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：
8681381
负责人：
Laurence J.N. Cooper
金额：
$ 30.85万
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/8681381
关键词：
Ablation Acute Lymphocytic Leukemia Address Adoptive Immunotherapy Adoptive Transfer Allogenic Anatomic Sites Apoptotic Applications Grants Arabinofuranosyluracil Asses Autologous B-Cell Neoplasm B-Lymphocytes Back Binding Biodistribution Biological Response Modifier Therapy Biopsy Blast Cell Bone Marrow Bone marrow biopsy CD19 Antigens CD19 gene CD28 gene CD3 Antigens CD80 gene Cancer Relapse Cell Lineage Cell surface Cells Clinical Trials Correlative Study Cytolysis DNA Data Development Disease remission Disease-Free Survival Dose Electroporation Engineering Engraftment Event Evolution Exhibits Firefly Luciferases Funding Ganciclovir Gene Transfer Generations Genes Grant Hematopoietic Stem Cell Transplantation Herpesvirus 1 Human Image Immune response Immunosuppression Incidence Infusion procedures Interleukin-2 Luciferases Lymphocyte Major Histocompatibility Complex Malignant Neoplasms Mediating Membrane Mus Non-Hodgkin&apos s Lymphoma Patients Phase I Clinical Trials Plasmids Positron-Emission Tomography Probability Production Recurrence Relapse Residual Neoplasm Residual Tumors Resistance Safety Sampling Scheme Signal Transduction Site Sleeping Beauty Specificity Specimen System T cell therapy T-Cell Activation T-Cell Immunologic Specificity T-Lymphocyte T-Lymphocyte Subsets TK Gene Thymidine Kinase Time Toxic effect Transgenes Transplantation Transposase Treatment Failure base chemotherapy chimeric antigen receptor 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 plasmid DNA 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）：本次修订后的 R01 拨款解决了同种异体造血干细胞移植 (HSCT) 后 B 系急性淋巴细胞白血病 (B-ALL) 复发的问题。我们假设，通过采用过继转移的供体来源的 T 细胞（经过基因改造，对 CD19 具有特异性）来靶向移植后 B-ALL 微小残留病 (MRD)，可以降低同种异体 HSCT 后癌症复发的发生率。为了巩固 HSCT，我们设计了一种下一代嵌合抗原受体 (CAR)，命名为 CD19RCD28，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，而与主要组织相容性复合体 (MHC) 无关。通过嵌合 CD28 和 CD3-6 裂解 B-ALL 激活的基因修饰 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) 系统与电穿孔相结合，引入 CAR 并共表达 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。目标#1中的研究现在将评估是否可以开发出全人类CD19特异性CAR（hCD19RCD28），该CAR可提供完全有效的激活信号，如CD19依赖性杀伤、细胞因子产生和T细胞持续增殖所确定的，已通过 SB 转座进行基因改造。播散性 B 系肿瘤的异种小鼠模型将用于确定采用非侵入性生物发光成像 (BLI) 和 <PET 的过继治疗的可行性和安全性，以纵向评估输注的 CAR+TK+ 细胞和抗 -肿瘤作用。目标 #2 将评估在高风险 CD19+ B-ALL 的同种异体 HSCT 后，输注递增剂量的有/无 TK 表达的供体来源的 hCD19RCD28+ T 细胞的安全性、可行性和持久性。表达 TK 的 T 细胞将通过 PET 成像。如有严重毒性，必要时给予更昔洛韦（GCV）有条件消融TK+细胞。目标#3 中的相关研究将使用对连续采集的样本进行载体特异性 Q-PCR 和 TCR 谱分析来描述在指定 T 细胞剂量水平下转移的 T 细胞的强度和持久性。其他相关研究将评估过继转移 T 细胞向骨髓 (BM) 样本的运输以及转移 T 细胞在 MRD 解剖部位的功能状态。使用 2'-脱氧-20-[18F]氟-5-乙基-1-2-D-阿拉伯呋喃糖尿嘧啶 ([18F]-FEAU) 进行人类 PET 成像，该 2'-Deoxy-20-[18F]氟-5-乙基-1-2-D-阿拉伯呋喃糖尿嘧啶 ([18F]-FEAU) 被输注的 CAR+ T 细胞中共表达的 TK 代谢/捕获。用于评估过继转移的 T 细胞的分布。总的来说，这些研究结果将促进利用供体来源的 CD19 特异性 T 细胞靶向 HSCT 后 MRD 的发展，以提高 B-ALL 患者的无病生存率。简单总结：我们将在移植后输注 CD19 特异性 T 细胞，以提高急性淋巴细胞白血病患者的生存率。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Good T cells for bad B cells.

好的 T 细胞代替坏的 B 细胞。

DOI：
发表时间：
2012-03-22
期刊：
影响因子：
20.3
作者：
Cooper, Laurence J N;Jena, Bipulendu;Bollard, Catherine M
通讯作者：
Bollard, Catherine M

Highlights of the second international conference on "Immunotherapy in Pediatric Oncology".

第二届“小儿肿瘤免疫治疗”国际会议亮点。

DOI：
发表时间：
2011-09
期刊：
影响因子：
1.7
作者：
Capitini, Christian M;Gottschalk, Stephen;Brenner, Malcolm;Cooper, Laurence J N;Handgretinger, Rupert;Mackall, Crystal L
通讯作者：
Mackall, Crystal L

Imaging of T cells expressing chimeric antigen receptors.

表达嵌合抗原受体的 T 细胞成像。