A Pull-Push Strategy for Lymphoma Immunotherapy

描述（由申请人提供）：尽管目前人类淋巴瘤的多模式治疗可以诱导很高的完全缓解率，但大多数患者最终复发并且无法治愈。因此，面临的挑战是开发更有效的策略，新的免疫治疗模式代表了一个有前途的领域。对肿瘤的免疫耐受和缺乏确定的肿瘤抗原是发展有效的癌症免疫疗法的两个主要障碍。树突状细胞（Dendritic cells，DC）是目前发现的最有效的抗原提呈细胞。最近令人信服的数据表明，DC及其与调节性T细胞（Treg）的相互作用在免疫自身耐受的产生和维持中起着关键作用。CD 4 + CD 25 + T淋巴细胞对于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，提供了证据表明CD 4 + CD 25 + Treg细胞在肿瘤微环境和侵袭性癌症患者外周血中的患病率增加，表明这些细胞在肿瘤免疫监视中可能发挥负面作用。 该提案的重点是淋巴瘤免疫治疗，并将解决这两个障碍，并提出了一个计划，以制定战略，以克服这些障碍。第一种假设是DC原位存在于肿瘤中，但通过调节性T细胞（CD 4 + CD 25+）或肿瘤细胞维持在非活性状态，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应答不会在肿瘤患者中自然发生。第二个假设是，由于DC功能障碍或原位DC数量有限，化疗或放疗后死亡肿瘤细胞释放的肿瘤抗原在体内不能有效地由DC交叉呈递。因此，淋巴瘤患者在化疗或放疗后不能有效诱导对淋巴瘤的全身免疫应答。 该提案的主要重点是描述人类淋巴瘤中CD 4 + CD 25+调节性T细胞的特征，并在化疗或局部放疗后将离体扩增的DC递送至肿瘤部位（Push）之前，在小鼠模型中开发对抗Treg细胞（Pull）的策略。目的是增强潜在肿瘤抗原在体内的交叉呈递（拉-推策略），从而诱导系统性抗肿瘤免疫并消除残留肿瘤。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体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.