Tzannou Ifigeneia, Papadopoulou Anastasia, Naik Swati, Leung Kathryn, Martinez Caridad A, Ramos Carlos A, Carrum George, Sasa Ghadir, Lulla Premal, Watanabe Ayumi, Kuvalekar Manik, Gee Adrian P, Wu Meng-Fen, Liu Hao, Grilley Bambi J, Krance Robert A, Gottschalk Stephen, Brenner Malcolm K, Rooney Cliona M, Heslop Helen E, Leen Ann M, Omer Bilal
Ifigeneia Tzannou, Anastasia Papadopoulou, Swati Naik, Kathryn Leung, Caridad A. Martinez, Carlos A. Ramos, George Carrum, Ghadir Sasa, Premal Lulla, Ayumi Watanabe, Manik Kuvalekar, Adrian P. Gee, Bambi J. Grilley, Robert A. Krance, Stephen Gottschalk, Malcolm K. Brenner, Cliona M. Rooney, Helen E. Heslop, Ann M. Leen, and Bilal Omer, Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, and Houston Methodist Hospital; Meng-Fen Wu and Hao Liu, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX.
J Clin Oncol. 2017 Nov 1;35(31):3547-3557. doi: 10.1200/JCO.2017.73.0655. Epub 2017 Aug 7.
Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.
目的 提高异基因造血干细胞移植（HSCT）患者的治愈率需要努力降低严重病毒感染导致的治疗相关死亡率。从符合条件的第三方供体产生的过继转移病毒特异性T细胞（VST）作为一种现成可用的产品，可为HSCT受者提供广泛的抗病毒保护。患者与方法 我们建立了一个可识别五种常见病毒病原体的VST库，这五种病原体为：爱泼斯坦-巴尔病毒（EBV）、腺病毒（AdV）、巨细胞病毒（CMV）、BK病毒（BKV）和人类疱疹病毒6型（HHV-6）。在一项II期临床试验中，将这些VST给予了38例发生45次感染的患者。结果 单次输注总体产生的累积完全或部分缓解率为92%（95%CI，78.1%至98.3%），按病毒分类的缓解率如下：BKV为100%（n = 16），CMV为94%（n = 17），AdV为71%（n = 7），EBV为100%（n = 2），HHV-6为67%（n = 3）。31例接受单一感染治疗的患者和7例接受多种合并感染治疗的患者获得了临床益处。14例因BKV相关性出血性膀胱炎接受治疗的患者中有13例在第6周时肉眼血尿完全消退。输注是安全的，仅观察到两例新发移植物抗宿主病（1级）。通过表位分析进行的VST追踪显示，第三方来源的功能性VST可持续长达12周。结论 使用库存的VST是治疗HSCT后严重且耐药感染的一种可行、安全且有效的方法，包括治疗两种以前从未用现成产品靶向治疗过的病毒（BKV和HHV-6）引起的感染。此外，VST的多特异性确保了广泛的抗病毒覆盖范围，这有利于治疗多种感染的患者。
