CANCER IMMUNOTHERAPY WITH ALLOGENEIC DONOR CELLS

该项目旨在开发一种新颖、更有效的方法 血液病和非血液病患者的免疫治疗 恶性肿瘤。癌症免疫治疗在很大程度上集中在 增强宿主的免疫系统只取得了不大的成功。这项建议 将测试同种异体免疫疗法的能力，而不是自体免疫疗法 在癌症患者中引发“移植物对肿瘤”反应。反- 供者免疫细胞的肿瘤潜能在两种动物中都已被证明 模型和骨髓移植(BMT)，其中捐赠者免疫细胞， 包括在骨髓移植中，对于治愈慢性髓细胞癌患者至关重要 白血病。目前的建议进一步基于研究表明 在复发的患者中诱导出显著的抗白血病反应 异基因骨髓移植后给予干扰素-α(IFN-α)和 捐献者的MNC输血。类似的治疗方法对后遗症患者有效。 移植B细胞淋巴瘤。现在有可能利用 这些供者细胞治疗其他疾病患者的免疫潜力 没有接受过骨髓移植的恶性肿瘤。 这将是一项人类白细胞抗原相合的同胞供者单核细胞的I/II期试验 单核细胞输注联合干扰素-α治疗急性髓系白血病 没有接受过骨髓移植的恶性肿瘤。该提案的第一个目的是 是为了确定这种疗法的毒性，包括移植的风险- VS宿主病和骨髓再生障碍性贫血。第二个目标是评估 输注的单核细胞在患者体内的存活。据推测，一种抗肿瘤药物 只有在注入的跨国公司不被迅速排斥的情况下，才会产生反应 由相对正常的宿主免疫系统。这项试验将测试捐赠者 通过多态DNA序列的分子分析来实现细胞存活 区分和量化供体细胞和宿主细胞。干扰素-α和4-单核细胞 第一阶段将进行输液。如果无反应、毒性或 供体细胞存活被注意到，一过性免疫抑制 化疗将在第二个疗程的供者单核细胞输注之前使用 为了提高供体细胞的存活率并留出时间进行 出现明显的抗肿瘤作用。第三个也是最终目标是 确定供者MNC提供的潜在移植物抗肿瘤效应。 支持性的实验室研究旨在阐明可能的反 通过研究潜在效应细胞和可能的肿瘤来研究肿瘤的机制 介导抗肿瘤反应的细胞抗原。 这种疗法最初适用于历史上的疾病。 对免疫调节的反应，如慢性粒细胞白血病、黑色素瘤、肾细胞 癌症，以及用标准疗法无法治愈的淋巴瘤。如果 有效，这种疗法可能会对这些患者产生巨大的影响 所有人的预后都很差。如果对慢性粒细胞白血病患者有效，可以 设想一种不需要骨髓的潜在治愈方法 移植。我们希望对错综复杂的 癌细胞与免疫系统的关系，并将能够 研究非移植环境下的移植物抗宿主病。最终， 这项试验可能开始定义一种治疗癌症的新的免疫学方法 心理治疗。

This project is designed to develop a novel, more effective means of immunotherapy for patients with hematologic and non-hematologic malignancies. Cancer immunotherapy has largely concentrated on methods to augment the host's immune system with only modest success. This proposal will test the ability of allogeneic, rather than autologous, immunotherapy to induce a "graft-vs-tumor" reaction in patients with cancer. The anti- tumor potential of donor immune cells has been demonstrated in both animal models and bone marrow transplantation (BMT) where donor immune cells, included in the marrow graft, are critical for the cure of patients with leukemia. The current proposal is further based on studies demonstrating that a striking anti-leukemic reaction is induced in patients who relapse after allogeneic BMT by administering interferon-alpha (IFN-alpha) and donor MNC infusions. Similar therapy is effective for patients with post- transplantation B-cell lymphomas. It may now be possible to harness the immune potential of these donor cells to treat patients with other malignancies without a prior BMT. This will be a phase I/II trial of HLA-matched sibling donor mononuclear cell (MNC) infusions combined with IFN-alpha to treat patients with malignancies who have not had a prior BMT. The first aim of the proposal is to determine the toxicity of this therapy including the risk of graft- vs-host-disease and marrow aplasia. The second goal is to evaluate the survival of the infused MNC in the patient. Presumably, an anti-tumor reaction will result only if the infused MNC are not be rapidly rejected by the relatively normal host immune system. The trial will test for donor cell survival using molecular analysis of polymorphic DNA sequences to distinguish and quantitate donor vs host cells. IFN-alpha and 4 MNC infusions will be given in the first phase. If no response, toxicity, or donor cell survival is noted, transient immuno-suppression with chemotherapy will be used prior to a second course of donor MNC infusions in an effort to enhance donor cell survival and allow time for a significant anti-tumor effect to occur. The third and ultimate aim is to identify potential graft-vs-tumor effects provided by donor MNC. Supportive laboratory studies are designed to shed light on possible anti- tumor mechanisms by studying potential effector cells, and possible tumor cell antigens mediating an anti-tumor response. This therapy will initially be appropriate for diseases historically responsive to immuno-modulation, such as CML, melanoma, renal cell carcinoma, and lymphoma that will be incurable with standard therapies. If effective, this therapy may have tremendous impact for these patients with a uniformly poor prognosis. If effective for patients with CML, one can envision a potentially curative therapy without the need for bone marrow transplantation. We hope to gain new insight into the intricate relationship between cancer cells and the immune system, and will be able to study graft-vs-host disease in a non-transplant setting. Ultimately, this trial may begin to define a novel immunologic approach to cancer therapy.