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

• 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
• 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' 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

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CAR（HCD19RCD28），该汽车提供了由CD19依赖性杀伤，细胞因子产生，以及在T细胞中持续促进的T细胞的完全竞争激活信号。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纵向纵向评估注入式CAR+ TK+细胞的持久性和抗肿瘤效应的持久性。 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-Arabinofuranosyluracil（[18F] -Feau）被TK共表达/捕获在注入的CAR+ T细胞中的TK代谢/捕获的人类PET成像，将用于评估过继转移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。