T Cell Activation for Cancer Immunotherapy

T 细胞激活用于癌症免疫治疗

• 批准号: 7390743
• 负责人: ALFRED E CHANG
• 金额: $ 31.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390743
• 关键词: Adoptive Immunotherapy; Adoptive Transfer; Antigens; Cells; Development; Disease regression; Effector Cell; Funding; Generations; Human; Immunotherapeutic agent; Immunotherapy; In Vitro; Interleukin-10; Interleukin-4; Investigation; Laboratories; Lymphoid Cell; Mediating; Methods; Monoclonal Antibody HuM291; Muromonab-CD3; Procedures; Site; T-Cell Activation; T-Lymphocyte; Translations; Treatment Efficacy; Tumor Antigens; Vaccination; Vaccines; base; cancer immunotherapy; cancer therapy; cytokine; experience; in vivo; insight; lymph nodes; novel; polarized cell; response; tumor

DESCRIPTION (provided by applicant): Our laboratory investigations have focused on the generation of tumor reactive T cells derived from lymph nodes (LNs) draining sites of progressive tumor or vaccines, and evaluating their anti-tumor reactivity. We have shown that these tumor-primed LNs can be secondarily activated in vitro by anti-CD3 as a surrogate antigen along with other costimulatory molecules (anti-CD28 and anti-4-1BB) to mature into potent effector cells that mediate tumor regression in adoptive immunotherapy. During the last funding period, we found that the in vitro activation of tumor-draining LN (TDLN) cells with an anti-CD3/anti-CD28/anti-4-1BB combination of mAbs resulted in polarization of the cytokine response mediated by the activated cells in response to tumor antigen. Polarized TDLN cells mediated a greater type 1 cytokine (i.e. IFNgamma) response and a decrease type 2 cytokine (ie. IL-4 and IL-10) response compared anti-CD3 activated TDLN cells. Furthermore, the polarized cells manifested significantly enhanced in vivo tumor regression upon adoptive transfer. Also, we have demonstrated that the in vivo administration of anti-4-1BB mAb resulted in the polarization of host lymphoid cells after tumor vaccination. This polarization augmented the therapeutic efficacy of DC-based vaccination in the treatment of established tumors. During the next funding period, we would like to investigate the mechanisms involved with 4-1BB co-stimulation of effector cells; develop additional activation methods to generate tumor-primed lymphoid cells; and, investigate the function of mature effector cells in the lymphopenic host. The specific aims of this proposal are: 1. Examine the in vitro mechanisms of 4-1BB co-stimulation on the polarization of tumor-primed lymphoid cells. 2. Examine the in vivo mechanisms of 4-1BB co-stimulation in T cell immunotherapy. 3. Develop novel methods to activate and expand tumor-primed lymphoid cells. 4. Evaluate the function of adoptively transferred effector cells in the lymphopenic host. The information derived from these studies will provide important insights for the development of immunotherapeutic strategies for the treatment of cancer. We have extensive experience in the conduct of adoptive immunotherapy and vaccine trials in humans that will allow translation of these findings.

描述（由申请人提供）：我们的实验室研究集中于产生源自淋巴结（LNS）排水部位的肿瘤反应性T细胞，并评估其抗肿瘤反应性。我们已经表明，这些肿瘤植入的LN可以在体外被抗CD3作为替代抗原以及其他共刺激分子（抗CD28和抗4-1BB）在体外激活，以成熟，以使肿瘤回归的有效效应细胞成熟，以使收养免疫疗法介导肿瘤。在最后一个资金期间，我们发现具有抗CD3/抗CD28/抗CD28/抗-4-1BB MAB组合的体外激活LN（TDLN）细胞的体外激活导致细胞因子反应的极化，由激活细胞介导的对肿瘤抗原反应的活化细胞介导。极化的TDLN细胞介导了更大的1型细胞因子（即IFNGAMMA）反应，并降低了2型细胞因子（即IE。IL-4和IL-10）反应，比较了抗CD3激活的TDLN细胞。此外，极化细胞在过继转移时显着增强了体内肿瘤回归。同样，我们已经证明，抗4-1BB MAB的体内给药导致肿瘤疫苗接种后宿主淋巴样细胞极化。这种极化增强了基于DC的疫苗接种在既定肿瘤治疗中的治疗功效。在下一个资金期间，我们想研究与4-1BB共同刺激效应细胞有关的机制。开发出其他激活方法来产生肿瘤引起的淋巴样细胞。并研究淋巴细胞宿主中成熟效应细胞的功能。该提案的具体目的是：1。检查4-1BB共同刺激对肿瘤培养的淋巴样细胞极化的体外机制。 2。检查T细胞免疫疗法中4-1BB共刺激的体内机理。 3。开发新的方法来激活和扩展肿瘤引发的淋巴样细胞。 4。评估淋巴细胞宿主中采用转移的效应细胞的功能。从这些研究中得出的信息将为开发癌症治疗的免疫治疗策略提供重要的见解。我们在人类中进行收养免疫疗法和疫苗试验方面拥有丰富的经验，这些经验将允许这些发现翻译。

项目成果

Adoptive transfer of tumor reactive B cells confers host T-cell immunity and tumor regression.

• DOI: 10.1158/1078-0432.ccr-11-0207
• 发表时间: 2011-08-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Li Q;Lao X;Pan Q;Ning N;Yet J;Xu Y;Li S;Chang AE
• 通讯作者: Chang AE

Cancer stem cell vaccination confers significant antitumor immunity.

• DOI: 10.1158/0008-5472.can-11-1400
• 发表时间: 2012-04-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Ning N;Pan Q;Zheng F;Teitz-Tennenbaum S;Egenti M;Yet J;Li M;Ginestier C;Wicha MS;Moyer JS;Prince ME;Xu Y;Zhang XL;Huang S;Chang AE;Li Q
• 通讯作者: Li Q

Generation of a novel dendritic-cell vaccine using melanoma and squamous cancer stem cells.

• DOI: 10.3791/50561
• 发表时间: 2014-01-06
• 期刊: Journal of visualized experiments : JoVE
• 作者: Li Q;Lu L;Tao H;Xue C;Teitz-Tennenbaum S;Owen JH;Moyer JS;Prince ME;Chang AE;Wicha MS
• 通讯作者: Wicha MS

Intratumoral dendritic cells and chemoradiation for the treatment of murine squamous cell carcinoma.

• DOI: 10.1097/cji.0b013e3181880f1e
• 发表时间: 2008-11
• 期刊: Journal of immunotherapy (Hagerstown, Md. : 1997)
• 作者: Moyer JS;Li J;Wei S;Teitz-Tennenbaum S;Chang AE
• 通讯作者: Chang AE

In vivo sensitized and in vitro activated B cells mediate tumor regression in cancer adoptive immunotherapy.

• DOI: 10.4049/jimmunol.0803773
• 发表时间: 2009-09-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Li Q;Teitz-Tennenbaum S;Donald EJ;Li M;Chang AE
• 通讯作者: Chang AE