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）：我们提出了一种新的细胞疗法，以解决机会性病毒感染和半相合干细胞移植（Haplo SCT）后B系恶性肿瘤复发的问题。病毒感染仍然是接受异基因造血干细胞移植（HSCT）的患者失败的重要原因。单倍相合（Haplo）供体移植物的受体处于特别的风险中，因为防止移植物抗宿主病（GvHD）所需的T细胞耗竭。抗病毒药物仅对某些病毒有效，并且大多数具有显著的毒性。我们的中心已经开发了一种新的方法，该方法在单一培养物中有效地从T细胞中扩增对巨细胞病毒、EB病毒和腺病毒特异性的细胞毒性T淋巴细胞（CTL）。这些多病毒特异性CTL（MV-CTL）从干细胞供体（包括Haplo供体）的连续转移已被证明是安全的并且在体内是高效的。然而，复发仍然是Haplo SCT后的一个重要问题，特别是对于B细胞恶性肿瘤患者。因此，我们设计了嵌合抗原受体（CAR）以将T细胞的抗原特异性重定向至B细胞谱系限制的细胞表面分子CD 19。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，MV-CTL经遗传修饰对肿瘤细胞表达的CD 19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CD 19-I-恶性肿瘤患者给予CAR-CD 19 -1- MV-CTL或不给予CTL。在目标2中，我们将描述：（i）持续的程度和持续时间，以及（ii）过继转移CTL的抗病毒和抗白血病作用。总之，研究结果将促进用病毒和CD 19特异性CTL靶向HapIo SCT后MRD的进展，以提高B细胞恶性肿瘤患者的无病生存期。我们的建议是可行的，因为我们的中心在开发、实施和完成细胞和基因治疗产品的复杂生物疗法方面拥有丰富的经验，并且已经在超过25个研究者发起的IND下成功申办和实施了40多项细胞和基因治疗研究，包括II期多中心研究。

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