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来自进行性肿瘤或疫苗的淋巴结（LN）引流部位的肿瘤反应性T细胞，并评价其抗肿瘤反应性。我们已经证明，这些肿瘤致敏的LN可以在体外被抗CD 3作为替代抗原沿着与其他共刺激分子（抗CD 28和抗4-1BB）一起激活，成熟为有效的效应细胞，在过继免疫治疗中介导肿瘤消退。在最后一个资助期内，我们发现用抗CD 3/抗CD 28/抗4-1BB单克隆抗体组合体外活化肿瘤引流LN（TDLN）细胞导致活化细胞介导的细胞因子应答极化，以响应肿瘤抗原。极化的TDLN细胞介导了更大的1型细胞因子（即IFN γ）应答和减少的2型细胞因子（即IFN γ）应答。IL-4和IL-10）应答的比较。此外，极化细胞表现出显着增强的体内肿瘤消退过继转移。此外，我们已经证明，体内施用抗4-1BB mAb导致肿瘤疫苗接种后宿主淋巴细胞的极化。这种极化增强了基于DC的疫苗接种在治疗已建立的肿瘤中的治疗功效。在下一个资助期间，我们希望研究与效应细胞的4-1BB共刺激有关的机制;开发额外的激活方法以产生肿瘤引发的淋巴样细胞;并研究成熟效应细胞在淋巴细胞减少宿主中的功能。该提案的具体目标是：1.检查4-1BB共刺激对肿瘤致敏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共刺激的体内机制。3.开发新的方法来激活和扩增肿瘤引发的淋巴细胞。4.评价过继转移效应细胞在淋巴细胞减少宿主中的功能。从这些研究中获得的信息将为癌症治疗的免疫策略的发展提供重要的见解。我们在人类过继免疫治疗和疫苗试验方面拥有丰富的经验，可以将这些发现转化为现实。

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.

使用黑色素瘤和鳞状癌干细胞生成新型的树突状疫苗。

• 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

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

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

肿瘤内树突状细胞和化学放疗，用于治疗鼠鳞状细胞癌。

• 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