Anti-melanoma Activity of Combined Lymphopenia and Immunotherapy

尽管在癌症患者的外周血和骨髓中检测到了肿瘤特异性T细胞，但这些T细胞在癌症患者的外周血和骨髓中的分布并不明显。 T细胞不能介导巨大肿瘤的完全消退。免疫学方法扩展 并且激活这些T细胞很少导致肿瘤的完全消退或治愈。在癌症患者中，许多因素 可能导致针对肿瘤的无效免疫，包括调节性免疫细胞如CD 4 * CD 25 * 调节性T细胞和GDI 1b* Gr 1 * 未成熟骨髓细胞。在这些研究中，我们打算减少免疫 介导的抑制和删除无反应的宿主抗肿瘤T细胞 全身照射（TBI）我们打算通过过继性免疫疗法用“新的”T细胞重建免疫系统。 初始T细胞的转移。我们将教育这些T细胞肽脉冲树突状细胞（DC）接种。 最初的研究表明，这种策略导致肿瘤生长延迟，但不会提高患者的生存率。 荷黑色素瘤小鼠。为了改进这一模型，对两种已知免疫原的重建和活性进行了研究。 将检查抑制性细胞群，CD 4 * CD 25 * foxp 3 * T细胞和CD 11b * Gr 1 * 未成熟骨髓细胞。 通过耗尽这些群体，我们将确定这些抑制性细胞对细胞的影响，如果有的话。 抗肿瘤免疫的发展。此外，导致抗肿瘤药物开发的策略 将探索记忆T细胞和长期免疫，包括肿瘤反应性T细胞的过继转移。 树突状细胞（Dendritic cells，DC）是一种有效的抗原提呈细胞，可诱导产生有效的抗肿瘤活性 主要和记忆T细胞反应。我已经证明，将肿瘤靶向DC上的细胞表面受体， 可以导致增强的抗肿瘤T细胞应答， 免疫佐剂可以改善针对肿瘤的DC疫苗接种。我假设， 黑色素瘤将需要多种免疫方法来诱导有效的抗肿瘤T细胞， 活动具体来说，我打算实施诱导强效抗肿瘤T细胞反应的疗法， 针对黑色素瘤通过以下具体目标：1.实验研究了 淋巴细胞减少症后诱导的免疫调节; 2.检测DC疫苗在 通过转移富含CDS* 记忆T细胞的T细胞来设置淋巴细胞减少症; 3.确定brigatinib的疗效 树突状细胞疫苗和CpG辅助治疗联合放射和过继性T细胞 转移在鼠黑素瘤模型中。本申请中概述的实验研究旨在 继续成功的临床前努力，以产生针对黑色素瘤的免疫策略。这些发现 对人类临床免疫试验有重要意义。

Despite detection of tumor-specific T cells in the peripheral blood and bone marrow of cancer patients, these T cells are unable to mediate total regression of bulky tumors. Immunotherapeutic approaches to expand and activate these T cells rarely result in total tumor regressions or cures. In cancer patients, many factors may contribute to ineffective immunity against tumors including regulatory immune cells such as CD4*CD25* regulatory T cells and GDI 1b* Gr1* immature myeloid cells. In these studies, we intend to decrease immune mediated suppression and delete unresponsive host anti-tumor T cells in tumor bearing mice by treatment with total body irradiation (TBI). We intend to reconstitute the immune system with "new" T cells by adoptive transfer of naive T cells. We will educate these T cells with peptide-pulsed dendritic cell (DC) vaccination. Initial studies have shown that this strategy leads to a delay in tumor growth but does not enhance survival in melanoma bearing mice. In order to improve this model, the reconstitution and activity of \wo known immune inhibitory populations, CD4*CD25*foxp3* T cells and CD11b*Gr1* immature myeloid cells, will be examined. By depleting these populations, we will determine the effects, if any, these inhibitory cells have on the development of anti-tumor immunity. In addition, strategies that lead to the development of anti-tumor memory T cells and long-term immunity will be explored, including adoptive transfer of tumor reactive T cells. Dendritic cells (DC) are potent antigen presenting cells required for the induction of effective anti-tumor primary and memory T cell responses. I have shown that targeting tumors to cell-surface receptors on DC can lead to enhanced anti-tumor T cell responses and combination therapy with bacterial derived immunoadjuvants can improve DC vaccination against tumors. I hypothesize that regression of established melanoma will require multiple immunotherapeutic approaches for the induction of effective anti-tumor T cell activity. Specifically, I intend to implement therapies for the induction of potent anti-tumor T cell responses against melanoma through the following Specific Aims: 1. To investigate experimentally the mechanisms of immune regulation induced after lymphopenia; 2.To examine the efficacy of DC-based vaccination in the setting of lymphopenia by transfer of T cells enriched in CDS* memory T cells; 3. To determine the efficacy of dendritic cell vaccination and CpG adjuvant therapy in combination with irradiation and adoptive T cell transfer in a murine melanoma model. The experimental studies outlined in this application are designed to continue successful preclinical efforts to generate immunization strategies against melanoma. These finding could have significant translation to human clinical immunotherapeutic trials.