Al-Akioui Sanz Karima, Echecopar Parente Carlos, Ferreras Cristina, Menéndez Ribes Marta, Navarro Alfonso, Mestre Carmen, Clares Laura, Vicario José Luis, Balas Antonio, De Paz Raquel, López Granados Eduardo, Sánchez Zapardiel Elena, Jiménez Carlos, López-Oliva María, Ramos Esther, Hernández-Oliveros Francisco, Pérez-Martínez Antonio
Hospital La Paz Institute for Health Research, Madrid, Spain.
Department of Pediatric Hemato-Oncology, La Paz University Hospital, Madrid, Spain.
Front Med (Lausanne). 2023 Feb 8;10:1083215. doi: 10.3389/fmed.2023.1083215. eCollection 2023.
Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. Most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. The transfer of pathogen-specific Cytotoxic T-Lymphocytes has shown a minimal toxicity profile and effectiveness in treating Cytomegalovirus, Adenovirus, Epstein - Barr virus, BK Virus and infections, but this therapy have the main limitations of regulatory issues, high cost, and absence of public cell banks. However, CD45RA cells containing pathogen-specific memory T-cells involve a less complex manufacturing and regulatory process and are cheaper, feasible, safe, and potentially effective.
We present preliminary data from six immunocompromised patients: four who had severe infectious diseases and two who had EBV lymphoproliferative disease. All of them underwent multiple safe familial CD45RA T-cell infusions as adoptive passive cell therapy, containing Cytomegalovirus, Epstein - Barr virus, BK virus, and -specific memory T-cells. We also present the method for selecting the best donors for CD45RA cells in each case and the procedure to isolate and store these cells.
The infusions were safe, there was no case of graft-versus host disease, and they showed a clear clinical benefit. The patients treated for BK virus nephritis, Cytomegalovirus encephalitis, Cytomegalovirus reactivation, and disseminated invasive aspergillosis experienced pathogen clearance, complete resolution of symptoms in 4-6 weeks and a lymphocyte increase in 3 of 4 cases after 3-4 months. Donor T cell transient microchimerism was detected in one patient. The two patients treated for EBV lymphoproliferative disease underwent chemotherapy and several infusions of CD45RA memory T-cells containing EBV cytotoxic lymphocytes. Donor T-cell microchimerism was observed in both patients. The viremia cleared in one of the patients, and in the other, despite the viremia not clearing, hepatic lymphoproliferative disease remained stable and was ultimately cured with EBV-specific Cytotoxic T-Lymphocytes.
The use of familial CD45RA T-cells containing specific Cytotoxic T-lymphocytes is a feasible, safe and potential effective approach for treating severe pathogen infections in immunocompromised patients through a third party donor. Furthermore, this approach might be of universal use with fewer institutional and regulatory barriers.
免疫功能低下的患者易患高危机会性感染和恶性疾病。大多数抗病毒和抗真菌药物毒性较大，相对无效，且长期使用会诱导耐药性。病原体特异性细胞毒性T淋巴细胞的转移在治疗巨细胞病毒、腺病毒、爱泼斯坦-巴尔病毒、BK病毒感染方面显示出极低的毒性和有效性，但这种疗法存在监管问题、成本高以及缺乏公共细胞库等主要局限性。然而，含有病原体特异性记忆T细胞的CD45RA细胞涉及的制造和监管过程较简单，成本更低，可行、安全且可能有效。
我们展示了6例免疫功能低下患者的初步数据：4例患有严重感染性疾病，2例患有爱泼斯坦-巴尔病毒淋巴增殖性疾病。他们均接受了多次安全的家族性CD45RA T细胞输注，作为过继性被动细胞疗法，其中包含巨细胞病毒、爱泼斯坦-巴尔病毒、BK病毒和特异性记忆T细胞。我们还展示了每种情况下选择最佳CD45RA细胞供体的方法以及分离和储存这些细胞的程序。
输注是安全的，没有发生移植物抗宿主病的病例，并且显示出明显的临床益处。接受BK病毒肾炎、巨细胞病毒脑炎、巨细胞病毒再激活和播散性侵袭性曲霉病治疗的患者病原体清除，4至6周内症状完全缓解，4例中有3例在3至4个月后淋巴细胞增多。在1例患者中检测到供体T细胞短暂微嵌合体。接受爱泼斯坦-巴尔病毒淋巴增殖性疾病治疗的2例患者接受了化疗和多次含有爱泼斯坦-巴尔病毒细胞毒性淋巴细胞的CD45RA记忆T细胞输注。在2例患者中均观察到供体T细胞微嵌合体。其中1例患者的病毒血症清除，另一例患者尽管病毒血症未清除，但肝淋巴增殖性疾病保持稳定，最终通过爱泼斯坦-巴尔病毒特异性细胞毒性T淋巴细胞治愈。
使用含有特异性细胞毒性T淋巴细胞的家族性CD45RA T细胞是一种可行、安全且可能有效的方法，可通过第三方供体治疗免疫功能低下患者的严重病原体感染。此外，这种方法可能具有普遍适用性，机构和监管障碍较少。
