The Importance of T cell Survival in Tumor Immunity

T 细胞存活在肿瘤免疫中的重要性

• 批准号: 8020895
• 负责人: Andrew D Weinberg
• 金额: $ 26.23万
• 依托单位: PROVIDENCE PORTLAND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020895
• 关键词: Adoptive Transfer; Agonist; Antibodies; Applications Grants; CD4 Positive T Lymphocytes; Cancer Patient; Cell Survival; Cells; Clinic; Clinical; Clinical Trials; Data; Equilibrium; Family member; Generations; Genomics; Grant; Immune; Immune response; Immune system; Immunity; Immunology; Immunotherapy; Individual; Interferon Type I; Interleukin-12; Knowledge; Learning; Link; Malignant Neoplasms; Mediating; Memory; Methods; Molecular; Mus; Natural Killer Cells; Pathway interactions; Peripheral; Phase I Clinical Trials; Production; Property; Proteins; Signal Transduction; T memory cell; T-Lymphocyte; TNFRSF1A gene; Testing; Treatment Efficacy; Tumor Immunity; Tumor Necrosis Factor Receptor; base; clinically relevant; cytokine; design; in vivo; memory CD4 T lymphocyte; neoplastic cell; research study; response; tumor; tumor immunology

A key component to enhance immune-based strategies in cancer-bearing individuals is to increase the survival of effector T cells specific for tumor Ag(s), which leads to increased tumor-specific memory. In cancer-bearing hosts it is important to maintain high levels of tumor Ag-specific T cells, because it is difficult to eliminate every last tumor cell. In essence this creates an ongoing battle between the tumor cells and the immune system and it is essential that the immune system win for the host to survive. Learning how to tip the balance in favor of effector T cell survival will be an important strategy for enhancing immunity in cancer- bearing individuals. A recent clinical trial dramatically increased the survival of adoptively transferred tumor Ag-specific T cells in cancer patients and this increase in T cell survival correlated with increased clinical responses. Thus, understanding the mechanisms involved in the T cell survival pathway is crucial to developing new strategies aimed at potentiating tumor immunity in cancer patients. Our group has been studying the biologic function of the TNF-receptor family member, OX40, which has been shown by our group and others to enhance CD4 and CDS T cell survival leading to increased memory. In particular, we have shown that OX40 engagement in tumor-bearing hosts enhances anti-tumor immunity leading to destruction of tumors. We have found that mice cured of tumors through OX40 engagement have tumor-specific memory T cells capable of eliciting potent anti-tumor immunity upon adoptive transfer into naive mice. Therefore we propose to study the mechanism(s) involved with anti-OX40 mediated T cell survival in tumor-bearing hosts to further understand the link between increased tumor Ag-specific T cell survival and immune-mediated therapeutic efficacy. The specific aims of the grant application are as follows: 1) To understand the contribution that IL-12 makes to anti-OX40 enhanced tumor-specific T cell memory, 2) To elucidate the molecular basis for anti-OX40 enhancement of CD4 and CDS T cell survival, and 3) To determine clinically relevant ways to elicit synergy between anti-OX40 and innate cytokines to enhance tumor-specific T cell memory and destruction of tumors. The knowledge gained from this grant will help us design more effective ways to enhance tumor immunotherapy, and ultimately gain a greater understanding of anti-OX40-specific therapy. OX40-specific augmentation of the immune system has recently increased in relevance, because we have produced clinical grade anti-OX40 antibody and treated the first three cancer patients with this antibody as part of a phase I clinical trial.

在患癌个体中加强基于免疫的策略的一个关键组成部分是增加

项目成果

Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo.

• DOI: 10.1002/eji.200939348
• 发表时间: 2009-08
• 期刊: EUROPEAN JOURNAL OF IMMUNOLOGY
• 影响因子: 5.4
• 作者: Redmond, William L.;Gough, Michael J.;Weinberg, Andrew D.
• 通讯作者: Weinberg, Andrew D.

The role of OX40-mediated co-stimulation in T-cell activation and survival.

• DOI: 10.1615/critrevimmunol.v29.i3.10
• 发表时间: 2009
• 期刊: Critical reviews in immunology
• 影响因子: 1.3
• 作者: Redmond WL;Ruby CE;Weinberg AD
• 通讯作者: Weinberg AD

OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis.

• DOI: 10.4049/jimmunol.1000404
• 发表时间: 2010-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Karulf M;Kelly A;Weinberg AD;Gold JA
• 通讯作者: Gold JA

Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice.

• DOI: 10.1097/cji.0b013e3181ee7095
• 发表时间: 2010-10
• 期刊: Journal of immunotherapy (Hagerstown, Md. : 1997)
• 作者: Gough MJ;Crittenden MR;Sarff M;Pang P;Seung SK;Vetto JT;Hu HM;Redmond WL;Holland J;Weinberg AD
• 通讯作者: Weinberg AD

The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy.

TNFRS OX40、4-1BB和CD40作为癌症免疫疗法的靶标。

• DOI: 10.1016/j.coi.2013.01.004
• 发表时间: 2013-04
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Moran AE;Kovacsovics-Bankowski M;Weinberg AD
• 通讯作者: Weinberg AD