Strategies for Distinguishing Success in Immunotherapy Treatments (PQ20)

免疫治疗取得成功的策略 (PQ20)

• 批准号: 8384688
• 负责人: James R. Heath
• 金额: $ 64.28万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384688
• 关键词: Address; Adoptive Cell Transfers; Algorithms; Antibodies; Antigen Receptors; Antigens; Antitumor Response; Autologous; Biological Assay; Biological Markers; Blood; CTLA4 gene; Cancer Patient; Cell Separation; Cells; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Computational algorithm; DNA; Data; Databases; Dendritic Cell Vaccine; Diagnostic; Engineering; Frequencies; Generations; Genetic Engineering; Goals; Imagery; Immune; Immune response; Immune system; Immunologic Monitoring; Immunotherapy; In complete remission; Infusion procedures; Interleukin-2; Joints; Lead; Libraries; Light; Linear Models; Lymphocyte; Malignant Neoplasms; Measures; Metastatic Melanoma; Microfluidics; Molecular; Nature; Nucleic Acids; Outcome; Patients; Performance; Peripheral Blood Lymphocyte; Phenotype; Population; Proteins; Recording of previous events; Recovery; Regimen; Resistance; Resolution; Retrospective Studies; Role; Running; Sampling; Series; Specificity; Staging; Surveys; T-Cell Receptor; T-Lymphocyte; Techniques; Technology; Testing; Therapeutic; Time; Treatment Efficacy; Tumor Antigens; Tumor Markers; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; Variant; base; cancer immunotherapy; cellular engineering; conditioning; demographics; design; experience; genetic analysis; improved; in vivo; insight; melanoma; patient population; predictive modeling; programs; response; single cell proteins; success; therapy design; tool; tumor

DESCRIPTION (provided by applicant): Cancer immunotherapy encompasses classes of treatments designed to attack cancer via activating or suppressing the tumor-associated immune response. Immunotherapies range from adoptive cell transfer (ACT) therapies to administered immuno-modulators such as IL-2 or anti-CTLA-4. Significant progress has been made in demonstrating the efficacy of immunotherapies for some patients, but responses are often transient, and pre-selecting likely responders, or modifying immunotherapies to improve response durabilities, is challenging. For many immunotherapies, traditional molecular or cellular biomarker assays rarely provide correlates with clinical outcomes. This situation will likely be further exacerbated as the field towards trials in which multiple immunotherapies are combined. We propose to address PQ20 through the use of advanced immune monitoring techniques that will initially be deployed retrospectively, and then integrated into well-designed immunotherapy clinical trials. Our specific focus is on late-stage melanoma patients participating in a variety of ACT trials. Our hypothesis is more general: We hypothesize that a comprehensive functional analysis of key, tumor-associated compartments of the immune system, measured across an immunotherapy regimen, can help answer PQ20. To test this hypothesis, we bring together three recently developed, highly multiplex immune monitoring tools to permit an unprecedented level of analysis of cancer patient immune system function: (1) The Single Cell Barcode Chip (SCBC) is designed to quantitate a panel of ~20 functional proteins from single cells, with >103-104 cells profiled in parallel, thus permitting a full functinal analysis of, for example, key T cell phenotypes associated with a given immunotherapy. (2) Nucleic Acid Cell Sorting (NACS), is a tetramer library approach for quantitating the populations of ~50 antigen specific T cells. (3) DNA-encoded antibody libraries (DEAL) integrated onto microfluidic chips; permit the quantitation of a large panel of blood-based biomarker proteins for surveying immune system functions and tumor markers. These assay results, plus additional (traditional) assays, patient demographics, etc., will be incorporated into algorithms for the analysis, dimensional reduction, integration, and visualization of the resultant data, which we anticipate will lead to a resolution of PQ20. We describe the recent application of our technologies towards analyzing the time-dependent responses of late-stage metastatic melanoma patients participating in an engineered T Cell Receptor (TCR) ACT immunotherapy trial. That trial involves multiple immunotherapies, including lymphodepletion of the host immune system, engineered TCR lymphocytes, dendritic cell vaccines, and IL-2. Traditional molecular diagnostic results did not correlate with clinical outcomes. However, application of the new immune monitoring tools yielded clear insights that strongly correlated with clinical outcomes, and those results have informed a clear direction for designing the proposed program. PUBLIC HEALTH RELEVANCE: Cancer immunotherapy describes treatments that attack cancer via activating or suppressing the tumor- associated immune response. While immunotherapies show great promise, most patient responses are transient, and it is challenging to stratify potential responders from non-responders. We propose to address this challenge by broadly applying of a new class of immune diagnostic tools designed to reveal the detailed functional performance of a patient's anti-tumor immune response.

描述（由申请人提供）：癌症免疫疗法包括旨在通过激活或抑制与肿瘤相关的免疫反应来攻击癌症的治疗类别。免疫疗法范围从收养细胞转移（ACT）疗法到施用的免疫调节剂，例如IL-2或抗CTLA-4。在证明某些患者的免疫疗法的功效方面取得了重大进展，但是反应通常是短暂的，预先选择的可能的反应者或修改免疫疗法以改善反应耐用性，这是具有挑战性的。对于许多免疫疗法，传统的分子或细胞生物标志物测定很少与临床结局相关。随着将多种免疫疗法合并的试验领域，这种情况可能会进一步加剧。我们建议通过使用先进的免疫监测技术来解决PQ20，这些技术最初将回顾性地部署，然后集成到设计良好的免疫疗法临床试验中。我们的具体重点是参加各种ACT试验的晚期黑色素瘤患者。我们的假设更为笼统：我们假设对跨免疫疗法方案测量的免疫系统的关键，与肿瘤相关的室的全面功能分析可以帮助回答PQ20。 To test this hypothesis, we bring together three recently developed, highly multiplex immune monitoring tools to permit an unprecedented level of analysis of cancer patient immune system function: (1) The Single Cell Barcode Chip (SCBC) is designed to quantitate a panel of ~20 functional proteins from single cells, with >103-104 cells profiled in parallel, thus permitting a full functinal analysis of, for example, key T cell phenotypes associated with a given免疫疗法。 （2）核酸细胞分选（NACS）是一种四聚体库方法，用于定量约50个抗原特异性T细胞的种群。 （3）集成在微流体芯片上的DNA编码抗体文库（交易）；允许定量大量基于血液的生物标志物蛋白，以测量免疫系统功能和肿瘤标记。这些测定结果，以及其他（传统的）测定，患者人口统计等，将纳入算法中，以进行分析，降低尺寸降低，集成和可视化结果数据，我们预计这将导致PQ20的分辨率。我们描述了我们的技术在分析参与工程T细胞受体（TCR）ACT ACT免疫疗法试验的晚期转移性黑色素瘤患者的时间依赖性反应。该试验涉及多种免疫疗法，包括宿主免疫系统的淋巴结炎，工程性TCR淋巴细胞，树突状细胞疫苗和IL-2。传统的分子诊断结果与临床结果无关。但是，新的免疫监测工具的应用产生了与临床结果密切相关的明确见解，这些结果为设计拟议程序的设计提供了明确的方向。 公共卫生相关性：癌症免疫疗法描述了通过激活或抑制肿瘤相关的免疫反应来攻击癌症的治疗方法。尽管免疫疗法表现出巨大的希望，但大多数患者反应是短暂的，并且将潜在的响应者从非反应者中分层是具有挑战性的。我们建议通过广泛应用一类新的免疫诊断工具来应对这一挑战，旨在揭示患者抗肿瘤免疫反应的详细功能性能。