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

• 批准号: 9069027
• 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
• 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/9069027
• 关键词: Acute Lymphocytic Leukemia; Address; Adenovirus Infections; Adenoviruses; Adoptive Transfer; Adult; Allogenic; Antibodies; 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; 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; Human Herpesvirus 4; Immune; Immunophenotyping; Incidence; Infection; Infection Control; Infection prevention; Infusion procedures; MS4A1 gene; Malignant Neoplasms; Measures; Medical; Minority; Molecular; Monitor; Morbidity - disease rate; Multicenter Studies; Non-Hodgkin' 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; Treatment-related toxicity; Viral; Viral Antigens; Viral Physiology; Virus; Virus Diseases; allotransplant; cancer therapy; chimeric antigen receptor; 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; novel therapeutics; peripheral blood; prevent; racial minority; receptor; reconstitution

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的细胞疗法，以解决机会性病毒感染的问题以及单倍性干细胞移植后B-Linege恶性肿瘤的复发（HAPLO SCT）。在接受同种异体造血干细胞移植（HSCT）的患者中，病毒感染仍然是导致失败的重大原因。单倍性（Haplo）供体移植物的受体特别有风险，因为预防移植物与宿主疾病（GVHD）所需的T细胞耗竭。抗病毒药物仅对某些病毒有效，大多数具有明显的毒性。我们的中心开发了一种新型方法，该方法有效地扩展了针对巨细胞病毒，爱泼斯坦 - 巴尔病毒和腺病毒的细胞毒性T淋巴细胞（CTL）。这些多病毒特异性CTL（包括Haplo供体）的收养转移已被证明是安全且在体内非常有效的。但是，在HAPLO SCT之后，特别是对于B细胞恶性肿瘤患者，复发仍然是一个重大问题。因此，我们设计了一种嵌合抗原受体（CAR），以将T细胞的抗原特异性重定向到B细胞谱系限制的细胞表面分子CD19。我们假设，可以通过继承转移的供体衍生的MV-CTL来降低病毒感染和复发后的发生率，从而在遗传上修饰，是针对由肿瘤细胞表达的CD19分子特异的。在AIM 1中，我们将进行II期随机临床试验，其中我们将为CD19-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-I-MA则则进行了临床试验。在AIM 2中，我们将描绘； （i）持久性的大小和持续时间以及（ii）采用转移的CTL的抗病毒和抗白血病作用。总体而言，研究结果将有助于用病毒和CD19特异性CTL靶向Hapio SCT MRD，以增强B细胞恶性肿瘤患者的疾病生存。我们的建议是可行的，因为我们的中心具有通过细胞和基因治疗产品开发，实施和完成复杂的生物学疗法的丰富经验，并且在25多个研究者启动的IND下，成功赞助并实施了40多个细胞和基因治疗研究，包括II期多中心研究。

项目成果

Generation of tumor antigen-specific T cell lines from pediatric patients with acute lymphoblastic leukemia--implications for immunotherapy.

• DOI: 10.1158/1078-0432.ccr-13-0955
• 发表时间: 2013-09-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Weber G;Caruana I;Rouce RH;Barrett AJ;Gerdemann U;Leen AM;Rabin KR;Bollard CM
• 通讯作者: Bollard CM