Anti-viral and antileukemic T-cell therapy as prophylaxis after HSCT

抗病毒和抗白血病 T 细胞治疗作为 HSCT 后的预防

基本信息

批准号：
8479213
负责人：
HELEN E HESLOP
金额：
$ 16.02万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-08 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8479213
关键词：
Acute Lymphocytic Leukemia Address Adenovirus Infections Adenoviruses Adoptive Transfer Adult Allogenic Antibodies Antigen Receptors Antigen Targeting Antigen-Presenting Cells Antigens Antiviral Agents Applications Grants B lymphoid malignancy B-Cell NonHodgkins Lymphoma B-Lymphocytes Binding Biological Assay Biological Response Modifier Therapy Blood CD19 Antigens CD19 gene CD3 Antigens Caucasians Caucasoid Race Cell Line Cell Lineage Cell Therapy Cell Transplants Cell surface Cells Childhood Chronic Lymphocytic Leukemia Clinical Clinical Trials Complex Cytomegalovirus Cytotoxic T-Lymphocytes DNA Disadvantaged Disease-Free Survival Donor Lymphocyte Infusion Effectiveness Effector Cell Evolution Failure Family Feces Foscarnet Ganciclovir Guanine Nucleotide Dissociation Inhibitors Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Herpesvirus 4 Immune Immunophenotyping Incidence Infection Infection Control Infection prevention Infusion procedures MS4A1 gene Malignant Neoplasms Measures Medical Minority Minority Groups Molecular Monitor Morbidity - disease rate Multicenter Studies Non-Hodgkin&apos s Lymphoma Patients Pharmaceutical Preparations Phase Pilot Projects Predisposition Prognostic Factor Prophylactic treatment Protocols documentation Randomized Randomized Clinical Trials Recurrence Recurrent disease Relapse Research Personnel Residual Neoplasm Resistance Risk Source Specificity Stem cell transplant Stem cells T cell therapy T-Cell Depletion T-Lymphocyte Testing Toxic effect Transgenes Transgenic Organisms Viral Viral Antigens Viral Physiology Virus Virus Diseases allotransplant cancer therapy common treatment cytotoxic design effective therapy experience gene therapy graft vs host disease improved in vivo leukemia leukemia/lymphoma mortality neoplastic cell novel novel strategies peripheral blood prevent receptor reconstitution

项目摘要

DESCRIPTION (provided by applicant): We propose a novel cellular therapy to address the problems of opportunistic viral infection and relapse of B-lineage malignancies after haploidentical stem cell transplantation (Haplo SCT). Viral infections remain a significant cause of failure in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Recipients of Haploidentical (Haplo) donor grafts are at particular risk because of the T-cell depletion required to prevent graft versus host disease (GvHD). Antiviral drugs are effective only for some viruses, and most have significant toxicities. Our center has developed a novel approach that effectively expands cytotoxic T lymphocytes (CTL) specific for cytomegalovirus, Epstein-Barr virus and adenoviruses from T- cells in a single culture. Adoptive transfer of these multivirus-specific CTL (MV-CTL) from stem cell donors (including Haplo donors) has proved safe and highly effective in vivo. However, relapse remains a significant problem after Haplo SCT especially for patients with B-cell malignancies. Therefore, we have designed a chimeric antigen receptor (CAR) to redirect antigen specificity of T cells to the B cell lineage-restricted cell- surface molecule CD19. We hypothesize that the incidence of viral infection and relapse following Haplo SCT can be reduced by adoptively transferred donor-derived MV-CTL, genetically modified to be specific for the CD19 molecule expressed by tumor cells. In Aim 1 we will conduct a Phase II randomized clinical trial in which we will give CAR-CD19-1- MV-CTL or no CTL to patients with CD19-I- malignancies who have received a Haplo SCT. In Aim 2, we will delineate; (i) the magnitude and duration of persistence and (ii) the anti-viral and anti-leukemic effects of adoptively transferred CTL. In aggregate, the results of the studies will facilitate the evolution of targeting post-HapIo SCT MRD with viral- and CD19-specific CTLs for enhanced disease- free survival of patients with B cell malignancies. Our proposal is feasible since our center has extensive experience developing, implementing and completing complex biological therapies with cell and gene therapy products and has successfully sponsored and implemented over 40 cell and gene therapy studies under more than 25 investigator initiated INDs, including Phase II multicenter studies .

描述（由申请人提供）：我们提出了一种新型细胞疗法来解决单倍体相合干细胞移植（Haplo SCT）后机会性病毒感染和B系恶性肿瘤复发的问题。病毒感染仍然是接受同种异体造血干细胞移植（HSCT）患者失败的一个重要原因。由于预防移植物抗宿主病 (GvHD) 所需的 T 细胞耗竭，单倍体 (Haplo) 供体移植物的受者面临特别的风险。抗病毒药物仅对某些病毒有效，并且大多数具有显着的毒性。我们中心开发了一种新方法，可以有效地从单一培养物中的 T 细胞中扩增针对巨细胞病毒、EB 病毒和腺病毒的细胞毒性 T 淋巴细胞 (CTL)。来自干细胞供体（包括 Haplo 供体）的这些多病毒特异性 CTL (MV-CTL) 的过继转移已被证明在体内安全且高效。然而，Haplo SCT 后复发仍然是一个重大问题，特别是对于 B 细胞恶性肿瘤患者。因此，我们设计了一种嵌合抗原受体（CAR），将T细胞的抗原特异性重定向至B细胞谱系限制性细胞表面分子CD19。我们假设，Haplo SCT 后病毒感染和复发的发生率可以通过过继转移供体来源的 MV-CTL 来降低，该 MV-CTL 经过基因改造，对肿瘤细胞表达的 CD19 分子具有特异性。在目标 1 中，我们将进行一项 II 期随机临床试验，其中我们将向接受 Haplo SCT 的 CD19-I-恶性肿瘤患者给予 CAR-CD19-1-MV-CTL 或不给予 CTL。在目标 2 中，我们将描绘； (i) 持续性的程度和持续时间以及 (ii) 过继转移的 CTL 的抗病毒和抗白血病作用。总的来说，这些研究结果将促进用病毒和 CD19 特异性 CTL 靶向 HapIo SCT MRD 的进化，以提高 B 细胞恶性肿瘤患者的无病生存率。我们的建议是可行的，因为我们的中心拥有利用细胞和基因治疗产品开发、实施和完成复杂生物疗法的丰富经验，并在超过 25 个研究者发起的 IND 下成功赞助和实施了 40 多项细胞和基因治疗研究，包括 II 期多中心研究。