T-cell Therapy for B-lineage Acute Lymphoblastic Leukemia

B 系急性淋巴细胞白血病的 T 细胞疗法

基本信息

批准号：
7888533
负责人：
Laurence J.N. Cooper
金额：
$ 30.38万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888533
关键词：
Ablation Acute Lymphocytic Leukemia Address Adoptive Immunotherapy Adoptive Transfer Allogenic Anatomic Sites Antigen Receptors Apoptosis Apoptotic Applications Grants Arabinofuranosyluracil Asses Autologous B-Cell Neoplasm B-Lymphocytes Back Binding Biodistribution Biological Markers Biological Response Modifier Therapy Biomanufacturing Biopsy Blast Cell Bone Marrow Bone marrow biopsy Build-it CD19 Antigens CD19 gene CD28 gene Cancer Relapse Cell Lineage Cell Therapy Cell surface Cells Chromosomes Clinical Clinical Trials Correlative Study Cytolysis DNA Data Data Set Development Dinucleotide Repeats Disease remission Disease-Free Survival Dose Electroporation Engineering Engraftment Ensure Event Evolution Exhibits Firefly Luciferases Funding Ganciclovir Gene Transfer Generations Genes Grant Hematopoietic Stem Cell Transplantation Herpesvirus 1 Human Image Immune response Immunocompromised Host Immunosuppression Incidence Infusion procedures Interleukin-2 Interleukin-7 K-562 Laboratory Study Life Link Luciferases Lymphocyte Major Histocompatibility Complex Malignant Neoplasms Measures Mediating Membrane Mus National Heart, Lung, and Blood Institute Non-Hodgkin&apos s Lymphoma Patients Phase I Clinical Trials Plasmids Positron-Emission Tomography Prevention Research Prior Chemotherapy Probability Production Publishing Recurrence Refractory Relapse Residual Neoplasm Residual Tumors Resistance Safety Sampling Scheme Series Signal Transduction Site Sleeping Beauty Specificity Specimen System T-Cell Activation T-Cell Immunologic Specificity T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TK Gene Therapeutic Effect Thymidine Kinase Time Toxic effect Transgenes Translational Research Transplantation Transposase Treatment Failure United States National Institutes of Health Viral Genes base cancer therapy cell bank chemotherapy clinical application cohort conventional therapy cost cytokine design functional status gene therapy graft vs host disease high risk immunogenicity improved in vivo innovation killings leukemia mouse model neoplastic cell new technology next generation novel plasmid DNA pre-clinical public health relevance research study trafficking transgene expression tumor vector

项目摘要

DESCRIPTION (provided by applicant): This revised R01 grant addresses the problem of relapse of B-lineage acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem-cell transplantation (HSCT). We hypothesize that the incidence of cancer relapse following allogeneic HSCT can be reduced by targeting post-transplant B-ALL minimal residual disease (MRD) with adoptively transferred donor-derived T cells genetically modified to be specific for CD19. To consolidate HSCT, we have designed a next-generation chimeric antigen receptor (CAR), designated CD19RCD28, to redirect specificity of T cells to the B-cell lineage-restricted cell-surface molecule CD19 independent of major histocompatibility complex (MHC). Genetically modified CD19RCD28+ T cells activated through chimeric CD28 and CD3-6 lyse B-ALL, upregulate production of IL-2 and anti-apoptotic genes, in a CAR-regulated manner. The Sleeping Beauty (SB) system has been combined with electroporation to introduce the CAR as well as co-express HSV-1 thymidine kinase (TK) for imaging by positron emission tomography (PET). The studies in Aim #1 will now evaluate whether an all-human CD19-specific CAR can be developed (hCD19RCD28) that provides a fully-competent activation signal as determined by CD19-dependent killing, cytokine production, and sustained proliferation in T cells that have been genetically modified by SB transposition. A xenogeneic mouse model of disseminated B-lineage tumor will be used to ascertain the feasibility and safety of adoptive therapy using non-invasive bioluminescent imaging (BLI) and <PET to longitudinally asses the persistence of the infused CAR+TK+ cells and the anti-tumor effect. Aim #2 will evaluate the safety, feasibility and persistence, of infusing escalating doses of donor-derived hCD19RCD28+ T cells with/without TK expression, after allogeneic HSCT for high-risk CD19+ B-ALL. T cells expressing TK will be imaged by PET. If necessary, ganciclovir (GCV) will be given for conditional ablation of TK+ cells in the event of serious toxicity. Correlative studies in Aim #3 will delineate the magnitude and persistence of transferred T cells at the prescribed T-cell Dose Levels using vector-specific Q-PCR and TCR spectratyping analyses on serially acquired specimens. Other correlative studies will evaluate the trafficking to sampled bone marrow (BM) of adoptively transferred T cells and the functional status of transferred T cells in this anatomic site of MRD. Human PET imaging using 2'-Deoxy-20-[18F]fluoro-5-ethyl-1-2-D-arabinofuranosyluracil ([18F]-FEAU) metabolized/trapped by TK co-expressed in infused CAR+ T cells, will be used to evaluate the distribution of adoptively transferred T cells. In aggregate, the results of the studies will facilitate the evolution of targeting post-HSCT MRD with donor-derived CD19-specific T cells for enhanced disease-free survival of patients with B-ALL. LAY SUMMARY: We will infuse CD19-specific T cells after transplantation to improve survival for patients with acute lymphoblastic leukemia.

