T Cell Activation for Cancer Immunotherapy

描述（由申请人提供）：我们的实验室研究集中于从进展性肿瘤或疫苗的淋巴结引流部位产生肿瘤反应性T细胞，并评估其抗肿瘤反应性。我们已经证明，这些肿瘤引发的LNs可以在体外被抗cd3作为替代抗原和其他共刺激分子（抗cd28和抗4- 1bb）二次激活，在过继免疫治疗中成熟为有效的效应细胞，介导肿瘤消退。在上一个资助期内，我们发现抗cd3 /抗cd28 /抗4- 1bb单抗组合在体外激活肿瘤引流LN （TDLN）细胞，导致被激活细胞对肿瘤抗原的细胞因子反应极化。极化的TDLN细胞介导了更大的1型细胞因子（即IFNgamma）反应和减少的2型细胞因子（即IFNgamma）。比较抗cd3激活的TDLN细胞IL-4和IL-10的反应。此外，在过继转移后，极化细胞在体内的肿瘤消退明显增强。此外，我们已经证明，体内给药抗-4- 1bb单抗可导致肿瘤疫苗接种后宿主淋巴样细胞的极化。这种极化增强了基于dc的疫苗在治疗已建立的肿瘤中的治疗效果。在下一个资助期内，我们希望研究效应细胞4-1BB共刺激的机制；开发其他激活方法以产生肿瘤引发的淋巴样细胞；研究成熟效应细胞在淋巴细胞减少宿主中的功能。本建议的具体目的是：1。研究4-1BB共刺激肿瘤淋巴样细胞极化的体外机制。2. 研究T细胞免疫治疗中4-1BB共刺激的体内机制。3. 发展新的方法来激活和扩大肿瘤淋巴样细胞。4. 评价过继性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免疫治疗策略的发展提供重要的见解。我们在过继性免疫治疗和人体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。

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.