD19指示嵌合抗原受体（CAR）T细胞（CAR19）产品在美国治疗继电器或难治性（RR）大B细胞淋巴瘤，经两种或多种全身性治疗，tisagenlecleclecel（kymriae）（kymriae）（kymriahe）和agycarecagta和axagecagta和a cycartae。不幸的是，在这两个试验中，都排除了已知HIV感染的患者。因此，在美国PLWH中，PLWH具有高度表达CCR5受体的Vδ2子集的深度，并相关的降低了对感染和肿瘤抗原的反应性。该项目提出，探索工程γδT细胞的概念，尤其是关键的Vγ9VΔ2子集，以通过将CAR19构建体敲入CCR5基因来靶向DLBCL。通过工程细胞具有新特性，我们将基因组编辑原理与合成生物学结合在一起。由此产生的γΔCAR19-CCR5KO细胞将有可能通过CAR19受体识别和杀死表达淋巴瘤和正常CD19细胞的CD19，并通过内源性γδTCR杀死淋巴瘤和HIVINECT的细胞。他们应该通过CAR19的激活而扩散，并且由于它们会抵抗艾滋病毒感染，因此不应被艾滋病毒杀死，也不应充当潜在艾滋病毒的未来港口。这些提出的研究将解决工程和扩展γδCAR19-CCR5KO细胞的可行性，然后测试其杀死淋巴瘤细胞的能力，并在细胞培养和小鼠肿瘤模型中可能清除HIV感染。这些翻译研究的结果将用于支持此概念的发展，以开发制造过程，作为辅助研究并导致临床试验。