描述（由申请人提供）：该修订后的R01赠款解决了同种异性造血干细胞移植（HSCT）后B型急性急性淋巴细胞白血病（B-ALL）复发的问题。我们假设可以通过针对移植后B-所有最小残留疾病（MRD）降低癌症复发的发生率，该疾病（MRD）具有继基因修饰的供体衍生的T细胞，以特异性转移了CD19。为了巩固HSCT，我们设计了一个指定的CD19RCD28的下一代嵌合抗原受体（CAR），以将T细胞的特异性重定向到B细胞谱系限制的细胞表面分子CD19 CD19独立于主要的组织相容性复合物（MHC）。通过嵌合CD28和CD3-6 Lyse B-all激活了基因修饰的CD19RCD28+ T细胞，以CAR调节的方式上调IL-2和抗凋亡基因的产生。睡美人（SB）系统已与电穿孔结合起来，以引入汽车以及共表达HSV-1胸苷激酶（TK），用于通过正电子发射断层扫描（PET）进行成像。 AIM＃1中的研究现在将评估是否可以开发全人类CD19特异性的汽车（HCD19RCD28），该汽车提供了由CD19依赖性杀伤，细胞因子产生和在T细胞中持续增殖的完全竞争激活信号，该信号在T细胞中持续增殖。已通过SB换位对基因修饰。传播B-LINEGE肿瘤的异构小鼠模型将用于确定使用非侵入性生物发光成像（BLI）（BLI）和<PET纵向纵向证实，纵向抑制注入的CAR+ TK+细胞的持久性和抗 - 肿瘤效应。 AIM＃2将评估在高风险CD19+ B-all的同种异体HSCT之后，以/不具有TK表达的供体衍生的HCD19RCD28+ T细胞的安全性，可行性和持久性。表达TK的T细胞将由PET成像。如有必要，在严重毒性的情况下，将给予Ganciclovir（GCV），以进行TK+细胞的条件消融。 AIM＃3中的相关性研究将使用媒介特异性Q-PCR和TCR频谱分析分析在规定的T细胞水平上描述转移的T细胞的幅度和持久性。其他相关研究将评估在此MRD的解剖部位中传递的T细胞的采样骨髓（BM）和转移T细胞转移的T细胞的功能状态。使用2'-Deoxy-20- [18F] Fluoro-5-乙基-1-2-D-D-D-D-D-Arabinosyluracil（[18F] -Feau）代谢/捕获的人类PET成像将是在注入的CAR+ T细胞中代谢/捕获的，将是用于评估过继转移的T细胞的分布。总体而言，研究结果将促进用供体衍生的CD19特异性T细胞靶向HSCT MRD的演变，以增强B-all患者的无疾病生存。摘要摘要：移植后我们将注入CD19特异性T细胞，以改善急性淋巴细胞白血病患者的存活率。