Integrating innate and adaptive immunity in cancer therapy

将先天免疫和适应性免疫整合到癌症治疗中

• 批准号: 8096730
• 负责人: NEJAT K EGILMEZ
• 金额: $ 29.92万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-21 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096730
• 关键词: Back; CD8B1 gene; Cell physiology; Cells; Chronic; Complex; Dendritic Cells; Development; Disease; Drug Formulations; Effector Cell; Event; Funding; Goals; Gold; Granulocyte-Macrophage Colony-Stimulating Factor; IFN consensus sequence binding protein; IL2RA gene; Immune; Immunosuppression; Immunotherapy; Interferons; Interleukin-12; Local Therapy; Mediating; Memory; Modeling; Molecular; Molecular Analysis; Monitor; Mus; Myelogenous; Natural Immunity; Natural Killer Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Primary Neoplasm; Recombinant Cytokines; Recombinant Proteins; Recruitment Activity; Regulation; Regulatory Pathway; Research; Research Design; Resectable; Role; Small Interfering RNA; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Technology; Testing; Treatment Efficacy; Work; adaptive immunity; base; cancer therapy; clinical efficacy; clinically relevant; controlled release; cytokine; immunogenic; improved; in vivo; inhibitor/antagonist; lymph nodes; macromolecule; nanorod; novel; paracrine; programs; public health relevance; response; small molecule; tumor; tumor eradication; tumor progression; Back; CD8B1 gene; Cell physiology; Cells; Chronic; Complex; Dendritic Cells; Development; Disease; Drug Formulations; Effector Cell; Event; Funding; Goals; Gold; Granulocyte-Macrophage Colony-Stimulating Factor; IFN consensus sequence binding protein; IL2RA gene; Immune; Immunosuppression; Immunotherapy; Interferons; Interleukin-12; Local Therapy; Mediating; Memory; Modeling; Molecular; Molecular Analysis; Monitor; Mus; Myelogenous; Natural Immunity; Natural Killer Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Primary Neoplasm; Recombinant Cytokines; Recombinant Proteins; Recruitment Activity; Regulation; Regulatory Pathway; Research; Research Design; Resectable; Role; Small Interfering RNA; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Technology; Testing; Treatment Efficacy; Work; adaptive immunity; base; cancer therapy; clinical efficacy; clinically relevant; controlled release; cytokine; immunogenic; improved; in vivo; inhibitor/antagonist; lymph nodes; macromolecule; nanorod; novel; paracrine; programs; public health relevance; response; small molecule; tumor; tumor eradication; tumor progression

DESCRIPTION (provided by applicant): Sustained delivery of Interleukin-12 and GM-CSF to the tumor microenvironment induces rapid activation of pre-existing CD8+ Teffector/memory cells, promotes elimination of CD4+ CD25+ Foxp3+ T-suppressor cells and results in the priming of a secondary CD8+ T-effector response in the tumor-draining lymph nodes (TDLN). However, reversal of tumor immune suppression is transient and effector activation is followed by a dramatic rebound of T-suppressor cells and return of T-effector quiescence. Re-stimulation results in the intensification of the regulatory rebound and ultimately, in the loss of therapeutic efficacy. Recent work demonstrated that both CD8+ T-effector cell priming and T-suppressor cell rebound were mediated by the same myeloid Dendritic cell (DC) population that was recruited to the TDLN following treatment. More importantly, IFN? was required for the development of both the initial immunogenic and the subsequent tolerogenic DC (tDC) phenotype. The broad hypothesis that will be tested in this application is that IFN?-driven immunogenic and tolerogenic pathways in DC can be uncoupled and that selective inhibition of the tolerogenic pathway will neutralize the homeostatic T-suppressor cell rebound, resulting in durable tumor regression. To this end, Aim 1 studies are designed to delineate the little-known mechanisms controlling the IFN?-driven differentiation of immunogenic DC (iDC) to tDC. More specifically, the specific roles of selected interferon regulatory factors (IRFs) in the differentiation of iDC and tDC phenotypes are elucidated to identify potential checkpoints that can be targeted for selective blocking of tDC development and persistence. In Aim 2, two different strategies aimed at abrogating counter-regulation via the use of unique in vivo macromolecule delivery technologies are tested. First, potential regulators of post-therapy tDC differentiation and activity, including IRF-8, SOCS-1, IDO-1/2, GCN-2 and MyD88 as well as additional candidates that are identified in Aim 1, are targeted via siRNA/gold nanorod complexes and sustained-release cytokine/small molecule drug formulations to block tDC function. Second, based on recent findings demonstrating considerable plasticity in T-suppressor cell phenotype, the above technologies are utilized to re-program rebounding T-suppressor cells via Foxp3 silencing and delivery of TH1/TH17-promoting cytokines. In Aim 3, the long-term curative potential of the above approach is investigated in two clinically-relevant tumor models. First, a surgical metastasis model is utilized to determine whether local abrogation of the T-suppressor cell rebound will result in enhanced eradication of disseminated disease. In the second model, the utility of chronic immune therapy in long-term management of non- resectable disease is evaluated in an advanced primary tumor model. Elucidation of the molecular basis of treatment-induced homeostatic counter-regulation and identification of potential regulatory checkpoints that can be targeted for neutralization of the T-suppressor rebound represents a new paradigm, which if successful, can significantly improve clinical efficacy of immune-based therapies. PUBLIC HEALTH RELEVANCE: This proposal will define the molecular mechanisms underlying the homeostatic regulatory rebound that short-circuits therapy-induced antitumor cytotoxic cell activity. Delineation of how treatment itself leads to the mobilization of a regulatory counter-response is expected to reveal checkpoints that can be targeted for abrogation of the regulatory rebound. To this end, novel controlled-release formulations of siRNA, recombinant proteins and small molecule drugs are utilized in conjunction with therapy to target anticipated checkpoints and reprogram regulatory cells to achieve durable tumor regression.

