Cancer and Stroma-Targeted Immunotherapy with a Gentically Modified DC Vaccine

使用转基因 DC 疫苗进行癌症和基质靶向免疫治疗

基本信息

批准号：
8513789
负责人：
Stephen Gottschalk
金额：
$ 30.6万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8513789
关键词：
Animal Model Antigen-Presenting Cells Antigens Antitumor Response Cancerous Cell physiology Cell secretion Cell surface Cells Clinical DNA Data Dendritic Cell Vaccine Dendritic Cells Development Disease remission Drug Formulations Effector Cell Environment Enzymes Epitopes Extracellular Matrix Fibroblasts Funding Human Immune Immune response Immune system Immunity Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In complete remission Infiltration Interleukin-10 Malignant Neoplasms Measures Mediating Modeling Monophenol Monooxygenase Mus NF-kappa B Normal tissue morphology Nutrient Peripheral Preventive Proteins Regulatory T-Lymphocyte Research Personnel Residual Tumors Resources Safety Self Tolerance Solid Neoplasm Sports T cell response T-Lymphocyte Testing Therapeutic Time Tumor Antigens Vaccines Validation Variant angiogenesis arginase cancer cell cytokine fibroblast-activating factor immunogenic inhibitor/antagonist innovation melanoma migration neoplastic cell novel pre-clinical prevent safety practice small hairpin RNA tumor tumor growth tumor microenvironment vaccine development vaccine efficacy vector

Animal Model Antigen-Presenting Cells Antigens Antitumor Response Cancerous Cell physiology Cell secretion Cell surface Cells Clinical DNA Data Dendritic Cell Vaccine Dendritic Cells Development Disease remission Drug Formulations Effector Cell Environment Enzymes Epitopes Extracellular Matrix Fibroblasts Funding Human Immune Immune response Immune system Immunity Immunosuppression Immunosuppressive Agents Immunotherapeutic agent Immunotherapy In complete remission Infiltration Interleukin-10 Malignant Neoplasms Measures Mediating Modeling Monophenol Monooxygenase Mus NF-kappa B Normal tissue morphology Nutrient Peripheral Preventive Proteins Regulatory T-Lymphocyte Research Personnel Residual Tumors Resources Safety Self Tolerance Solid Neoplasm Sports T cell response T-Lymphocyte Testing Therapeutic Time Tumor Antigens Vaccines Validation Variant angiogenesis arginase cancer cell cytokine fibroblast-activating factor immunogenic inhibitor/antagonist innovation melanoma migration neoplastic cell novel pre-clinical prevent safety practice small hairpin RNA tumor tumor growth tumor microenvironment vaccine development vaccine efficacy vector

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项目摘要

DESCRIPTION (provided by applicant): The intent of this project is to develop an effective dendritic cell (DC) vaccine for solid tumors. While DC vaccines can induce potent peripheral T-cell immunity, their antitumor effects have been limited. This is most likely due to the presence of immunosuppressive cells within the tumor, such as regulatory T cells (Tregs), as well as tumor sporting stroma. While vaccine strategies targeting Tregs or cancer associated fibroblasts (CAFs, the major component of tumor stroma) have produced complete responses in animal models, tumors inevitably recur, as effector T-cell functions are eroded and/or subverted. We now hypothesize that by targeting not only the tumor and Tregs, but also CAFs, T-cell effector function will be retained for longer and the local 'tumor promoting heaven' will be destroyed resulting in sustained tumor remissions. We further hypothesize that the potent immunostimulatory environment created in the tumor will result in epitope spreading as newly activated antigen presenting cells within the tumor stroma 'cross-present' dying tumor cells. To test these hypotheses we will take advantage of our preliminary studies in which we have demonstrated that silencing the negative regulator A20 in DC can overcome Treg mediated immune suppression resulting in potent antitumor responses in the B16 model. In addition, we have shown that an A20-silenced DC vaccine can induce potent immune responses against fibroblast activating protein (FAP) expressed on the cell surface of CAFs. Using the B16 model, we will evaluate in Aim 1 if a DC vaccine coexpressing A20-shRNA, FAP and TRP2 (DC-shA20-FAP-TRP2) reverses the suppressive tumor microenvironment and facilitates T-cell infiltration into tumors, and determine in Aim 2 the potency of our vaccine to induce bystander T-cell responses (epitope spreading), leading to elimination of tumor antigen loss variants. In Aim 3 we will then evaluate the efficacy and safety of our vaccine in a spontaneous murine Hgf-Cdk4R24c melanoma model. The proposed study is highly innovative since it will test for the first time the ability of genetically modified DCs to induce T-cell responses against cancer cells and their supporting stroma, while concomitantly overcoming Treg-mediated immunosuppression in a single vaccine formulation. If this pre-clinical approach is successful and clinical validation appears justified, we have the resources to prepare vector and cellular components that conform to the appropriate Good Manufacturing Practices safety standards, and will seek separate funding for such a study.

描述（由申请人提供）：该项目的目的是为实体瘤开发有效的树突状细胞（DC）疫苗。尽管直流疫苗可以诱导有效的外围T细胞免疫，但它们的抗肿瘤作用受到限制。这很可能是由于肿瘤中存在免疫抑制细胞的原因，例如调节性T细胞（Treg）以及肿瘤运动基质。尽管针对TREG或癌症相关的成纤维细胞（CAF，肿瘤基质的主要成分）的疫苗策略已在动物模型中产生完全反应，但由于效应T细胞功能被侵蚀和/或颠覆，肿瘤不可避免地会复发。我们现在假设，不仅针对肿瘤和Treg，而且CAFS，T细胞效应子功能将被保留更长的时间，而局部“促进天堂肿瘤”将被破坏，从而导致持续的肿瘤缓解。我们进一步假设肿瘤中产生的有效免疫刺激环境将导致表位扩散，因为在肿瘤基质“跨表达”染色的染色肿瘤细胞中，新激活的抗原呈现细胞。为了检验这些假设，我们将利用我们的初步研究，在这些研究中，我们已经证明，在DC中对阴性调节剂A20沉默可以克服Treg介导的免疫抑制，从而导致B16模型中有效的抗肿瘤反应。此外，我们已经表明，A20脱水的直流疫苗可以针对在CAF的细胞表面表达的成纤维细胞激活蛋白（FAP）诱导有效的免疫反应。 Using the B16 model, we will evaluate in Aim 1 if a DC vaccine coexpressing A20-shRNA, FAP and TRP2 (DC-shA20-FAP-TRP2) reverses the suppressive tumor microenvironment and facilitates T-cell infiltration into tumors, and determine in Aim 2 the potency of our vaccine to induce bystander T-cell responses (epitope spreading), leading to elimination of肿瘤抗原损失变体。在AIM 3中，我们将评估疫苗在自发的鼠HGF-CDK4R24C黑色素瘤模型中的疗效和安全性。拟议的研究具有很高的创新性，因为它将首次测试转基因DC诱导针对癌细胞及其支撑基质的T细胞反应的能力，同时同时克服了单个疫苗配方中Treg介导的免疫抑制。如果这种临床前方法是成功的，并且临床验证似乎是合理的，那么我们就有资源来准备符合适当良好制造实践安全标准的矢量和细胞组件，并将为这项研究寻求单独的资金。