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，导致往往致命的复发。其背后的假说是 建议的研究是，免疫细胞，即T淋巴细胞和自然杀伤(NK)细胞，由 基因工程(“嵌合”)抗原受体可以根除抗药性ALL。在预赛中 研究表明，识别CD19(一种在所有细胞中高表达，在所有正常细胞中缺失的分子)的受体 B淋巴细胞除外)向免疫细胞传递刺激信号，导致强大的细胞毒作用 抗CD19+ALL细胞。 具体目标1是识别刺激信号分子，诱导最大限度的扩增和抗CD19 对NK细胞的细胞毒作用。这些研究源于观察到抗CD19受体的表达 NK细胞绕过了抑制机制，具有抗ALL细胞毒作用，并依赖于一种新的方法来 有效地转导NK细胞中的受体。这一结果应该会导致对自然杀伤细胞的临床研究 难治性急性淋巴细胞白血病患者，并可能扩大这些细胞在癌症治疗中的临床应用。研究项目： 特异性目标2将确定表达抗CD19受体的免疫细胞是否能根除ALL 异种小鼠白血病模型。NK细胞和T细胞的相对抗白血病能力 4-IBB和CD28联合刺激的潜在益处以及定向输注细胞的有效性 将对两种不同的白血病相关抗原进行评估。如果前景看好，结果应该会提供一个强有力的 受体修饰的自体和同种异体免疫细胞临床检测的理论基础 耐药的ALL。具体目标3是提高受体修饰免疫细胞的临床安全性。基因 将开发允许受体和CD20同时表达的结构，以努力 使转导细胞对使用抗CD20抗体的利妥昔单抗介导的细胞毒敏感 从临床上看。转导这些载体的T细胞和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。 嵌合受体导向免疫治疗是癌症研究的一个新兴领域。这项研究建议 不仅应该促进难治性ALL患者免疫细胞的临床研究，而且还应该促进 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.