Novel Immune Pathways for Lung Cancer Therapy

肺癌治疗的新型免疫途径

• 批准号: 7474084
• 负责人: SHERVEN SHARMA
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7474084
• 关键词: Address; Adenoviruses; Antigen Presentation; Area; CCL21 gene; Cancer Etiology; Cancer Model; Cancer Patient; Cessation of life; Data; Dendritic Cells; Diagnosis; Dose; Effector Cell; Environment; Fibroblasts; Gene-Modified; Immune; Immune response; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Injection of therapeutic agent; Interleukin-7; Investigation; Laboratories; Lead; Ligands; Lung Neoplasms; Lymphocyte; MADH7 gene; Malignant neoplasm of lung; Mediating; Methods; Molecular; Monitor; Mus; Myeloid Cells; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; PTGS2 gene; Pathway interactions; Patients; Prostaglandin-Endoperoxide Synthase; Protocols documentation; Public Health; Rapid Access to Intervention Development; Research; Research Ethics Committees; Resistance; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Testing; Therapeutic; Translating; Tumor Antigens; Tumor Burden; United States; United States Food and Drug Administration; United States National Institutes of Health; base; cancer immunotherapy; cancer therapy; clinical application; cyclooxygenase 1; day; improved; inhibitor/antagonist; novel; novel strategies; novel therapeutics; programs; research study; response; restoration; statistics; tumor

DESCRIPTION (provided by applicant): Our efforts to produce effective cancer therapy focus on methods to address the immune deficits in the lung tumor microenvironment. To restore tumor antigen presentation and antitumor effector activities we are evaluating the intratumoral administration of CCL21 gene modified dendritic cells (DC-AdCCL21) or fibroblasts (Fib-AdCCL21) or replicating deficient adenovirus expressing CCL21 (AdCCL21). Defining alternative strategies for AdCCL21 delivery for intratumoral expression will provide us with more options and further enhance the translational significance of the proposal. Based on our initial findings in the laboratory, we are now translating intratumoral DC-AdCCL21 method to treat lung cancer patients supported by NCI R21 and the NIH RAID program. We have IRB, RAC and FDA approved protocol for a phase1 trial to evaluate DC-AdCCL21 in patients with advanced NSCLC. The trial includes a dose-escalation of DC-AdCCL21 administered intratumorally by injection in patients with inoperable non-small cell lung cancer. Patients will be monitored for specific immune responses. While these translational investigations proceed, in this proposal, in an established orthotopic murine lung cancer model, we will define the cellular and molecular pathways of novel approaches to augment CCL21 therapy. Based on our data in the laboratory we note that while small tumors (5-7 day old) are highly responsive to CCR7 ligand therapy, larger tumors (>10 day old) progress despite therapy. Based on our studies of the tumor microenvironment, we anticipate that therapies targeting multiple immunologic pathways will be necessary to combat lung cancer. Our intent is to translate the findings of this research to treat patients with lung cancer to enhance the efficacy of DC-AdCCL21 therapy. Hypothesis: We hypothesize that rational multimodal targeting of discrete immune effector pathways will circumvent tumor induced immune suppression, facilitate survival of effector cells in the tumor microenvironment, and augment innate and adaptive immunity in lung cancer. We hypothesize that: (1) COX- 2 inhibitors will effectively overcome the immunosuppressive environment within the tumor, (2) IL-7 will effectively expand and facilitate the survival of effector T and NK cells and (3) restoration of SMAD7 in T lymphocytes by IL-7 will serve to heighten the resistance to TGF2 mediated immunosuppressive effects. Specific Aims: We will define the specific cellular and molecular mechanistic pathways whereby COX-2 inhibition or IL-7 augment CCL21 immune responses in a murine lung cancer model. We will evaluate anti tumor efficacy (as quantified by changes in tumor burden and in survival), and characterize the mechanisms (innate and tumor specific lymphocyte responses, modulation of Treg cell and myeloid immune suppressor cell activities) underlying the effects. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer death in the United States and with the existing therapeutic efforts; only about 15 % of the patients survive 5 years following diagnosis. This statistic has changed minimally in the last 30 years and, therefore, new therapeutic strategies are clearly needed. The experiments in this proposal to test novel combined immune-based approaches and characterize in detail the antitumor immune mechanisms are relevant because it will lead to a highly significant area of clinical application and has the potential to improve lung cancer immunotherapy.

描述（由申请人提供）：我们为有效的癌症疗法的努力重点关注解决肺部肿瘤微环境中免疫缺陷的方法。为了恢复肿瘤抗原表现和抗肿瘤效应活性，我们正在评估CCL21基因修饰的树突状细胞（DC-ADCCL21）或成纤维细胞（FIB-ADCCL21）或复制腺病毒表达CCL21（ADCCL21）的肿瘤内给药。定义用于肿瘤内表达的ADCCL21的替代策略将为我们提供更多选择，并进一步增强该提案的翻译意义。根据我们在实验室中的初步发现，我们现在正在翻译肿瘤内DC-ADCCL21方法，以治疗NCI R21支持的肺癌患者和NIH RAID计划。我们有IRB，RAC和FDA批准的第1阶段试验方案，用于评估晚期NSCLC患者的DC-ADCCL21。该试验包括通过注射术内注射的DC-ADCCL21的剂量升级，对无法手术的非小细胞肺癌患者。将监测患者的特定免疫反应。尽管这些翻译研究进行了，但在该提案中，在已建立的原始鼠肺癌模型中，我们将定义新型CCL21治疗方法的细胞和分子途径。根据我们在实验室中的数据，我们注意到，虽然小肿瘤（5-7天大）对CCR7配体疗法的反应很高，但尽管治疗了，但较大的肿瘤（> 10天）进展。根据我们对肿瘤微环境的研究，我们预计针对多种免疫途径的疗法对抗肺癌。我们的目的是翻译这项研究的结果，以治疗肺癌患者，以增强DC-ADCCL21治疗的功效。假设：我们假设离散免疫效应途径的合理多模式靶向将避免肿瘤诱导的免疫抑制，促进肿瘤微环境中效应细胞的存活，并增强肺癌中的先天和适应性免疫。我们假设：（1）COX-2抑制剂将有效克服肿瘤内的免疫抑制环境，（2）IL-7将有效扩展并促进效应T和NK细胞的存活，以及（3）由IL-7恢复Smad7在IL-7中的smad7在IL-7中的恢复，可以使IL-7的耐药性施加耐药性，从而使TGFFFFF2 MEDIND MEDIND MEDUNS MEDUNS MEDUNS MEDUN。具体目的：我们将定义特定的细胞和分子机械途径，在鼠肺癌模型中，COX-2抑制或IL-7增强CCL21免疫反应。我们将评估抗肿瘤功效（通过肿瘤负担的变化和存活中的变化来量化），并表征了作用的机制（先天和肿瘤特异性淋巴细胞反应，Treg细胞的调节和髓样免疫抑制细胞活性）。 公共卫生相关性：肺癌是美国癌症死亡的主要原因，并且在现有的治疗努力下；诊断后5年只有大约15％的患者生存。在过去的30年中，这种统计数据的变化很小，因此显然需要新的治疗策略。该提案的实验测试了新型的基于免疫的方法并详细表征抗肿瘤免疫机制，因为它将导致临床应用高度显着，并有可能改善肺癌免疫疗法。