Cell Therapy of Refractory Leukemia

难治性白血病的细胞疗法

• 批准号: 7741738
• 负责人: DARIO CAMPANA
• 金额: $ 28.96万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7741738
• 关键词: Acute Lymphocytic Leukemia; Adult; Allogenic; Antigen Receptors; Antigens; Area; Autologous; B-Lymphocytes; Bone Marrow; Bypass; CD19 gene; CD20 Antigens; CD28 gene; Cell Culture Techniques; Cell Line; Cell Therapy; Cells; Child; Clinical; Clinical Research; Clinical Trials; Development; Donor person; Drug resistance; Effectiveness; Engineering; Engraftment; Genes; HLA Antigens; Hematopoietic stem cells; Immune; Immunotherapy; Insertional Mutagenesis; Intervention; Lead; Leukemic Cell; MS4A1 gene; Mediating; Mesenchymal; Methods; Modeling; Mus; Natural Killer Cells; Neoplasms; Normal Cell; Organ; Patients; Refractory; Relapse; Relative (related person); Research; Research Personnel; Retroviral Vector; Risk; Safety; Signal Transduction; Signaling Molecule; Stem cell transplant; System; T-Lymphocyte; T-Lymphocyte and Natural Killer Cell; Testing; Tissues; Toxic effect; Translations; anticancer research; cancer therapy; cellular transduction; chemotherapy; cytotoxicity; in vitro testing; in vivo; leukemia; novel; programs; receptor; receptor expression; research clinical testing; rituximab; stem; tositumomab

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.

大约 20% 的儿童和 65% 的成人患有急性淋巴细胞白血病 (ALL) 尽管进行了强化化疗，细胞仍然存在，导致常常致命的复发。所依据的假设 研究提出，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”）抗原受体可以根除耐药性 ALL。在初步 研究发现，识别 CD19 的受体（一种在 ALL 细胞中高度表达且在所有正常细胞中不存在的分子） 除 B 淋巴细胞外的细胞）向免疫细胞传递刺激信号，从而产生强大的细胞毒性 对抗 CD19+ALL 细胞。 具体目标 1 是识别诱导最大扩增和抗 CD19 的刺激信号分子 NK 细胞的细胞毒性。这些研究源于观察到抗 CD19 受体的表达 NK 细胞绕过抑制机制并赋予抗 ALL 细胞毒性，并依靠一种新方法来 有效转导 NK 细胞中的受体。该结果应导致 NK 细胞的临床研究 难治性 ALL 患者，可能会扩大这些细胞在癌症治疗中的临床应用。研究于 具体目标 2 将确定表达抗 CD19 受体的免疫细胞是否可以根除 ALL 白血病异种小鼠模型。 NK细胞和T细胞的相对抗白血病能力 4-IBB 和 CD28 共刺激的潜在益处，以及输注细胞的有效性 将评估两种不同的白血病相关抗原。如果有希望，结果应该提供强有力的 对患有以下疾病的患者进行受体修饰的自体和同种异体免疫细胞临床测试的基本原理 耐药性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 同时表达的构建体 使转导细胞对利妥昔单抗（一种使用的抗 CD20 抗体）介导的细胞毒性敏感 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。 嵌合受体定向免疫疗法是癌症研究的一个新兴领域。研究提出 不仅应该促进难治性 ALL 患者免疫细胞的临床研究，而且还有助于促进 开发针对其他肿瘤的有效细胞疗法。

项目成果

Replicative potential of human natural killer cells.

人类自然杀伤细胞的复制潜力。

• 发表时间: 2009-06
• 影响因子: 6.5
• 作者: Fujisaki, Hiroyuki;Kakuda, Harumi;Imai, Chihaya;Mullighan, Charles G;Campana, Dario
• 通讯作者: Campana, Dario

2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells.

重组抗原特异性嵌合受体的 2B4 (CD244) 信号传导共同刺激白血病和神经母细胞瘤细胞的自然杀伤细胞活化。

• 发表时间: 2009-08-01
• 作者: Altvater, Bianca;Landmeier, Silke;Pscherer, Sibylle;Temme, Jaane;Schweer, Katharina;Kailayangiri, Sareetha;Campana, Dario;Juergens, Heribert;Pule, Martin;Rossig, Claudia
• 通讯作者: Rossig, Claudia

Natural killer cell engineering for cellular therapy of cancer.

用于癌症细胞治疗的自然杀伤细胞工程。

• 发表时间: 2011-12
• 作者: Shook DR;Campana D
• 通讯作者: Campana D

Expression of chimeric antigen receptors in natural killer cells with a regulatory-compliant non-viral method.

使用符合法规的非病毒方法在自然杀伤细胞中表达嵌合抗原受体。

• 发表时间: 2010-03
• 影响因子: 6.4
• 作者: Li, L;Liu, L N;Feller, S;Allen, C;Shivakumar, R;Fratantoni, J;Wolfraim, L A;Fujisaki, H;Campana, D;Chopas, N;Dzekunov, S;Peshwa, M
• 通讯作者: Peshwa, M

Natural killer cell reprogramming with chimeric immune receptors.

用嵌合免疫受体对自然杀伤细胞进行重编程。

• 发表时间: 2013
• 作者: Shimasaki, Noriko;Campana, Dario
• 通讯作者: Campana, Dario