Allogeneic Stem Cell Transplants for HPV+Cervical Cancer

同种异体干细胞移植治疗 HPV 宫颈癌

• 批准号: 6626173
• 负责人: ALEXANDER FEFER
• 金额: $ 21.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626173
• 关键词: T lymphocyte; artificial immunosuppression; cervix neoplasms; clinical research; clinical trial phase II; colony stimulating factor; female; homologous transplantation; human papillomavirus; human subject; human therapy evaluation; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; stem cell transplantation; virus related neoplasm /cancer; women's health

DESCRIPTION (PROVIDED BY APPLICANT): Our long-range goal is to develop tumor-specific allogeneic adoptive T-cell immunotherapy in the context of non-myeloablative allogeneic hematopoietic stem cell transplantation (NST) for the treatment of non-hematologic malignancies. We have selected Human Papilloma Virus (HPV)-associated cervical cancer as a model because it constitutively expresses HPV genes E6/E7, which are appropriate targets for immunotherapy, and because, when advanced, its prognosis with conventional therapies is dismal. However, in order to ultimately design a clinical trial of HPVE6/E7-specific allogeneic T-cell therapy, we first need to a) determine whether NST alone will exert a clinically detectable anti-tumor effect, and b) determine whether lymphocytes derived from donor stem cells and exposed to host tumor in vivo will acquire HPV E6/E7-specific reactivity detectable in vitro, and whether such reactivity can be augmented in vivo. Thus, as a first step, we propose to perform a Phase II clinical trial to a) study the anti-tumor efficacy, b) document the safety, c) monitor hematopoietic engraftment and lymphoid chimerism, and d) determine by concurrent immunologic monitoring whether T cells from the normal ste cell donors can acquire HPVE6/E7-specific reactivity in vivo or in vitro, with a view to eventual (after this grant period) ex vivo generation and expansion of HPVE6/E7-specific T cells for infusion. NST will consist of low-intensity, non-myeloablative but immunosuppressive conditioning, infusion of granulocyte-colony stimulating factor (G-CSF)-mobilized allogeneic peripheral blood stem cell (PBSC), post-transplant immnosuppression and, if there is progressive disease and/or mixed lymphoid chimerism after PBSC infusion, donor lymphocyte infusion (DLI). Accordingly, our specific aims are: 1. To perform a clinical trial of allogeneic NST in patients with advanced cervical carcinoma to: a. Determine the anti-tumor efficacy, b. Determine the safety, c. Monitor donor hematopoietic and lymphoid chimerism, 2. To perform laboratory immunologic monitoring studies to determine whether: a. Donor-derived cells obtained from recipients serially after NST have acquired HPV E6/E7-specific reactivity by exposure in vivo ("priming") to persisting tumor expressing these antigens, and b. Cells obtained directly from donors can acquire HPV E6/E7-specific reactivity after exposure in vitro to HPV E6/E7 synthetic peptides or recombinant proteins. The clinical and laboratory results are expected to provide a rational basis and direction for the design of subsequent trials of tumor-specific adoptive cellular immunotherapy in the context of this treatment regimen.

描述（由申请人提供）：我们的远程目标是发展 肿瘤特异性同种异体产物T细胞免疫疗法 非毛囊同种异体造血干细胞移植（NST） 非血液学恶性肿瘤的治疗。我们选择了人类乳头瘤 病毒（HPV）相关的宫颈癌作为模型，因为它组成性地 表达HPV基因E6/E7，是免疫疗法的适当靶标，并且 因为，当先进的情况下，其对常规疗法的预后令人沮丧。 但是，为了最终设计HPVE6/E7特异性的临床试验 同种异体T细胞疗法，我们首先需要a）确定NST是否会单独 发挥临床可检测到的抗肿瘤作用，b）确定是否确定是否 源自供体干细胞并在体内暴露于宿主肿瘤的淋巴细胞 将在体外检测到的HPV E6/E7特异性反应性，以及是否是否 这种反应性可以在体内增强。因此，作为第一步，我们建议 进行II期临床试验a）研究抗肿瘤功效，b） 记录安全性，c）监测造血植入和淋巴样 Chimerism和D）通过同时进行免疫监测来确定是否t 来自正常Ste细胞供体的细胞可以获取HPVE6/E7特异性反应性 体内或体外 HPVE6/E7特异性T细胞的产生和扩展用于输注。 nst 由低强度，非毛囊但免疫抑制条件组成， 输注粒细胞 - 粘液刺激因子（G-CSF）的同种异体化合物 外周血干细胞（PBSC），移植后的Immnospresprys，如果 PBSC后有进行性疾病和/或混合淋巴嵌合体 输注，供体淋巴细胞输注（DLI）。因此，我们的具体目的是： 1。在患有晚期患者中进行同种异体NST的临床试验 宫颈癌至： 一个。确定抗肿瘤功效， b。确定安全性 c。监测供体造血和淋巴嵌合， 2。进行实验室免疫监测研究以确定是否： 一个。 NST之后从受体获得的供体衍生的细胞具有 通过在体内暴露（“启动”）对获得HPV E6/E7特异性反应性 持续表达这些抗原的肿瘤，以及 b。直接从供体获得的细胞可以获取HPV E6/E7特异性 体外暴露于HPV E6/E7合成肽或 重组蛋白。 预计临床和实验室结果将提供合理的基础 以及设计随后的肿瘤特异性收养试验的方向 在该治疗方案的背景下，细胞免疫疗法。