Durable CD4+ T-cell Tumor Immunity Following Gene-modified HPSC

基因修饰 HPSC 后的持久 CD4 T 细胞肿瘤免疫

• 批准号: 8444280
• 负责人: Christopher E. Touloukian
• 金额: $ 28.38万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-22 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444280
• 关键词: Activated Lymphocyte; Adoptive Transfer; Advanced Malignant Neoplasm; Alleles; Animal Model; Antigens; Applications Grants; Autoantigens; Autoimmune Process; Autoimmunity; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Characteristics; Data; Development; Differentiation Antigens; Effectiveness; Engraftment; Event; Experimental Designs; Exposure to; Frequencies; Gene Silencing; Gene-Modified; Goals; HLA-DR4 Antigen; Health; Helper-Inducer T-Lymphocyte; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunization; Immunology; Immunotherapy; Infusion procedures; Interleukin-7; Kinetics; Knock-out; Lead; Leukocytes; Longevity; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; MHC Class II Genes; Malignant Neoplasms; Mediating; Metastatic Melanoma; Modeling; Molecular Genetics; Mus; Patients; Peripheral; Physiological; Play; Population; Positioning Attribute; Proteins; Research Proposals; Role; Running; Self Tolerance; Stem cell transplant; Stem cells; Surface; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Thymus Gland; Transplantation; Tumor Escape; Tumor Immunity; Tyrosinase related protein-1; Ursidae Family; Vaccination; Vitiligo; arm; base; cancer immunotherapy; cancer therapy; clinical application; cytokine; design; gene therapy; human TYRP1 protein; immune activation; immunogenicity; improved; innovation; melanocyte; melanoma; novel; novel therapeutics; public health relevance; research study; tumor; tumor eradication

DESCRIPTION (provided by applicant): Over the past 25 years, cancer immunotherapy has undergone tremendous innovation and progress with developments running parallel to advances in basic immunology, molecular genetics and gene therapy. Many of these treatments which have included potent cytokine infusions, the adoptive transfer of activated lymphocytes, and a wide array of cancer vaccines, have been largely applied to patients with metastatic melanoma. These treatments, however, have been consistently hampered by poor immunogenicity, limited immune durability, immune tolerance and tumor escape. To improve upon existing treatments and to help answer basic questions about mechanisms that fundamentally inhibit immune responses to cancer, we sought to develop a novel translational model of cancer immunotherapy. Supported by our preliminary studies, we focused our experimental efforts on further understanding the effects of antigen expression on lymphocyte selection, immune activation, autoimmunity, and cancer treatment. To investigate these issues, we designed a melanoma-based model composed of four critical components: 1) the use of two different experimental mice, one expressing a human class II allele (HLA-DR4), the other knocked-out in the expression of a melanocyte-differentiation antigen called tyrosinase-related-protein-1 (TRP-1); 2) the study of a crucial subset of T-cells (T-helper cells or CD4+ T-cells) which react against TRP-1; 3) the use of lentiviral technology to deliver to hematopoetic stem cells (HPSC) a CD4+ T-cell receptor (TCR) which reacts against TRP-1; and 4) the transplantation and immune reconfiguration with gene-modified HPSC. To achieve these ends we have broken down the overall goal into three specific aims: 1) Does gene-modified HPSC transplantation lead to competent T-cell development and function and can that functionality be further amplified with supplemental IL-7, vaccination, or by early antigen-driven homeostatic proliferation? 2) Does endogenous TRP-1 expression have a direct impact on immunoselection and immune tolerance following gene-modified HPSC transplantation? 3) What are the autoimmune, anti-tumor effects, and mechanisms-of-action of TRP-1-specific CD4+ T-cells following gene-modified HPSC transplantation? We believe this research proposal builds upon existing treatments and technologies in cancer immunotherapy. What makes this model unique however, is both the role of antigen to control the composition of the T-cell repertoire and the critical position that CD4+ T-cells play in global immune activation and anti-tumor activity. We believe that experimental approaches, which facilitate the long-term engraftment, expansion and activation of highly reactive CD4+ T-cells, ultimately produce more effective cancer immunotherapies.

描述(申请人提供)：在过去的25年里，癌症免疫疗法经历了巨大的创新和进步，与基础免疫学、分子遗传学和基因疗法的进步同步发展。其中许多治疗方法包括有效的细胞因子输注、活化淋巴细胞的过继转移和广泛的癌症疫苗，已在很大程度上应用于转移性黑色素瘤患者。然而，这些治疗一直受到免疫原性差、免疫耐受性有限、免疫耐受和肿瘤逃逸的阻碍。为了改进现有的治疗方法，并帮助回答有关从根本上抑制癌症免疫反应的机制的基本问题，我们试图开发一种新的癌症免疫治疗的翻译模型。在我们的初步研究的支持下，我们的实验努力集中在进一步了解抗原表达对淋巴细胞选择、免疫激活、自身免疫和癌症治疗的影响。为了研究这些问题，我们设计了一个基于黑色素瘤的模型，由四个关键部分组成：1)使用两种不同的实验小鼠，一种表达人类II类等位基因(HLA-DR4)，另一种表达被称为酪氨酸酶相关蛋白-1(Trp-1)的黑素细胞分化抗原(TRP-1)；2)研究T细胞的一个关键亚群(T辅助细胞或CD4+T细胞)对TRP-1的反应；3)使用慢病毒技术向造血干细胞(HPSC)输送一种针对TRP-1的CD4+T细胞受体(TCR)；(4)基因修饰的HPSC的移植和免疫重构。为了实现这些目标，我们将总体目标分解为三个具体目标：1)基因修饰的HPSC移植是否导致有能力的T细胞发育和功能，以及补充IL-7、疫苗接种或早期抗原驱动的动态平衡增殖能否进一步放大这一功能？2)内源性TRP-1的表达是否直接影响基因修饰的HPSC移植后的免疫选择和免疫耐受？3)基因修饰的HPSC移植后的自身免疫、抗肿瘤效果和作用机制是什么？我们相信，这项研究计划建立在癌症免疫治疗现有治疗方法和技术的基础上。然而，这一模型的独特之处在于，抗原在控制T细胞谱系组成方面的作用，以及CD4+T细胞在全球免疫激活和抗肿瘤活动中发挥的关键地位。我们相信，促进高反应性CD4+T细胞长期植入、扩增和激活的实验方法，最终会产生更有效的癌症免疫疗法。