LYMPHOKINES AND IMMUNOTHERAPY FOLLOWING BONE MARROW TRANSPLANTATION

骨髓移植后的淋巴细胞因子和免疫治疗

• 批准号: 3813027
• 负责人: ALEXANDER FEFER
• 金额: --
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3813027
• 关键词: autologous transplantation; bone marrow transplantation; dosage; gene expression; genetic manipulation; human subject; human therapy evaluation; interleukin 2; leukemia; lymphocyte; lymphoma; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; passive immunization

The success of autologous marrow transplantation (AMT) for the treatment of patients ,with leukemia or lymphoma in limited largely by the high incidence of recurrence of the malignancy after AMT. Interleukin-2 (IL-2), alone or in conjunction with adoptively transferred lymphocytes, has been effective against cancer in animal models. Similarly, in preliminary clinical trials, immunotherapy in the form of recombinant human IL-2 used alone or with ex vivo-generated lymphokine activated killer (LAK) cells, has induced regression of advanced cancer in some patients. Animal data attest to the curative potential of adoptive immunotherapy for hematologic malignancies. Although little is known about responsiveness of patients with hematologic malignancies to treatment with IL-2/LAK, human leukemia and lymphoma cells are known to be susceptible to LAK cytotoxicity in vitro. IL-2/LAK therapy could potentially represent a treatment modality which would be non-cross resistant with chemoradiotherapy and AMT in the treatment of this group of patients. IL-2 + LAK has been used mostly in the presence of large tumor burdens and have induced predominantly partial regressions. Our goal is to use this approach in a setting of minimal residual disease, such as in selected patients who have no evidence of disease after undergoing AMT but who are at very high risk for recurrence. Accordingly, the specific aims of this project are as follows: (1) to determine the kinetics of appearance of circulating IL-2 responsive LAK precursor cells after chemoradiotherapy and AMT; (2) to phenotypically and functionally characterize LAK precursor and effector cells after AMT; (3) to assess the toxicity and immunomodulatory effects of systemically administered IL-2 after AMT in a Phase Ib clinical trial for patients with leukemia and lymphoma; and (4) based on data anticipated from specific aims 1- 3, to design and perform a Phase II clinical trial using a combination of systemically administered IL-2 and ex vivo generated autologous LAK cells in patients who have undergone AMT for resistant or relapsed lymphoma. The results might lead to an effective new treatment modality to be used in the context of AMT for hematologic malignancies.

自体骨髓移植（AMT）的成功 患者的治疗，白血病或淋巴瘤在有限的 通过AMT后恶性复发的高发生率。 白介素2（IL-2），单独或与众不同 转移的淋巴细胞在癌症中有效 动物模型。 同样，在初步临床试验中， 以重组人IL-2的形式免疫疗法单独使用或 伴有体内生成的淋巴动物活化杀手（LAK）细胞的具有 某些患者诱导晚期癌症的消退。 动物 数据证明了收养免疫疗法的治疗潜力 血液学恶性肿瘤。 虽然对 血液学恶性肿瘤患者对 用IL-2/LAK，人白血病和淋巴瘤细胞治疗是 已知在体外容易受到LAK细胞毒性的影响。 IL-2/lak 治疗可能代表一种治疗方式 对化学放疗和AMT在 这组患者的治疗。 IL-2 + LAK已被使用 主要是在大肿瘤负担的情况下 主要是部分回归。 我们的目标是使用它 在最小残留疾病的情况下，例如 选择没有疾病证据的患者 AMT，但他们的复发风险很高。 因此，该项目的具体目的如下： （1）确定循环IL-2出现的动力学 化学放放疗法和AMT后反应性的LAK前体细胞； （2）在表型和功能上表征Lak前体 AMT后的效应细胞； （3）评估毒性和 在系统施用的IL-2之后的免疫调节作用 在一项IB期临床试验中，AMT针对白血病患者和 淋巴瘤； （4）基于从特定目的1-预期的数据。 3，使用A设计和执行II期临床试验 系统施用的IL-2和离体产生的组合 经过AMT的患者的自体LAK细胞 抗性或复发性淋巴瘤。 结果可能会导致 在AMT背景下使用的有效新治疗方式 用于血液学恶性肿瘤。