Dendritics Cell Immunotherapy for Colorectal Cancer

结直肠癌的树突状细胞免疫疗法

• 批准号: 7227415
• 负责人: Lawrence Fong
• 金额: $ 28.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227415
• 关键词: Adam11 gene; Address; Agonist; Amino Acid Substitution; Animal Model; Antigen Targeting; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biological Assay; Blood; Bone Marrow; CCL22 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Patient; Carcinoembryonic Antigen; Cells; Centrifugation; Clinical; Clinical Research; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Dendritic Cell Vaccine; Dendritic Cells; Disease; Foundations; Future; Generations; Goals; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunity; Immunization; Immunologic Monitoring; Immunologics; Immunotherapeutic agent; Immunotherapy; In Vitro; In complete remission; Large Intestine Carcinoma; Lead; Lymphoma; Malignant Neoplasms; Malignant neoplasm of prostate; Membrane Proteins; Methodology; Multiple Myeloma; Non-Hodgkin' s Lymphoma; PDC gene; Patients; Peptides; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population Heterogeneity; Process; Protein Overexpression; Relative (related person); Research Personnel; Safety; T-Lymphocyte; Techniques; Tumor Antigens; Upper arm; Vaccinated; Vaccination; Vaccines; base; cancer immunotherapy; cell type; chlorambucil/dactinomycin/methotrexate protocol; density; immunogenic; immunogenicity; improved; in vitro Assay; in vivo; melanoma; metastatic colorectal; neoplastic cell; novel; phosducin; pilot trial; pre-clinical; programs; response; tumor; vaccine efficacy

DESCRIPTION (provided by applicant): Despite the identification of tumor-associated antigens in various malignancies, the vast majority of the antigens are at best weakly immunogenic. Dendritic cells (DC), which are extremely efficient antigen presenting cells uniquely capable of sensitizing naive T cells to antigen, have been used to reverse this immunologic unresponsiveness against different tumors. Armed with tumor-associated antigens, DC are capable of priming tumor specific immune responses in vitro and in vivo, often leading to tumor protection in various animal models. Clinical trials using DC have demonstrated that they can induce T cell and B cell immune responses against tumor associated antigens. Moreover, clinical responses have been observed in some patients, particularly with immunogenic tumors such as lymphoma and melanoma. Recently, we have demonstrated that DC loaded with a peptide derived from carcinoembryonic antigen (CEA) can induce T cell immunity to this antigen. Vaccination of fifteen patients with metastatic colorectal cancer who were treated resulted in clinical responses including two complete responses. Nevertheless, advances making DC-based vaccination more potent will be required if this immunotherapeutic approach is to succeed clinically. The current proposal seeks to address several fundamental issues in DC immunotherapy through preclinical and clinical studies in colorectal cancer patients. While our prior studies have utilized blood derived DC enriched through density gradients, recent studies have demonstrated that blood dendritic cells are comprised of at least 2 major subtypes that may prime immunity differently. We will explore the immunogenicity of the two distinct DC subtypes to induce immunity in vitro and in vivo by purifying them directly from the blood and examining their relative capacity to process and present antigen. Moreover, we will develop techniques to purify the different DC subtypes on a clinical scale and vaccinate patients with these subsets to assess whether the different subtypes in fact induce a qualitatively different immune response in vivo. We will also continue to develop and perform immunologic monitoring in these patients with novel in vitro assays to evaluate the immunologic efficacy of these vaccine strategies. The proposed studies will provide the foundation for a more potent DC targeted cancer immunotherapy for the future.

描述（由申请人提供）：尽管在各种恶性肿瘤中鉴定出与肿瘤相关的抗原，但绝大多数抗原充其量是弱免疫原性的。树突状细胞（DC）是极有效的抗原呈现的细胞，能够使幼稚T细胞敏感到抗原，已被用来逆转这种免疫学对不同肿瘤的无反应性。 DC由肿瘤相关的抗原武装，能够在体外和体内启动肿瘤特异性免疫反应，通常在各种动物模型中导致肿瘤保护。使用DC进行的临床试验表明，它们可以诱导与肿瘤相关抗原的T细胞和B细胞免疫反应。此外，在某些患者中已经观察到临床反应，特别是患有淋巴瘤和黑色素瘤等免疫原性肿瘤。最近，我们已经证明了源自癌胚抗原（CEA）的肽的DC可以诱导T细胞免疫对这种抗原。接受治疗的15例转移性结直肠癌患者的疫苗接种导致临床反应，包括两种完全反应。然而，如果这种免疫治疗方法是在临床上取得成功，则需要提高基于DC的疫苗接种。当前的提案旨在通过结直肠癌患者的临床前和临床研究来解决DC免疫疗法中的几个基本问​​题。尽管我们先前的研究利用了通过密度梯度富集的血液衍生的DC，但最近的研究表明，血液树突状细胞至少由至少2种可能具有不同免疫力的主要亚型组成。我们将通过直接从血液中纯化它们并检查它们的相对能力进行处理和抗原，从而探索两种不同DC亚型的免疫原性，以在体外和体内诱导免疫力。此外，我们将开发技术以在临床范围内纯化不同的DC亚型，并用这些亚群疫苗接种患者，以评估不同亚型实际上是否诱导体内质量不同的免疫反应。我们还将继续在这些新型体外测定的患者中开发和进行免疫监测，以评估这些疫苗策略的免疫学疗效。拟议的研究将为未来的更有效的DC靶向癌症免疫疗法提供基础。