Dendritics Cell Immunotherapy for Colorectal Cancer

结直肠癌的树突状细胞免疫疗法

基本信息

批准号：
7367916
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
项目类别：
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/7367916
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&apos 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

项目摘要

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肿瘤相关抗原，但绝大多数抗原至多具有弱免疫原性。树突状细胞 (DC) 是极其有效的抗原呈递细胞，具有独特的能力使幼稚 T 细胞对抗原敏感，已被用来逆转这种针对不同肿瘤的免疫无反应。 DC 配备有肿瘤相关抗原，能够在体外和体内引发肿瘤特异性免疫反应，通常在各种动物模型中产生肿瘤保护作用。使用 DC 的临床试验表明，它们可以诱导针对肿瘤相关抗原的 T 细胞和 B 细胞免疫反应。此外，在一些患者中观察到了临床反应，特别是免疫原性肿瘤，如淋巴瘤和黑色素瘤。最近，我们证明负载癌胚抗原（CEA）衍生肽的 DC 可以诱导针对该抗原的 T 细胞免疫。十五名接受治疗的转移性结直肠癌患者接种疫苗产生了临床反应，其中包括两名完全反应。然而，如果这种免疫治疗方法要在临床上取得成功，就需要使基于 DC 的疫苗接种更加有效。目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 免疫治疗的几个基本问题。虽然我们之前的研究使用了通过密度梯度富集的血源 DC，但最近的研究表明，血液树突状细胞由至少 2 种主要亚型组成，这些亚型可能以不同的方式启动免疫。我们将通过直接从血液中纯化两种不同的 DC 亚型并检查它们处理和呈递抗原的相对能力，探索两种不同 DC 亚型在体外和体内诱导免疫的免疫原性。此外，我们将开发在临床规模上纯化不同 DC 亚型的技术，并用这些亚型对患者进行疫苗接种，以评估不同亚型是否实际上在体内诱导了性质不同的免疫反应。我们还将继续通过新型体外检测方法开发和对这些患者进行免疫监测，以评估这些疫苗策略的免疫功效。拟议的研究将为未来更有效的 DC 靶向癌症免疫疗法奠定基础。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Interplay between CD8α+ dendritic cells and monocytes in response to Listeria monocytogenes infection attenuates T cell responses.

CD8α 树突状细胞和单核细胞之间的相互作用对单增李斯特菌感染的反应减弱了 T 细胞反应。

DOI：
发表时间：
2011-04-29
期刊：
影响因子：
3.7
作者：
Kapadia, Dilnawaz;Sadikovic, Aida;Vanloubbeeck, Yannick;Brockstedt, Dirk;Fong, Lawrence
通讯作者：
Fong, Lawrence

Distinct CD8+ T cell repertoires primed with agonist and native peptides derived from a tumor-associated antigen.

独特的 CD8 T 细胞库由源自肿瘤相关抗原的激动剂和天然肽引发。

DOI：
发表时间：
2008-02-01
期刊：
影响因子：
0
作者：
Hou, Yafei;Kavanagh, Brian;Fong, Lawrence
通讯作者：
Fong, Lawrence

Vaccination of metastatic colorectal cancer patients with matured dendritic cells loaded with multiple major histocompatibility complex class I peptides.

使用负载多种主要组织相容性复合物 I 类肽的成熟树突状细胞对转移性结直肠癌患者进行疫苗接种。

DOI：
发表时间：
2007-10
期刊：
影响因子：
0
作者：
Kavanagh, Brian;Ko, Andrew;Venook, Alan;Margolin, Kim;Zeh, Herbert;Lotze, Michael;Schillinger, Brian;Liu, Weihong;Lu, Ying;Mitsky, Peggie;Schilling, Marta;Bercovici, Nadege;Loudovaris, Maureen;Guillermo, Roy;Lee, Sun Min;Bender, James;Mill
通讯作者：
Mill