描述（由申请人提供）：持续将白介素-12和GM-CSF持续传递到肿瘤微环境中，可诱导预先存在的CD8+ TEFFECTOR/记忆细胞快速激活CD4+ CD25+ FOXP3+ FOXP3+ T-Suppressor细胞的消除，并在二次CD8+ T-FEFTER响应中启动（tymor）（lymor）（tymor）的结果（然而，肿瘤免疫抑制的逆转是瞬态的，效应子激活之后是T-抑制细胞的戏剧性反弹和T-效应器静脉的返回。重新刺激导致调节反弹的加剧，并最终导致治疗功效的丧失。最近的工作表明，CD8+ T-效应器细胞启动和T-抑制细胞的反弹均由相同的髓样树突状细胞（DC）群介导，后者在治疗后被招募到TDLN。更重要的是，IFN？开发初始免疫原性和随后的耐受性DC（TDC）表型所必需的。在此应用中将测试的广泛假设是，可以取消偶联的IFN？驱动的免疫原性和耐受性途径，并且对耐受性途径的选择性抑制作用将中和稳态T-抑制细胞反弹，从而导致耐用的肿瘤回归。为此，AIM 1研究旨在描述控制IFN？驱动的免疫原性DC（IDC）对TDC的鲜为人知的机制。更具体地说，阐明了选定的干扰素调节因子（IRF）在IDC和TDC表型分化中的特定作用，以识别可以针对选择性阻断TDC发展和持久性的潜在检查点。在AIM 2中，测试了旨在通过使用独特的体内大分子递送技术来消除反调节的两种不同策略。首先，疗法后TDC分化和活性的潜在调节剂，包括IRF-8，SOCS-1，IDO-1/2，GCN-2和MYD88，以及在AIM 1中鉴定出的其他候选者，通过siRNA/Gold nanorod络合物和持续性的细胞因子/小分子药物来构成siRNA/金纳米棒综合体，以封闭TDC TDC的功能。其次，基于最近的发现证明了T-抑制器细胞表型的可塑性，上述技术可通过FOXP3沉默和TH1/TH17促进细胞因子的递送来重新编程T-suppressor细胞。在AIM 3中，在两个与临床上与临床相关的肿瘤模型中研究了上述方法的长期治愈潜力。首先，利用手术转移模型来确定T-抑制细胞反弹的局部废除是否会增强消除传播疾病。在第二个模型中，在晚期原发性肿瘤模型中评估了慢性免疫治疗在长期管理不可切除的疾病中的实用性。阐明治疗诱导的稳态反调节的分子基础和可能针对中和T-抑制器反弹的潜在调节检查​​点的鉴定代表了一种新的范式，如果成功的话，如果成功，则可以显着提高基于免疫疗法的临床疗效。 公共卫生相关性：该提案将定义稳态调节反弹的基础分子机制，即短路治疗诱导的抗肿瘤细胞毒性细胞活性。预计治疗本身如何导致调节反应的动员的描述有望揭示可用于废除调节反弹的检查点。为此，将新型的siRNA，重组蛋白和小分子药物的受控释放配方与治疗结合使用，以靶向预期的检查点和重编程调节细胞，以实现耐用的肿瘤回归。