Cell Therapy of Refractory Leukemia

在大约20%的儿童和65%的成人急性淋巴细胞白血病（ALL）中，白血病 尽管进行了密集的化疗，但细胞仍然存在，导致通常致命的复发。这一假设的基础是 提出的研究是免疫细胞，即，T淋巴细胞和自然杀伤（NK）细胞，通过 基因工程（“嵌合”）抗原受体可根除耐药ALL。初步 研究表明，识别CD 19的受体（一种在ALL细胞中高度表达而在所有正常细胞中缺失的分子） 除B淋巴细胞外的细胞）向免疫细胞传递刺激信号，导致强大的细胞毒性 抗CD 19 +ALL细胞。 具体目标1是鉴定诱导最大扩增和抗CD 19的刺激性信号传导分子 NK细胞的细胞毒性。这些研究源于T.他的观察，即抗CD 19受体在细胞中的表达， NK细胞绕过抑制机制并赋予抗ALL细胞毒性，并依赖于一种新的方法， 有效地抑制NK细胞中的受体。这一结果将导致NK细胞的临床研究， 患者的难治性ALL，并可能扩大这些细胞在癌症治疗中的临床应用。研究 特异性目标2将确定表达抗CD 19受体的免疫细胞是否可以根除ALL。 白血病的异种鼠模型。NK细胞和T细胞的相对抗白血病能力， 4-伊布和CD 28共刺激的潜在益处，以及输注细胞针对 将评估两种不同的白血病相关抗原。如果有希望，结果应该提供一个强有力的 受体修饰的自体和同种异体免疫细胞在患有 耐药ALL。具体目标3是增加受体修饰的免疫细胞的临床安全性。基因 将开发允许同时表达受体和CD 20的构建体， 使转导细胞对利妥昔单抗介导的细胞毒性敏感，利妥昔单抗是一种使用的抗CD 20抗体， 临床上用这些构建体转导的T和NK细胞的功能及其对利妥昔单抗的敏感性 将在体外和体内进行测试。 嵌合受体介导的免疫治疗是癌症研究的一个新兴领域。研究提出， 这不仅将刺激对难治性ALL患者免疫细胞的临床研究， 为其他肿瘤开发有效的细胞疗法。

In approximately 20% of children and 65% of adults with acute lymphoblastic leukemia (ALL), leukemic cells persist despite intensive chemotherapy, leading to often fatal relapse. The hypothesis underlying the research proposed is that immune cells, i.e., T lymphocytes and natural killer (NK)cells, redirected by genetically-engineered ("chimeric") antigen receptors can eradicate drug-resistant ALL. In preliminary studies, receptors that recognize CD19 (a molecule highly expressed in ALL cells and absent in all normal cells except B lymphocytes) deliver stimulatory signals to immune cells resulting in powerful cytotoxicity against CD19+ALL cells. Specific Aim 1 is to identify stimulatory signaling molecules that induce maximum expansion and anti-CD19 cytotoxicity in NK cells. These studies stem from T.he observation that expression of anti-CD19 receptors in NK cells bypasses inhibitory mechanisms and confers anti-ALL cytotoxicity, and rely on a novel method to efficiently transduce the receptors in NK cells. The results should lead to clinical studies of NK cells in patients with refractory ALL and may expand the clinical use of these cells in cancer therapy. Studies in Specific Aim 2 will determine whether immune cells expressing anti-CD19 receptors can eradicate ALL in xenogeneic murine models of leukemia. The relative anti-leukemic capacity of NK cells and T cells, the potential benefits of 4-IBB and CD28 co-stimulation, and the effectiveness of infusing cells directed against two different leukemia-associated antigens will be assessed. If promising, the results should provide a strong rationale for clinical testing of receptor-modified autologous and allogeneic immune cells in patients with drug-resistant ALL. Specific Aim 3 is to increase the clinical safety of receptor-modified immune cells. Gene constructs that allow simultaneous expression of the receptors and of CD20 will be developed in efforts to render transduced cells susceptible to cytotoxicity mediated by Rituximab, an anti-CD20 antibody used clinically. The function of T and NK cells transduced with these constructs and their sensitivity to Rituximab will be tested in vitro and in vivo. Chimeric receptor-directed immunotherapy is an emerging area of cancer research. The research proposed should not only spur clinical studies of immune cells in patients with refractory ALL but also facilitate the development of effective cell therapies for other neoplasms.