Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer
Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer
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DOI：
10.1182/blood-2007-05-091280
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发表时间：
2007-10-15
期刊：
影响因子：
20.3
通讯作者：
Heslop, Helen E.
中科院分区：
文献类型：
--
作者：
Bollard, Catherine M.;Gottschalk, Stephen;Heslop, Helen E.
eb病毒（EBV）相关肿瘤在免疫能力强的个体中发展，对免疫治疗提出了挑战，因为它们缺乏免疫优势病毒抗原的表达。然而，肿瘤始终表达包括LMP2在内的病毒蛋白，这些蛋白在免疫学上是“弱”的，但仍然可能是免疫T细胞的靶标。我们之前的研究表明，使用ebv转化的b淋巴母细胞样细胞系（LCLs）重新激活的大多数细胞毒性T淋巴细胞（ctl）含有少量lmp2特异性T细胞群并归巢到肿瘤部位。然而，它们在大体积疾病患者中没有产生缓解。我们现在已经使用基因转移到抗原呈递细胞（APCs）来增强LMP2的表达和免疫原性。与未修饰的LCL-APCs相比，这些修饰的APCs使lmp2特异性ctl的频率增加了100倍。lmp2特异性群体在体内扩大并持续存在，没有不良反应。10例高危疾病缓解期患者中有9例仍处于缓解期，6例活动性复发疾病患者中有5例肿瘤缓解，4例完全缓解，持续时间超过9个月。因此，通过对apc和ctl进行体外遗传修饰，可以产生对弱肿瘤抗原的免疫应答；因此所生产的可具有较强的抗肿瘤活性。
Epstein-Barr virus (EBV)-associated tumors developing in immunocompetent individuals present a challenge to immunotherapy, since they lack expression of immunodominant viral antigens. However, the tumors consistently express viral proteins including LMP2, which are immunologically "weak" but may nonetheless be targets for immune T cells. We previously showed that a majority of cytotoxic T lymphocytes (CTLs) reactivated using EBV-transformed B-lymphoblastoid cells lines (LCLs) contained minor populations of LMP2-specific T cells and homed to tumor sites. However, they did not produce remissions in patients with bulky disease. We have now used gene transfer into antigen-presenting cells (APCs) to augment the expression and immunogenicity of LMP2. These modified APCs increased the frequency of LMP2-specific CTLs by up to 100-fold compared with unmodified LCL-APCs. The LMP2-specific population expanded and persisted in vivo without adverse effects. Nine of 10 patients treated in remission of high-risk disease remain in remission, and 5 of 6 patients with active relapsed disease had a tumor response, which was complete in 4 and sustained for more than 9 months. it is therefore possible to generate immune responses to weak tumor antigens by ex vivo genetic modification of APCs and the CTLs; so produced can have substantial antitumor activity.