A Pull-Push Strategy for Lymphoma Immunotherapy

描述(申请人提供)：尽管目前人类淋巴瘤的多种治疗方法可以诱导很高的完全缓解率，但大多数患者最终会复发，无法治愈。因此，挑战是开发更有效的策略，新的免疫疗法是一个很有前途的领域。肿瘤免疫耐受和缺乏明确的肿瘤抗原是发展有效的肿瘤免疫治疗的两大障碍。树突状细胞(DC)是功能最强的抗原提呈细胞。最近引人注目的数据表明，DC及其与调节性T细胞(Treg)的相互作用在免疫自我耐受的产生和维持中发挥着关键作用。CD4+CD25+Tregs对自身免疫性疾病的预防至关重要。快速积累的数据，包括我们的初步数据，提供了肿瘤微环境和浸润性癌症患者外周血中CD4+CD25+Treg细胞增加的证据，表明这些细胞在肿瘤免疫监控中可能起到负面作用。 这项提案侧重于淋巴瘤免疫治疗，并将解决这两个障碍，并提出了一项制定战略以克服这些障碍的计划。第一种假说认为，DC在肿瘤中原位存在，但由调节性T细胞(CD4+CD25+)或肿瘤细胞维持在非活动状态，从而导致对肿瘤抗原的免疫耐受。因此，对淋巴瘤的有效免疫反应并不是肿瘤患者自然产生的。第二种假说认为，由于DC功能障碍或原位DC数量有限，化疗或放射治疗后死亡的肿瘤细胞释放的肿瘤抗原不能有效地被DC在体内交叉递送。因此，在淋巴瘤患者接受化疗或放疗后，不能有效地诱导对淋巴瘤的全身免疫反应。 这项建议的主要重点是描述人类淋巴瘤中CD4+CD25+调节性T细胞的特征，并在小鼠模型中开发在化疗或局部放射治疗后将体外扩增的DC运送到肿瘤部位(PUSH)之前抵消Treg细胞(Pull)的策略。其目的是增强体内潜在肿瘤抗原的交叉呈递(Pull-Push策略)，从而诱导全身抗肿瘤免疫，消除残留肿瘤。希望这些研究将为新的免疫治疗策略铺平道路，这些策略将在未来的人类临床试验中进行测试。

DESCRIPTION (provided by applicant): Despite the fact that current multi-modality treatment of human lymphomas can induce a high rate of complete remission, the majority of patients ultimately relapse and cannot be cured. The challenge, then, is to develop more effective strategies, with new immunotherapy modalities representing a promising area. Immunological tolerance to tumors and the lack of defined tumor antigens are the two major hurdles for the development of effective cancer immunotherapy. Dendritic cells (DCs) are the most potent antigen presenting cells. Recent compelling data suggest that DCs and their interaction with regulatory T cells (Treg) play critical roles in the generation and maintenance of immunologic self-tolerance. CD4+CD25+ Tregs are crucial for the prevention of autoimmune diseases. Rapidly accumulating data, including our preliminary data, provide evidence for an increased prevalence of CD4+CD25+ Treg cells in the tumor microenvironment and in the peripheral blood of patients with invasive cancers, indicating a potential negative role by these cells in tumor immunosurveillance. This proposal focuses on lymphoma immunotherapy and will address the two hurdles, and presents a plan to develop strategies to overcome these hurdles. The first hypothesis is that DCs are present in situ in the tumor, but are maintained in an inactive state either by regulatory T cells (CD4+CD25+) or by tumor cells, thereby leading to immunological tolerance to tumor antigens. Therefore effective immune responses to lymphomas do not occur naturally in patients with the tumors. The second hypothesis is that tumor antigens released by dying tumor cells after chemo- or radiation therapy are not efficiently cross-presented in vivo by DCs, due to either DC dysfunction or limited DC number in situ. Therefore systemic immune responses to lymphomas are not efficiently induced after chemo- or radiation therapy in patients with lymphomas. The major focus of this proposal is to characterize CD4+CD25+ regulatory T cells in human lymphomas, and to develop strategies in mouse models to counteract Treg cells (Pull) before delivering ex vivo expanded DCs to tumor sites (Push) after chemotherapy or local radiation therapy. The goal is to enhance cross-presentation of potential tumor antigens in vivo (Pull-Push strategy) and thus to induce systemic anti-tumor immunity and to eliminate the residual tumor. Hopefully these studies will pave the way for novel immunotherapy strategies which will be tested in future human clinical trials.