Redman B G, Chou T H, Zalupski M, Uberti J, Flaherty L, Dan M, Sensenbrenner L
Division of Hematology-Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA.
J Immunother Emphasis Tumor Immunol. 1995 Aug;18(2):115-8.
Previous reports of autologous bone marrow transplant (auto-BMT) have demonstrated that myeloablative therapy followed by cyclosporin A (CsA), with and without interferon (IFN), can generate autoreactive cytotoxic T lymphocytes (auto-CTL) with potential therapeutic benefit. This is the first report of an attempt to generate auto-CTL using CsA and IFN after a non-myeloablative regimen. Cyclophosphamide (CTX) 1,200 mg/m2 i.v. day 1 was followed by CsA and IFN-alpha days 2-28, administered in a sequential three-step Phase I dose-escalation scheme. Patients were evaluated twice weekly for clinical evidence of graft-versus-host (GVH) reaction. Peripheral blood mononuclear cells (PBMCs) were obtained before treatment, at time of clinical GVH reaction, and days 21 and 28, and analyzed for auto-CTL, natural killer (NK) cell, and lymphokine-activated killer (LAK) cell activity. Patients also underwent punch skin biopsy at the time of clinical GVH reaction or day 21 to identify histologic evidence of GVH. Fourteen patients completed therapy and were evaluable for immunologic studies and anti-tumor response. No increase in auto-CTL, NK cell, or LAK cell activity was seen. Clinical or histologic evidence of GVH reaction did not occur. We conclude that this myelosuppressive dose of CTX combined with CsA and IFN is unable to generate clinical or immunologic evidence of an auto-GVH reaction. Further efforts are warranted to evaluate other therapeutic attempts to generate auto-CTL with anti-tumor activity based on preliminary results of clinical benefit in auto-BMT.
先前关于自体骨髓移植（auto - BMT）的报告表明，在使用环孢菌素A（CsA）（有无干扰素（IFN））进行清髓性治疗后，可产生具有潜在治疗益处的自身反应性细胞毒性T淋巴细胞（auto - CTL）。这是首篇关于在非清髓性方案后尝试使用CsA和IFN产生auto - CTL的报告。第1天静脉注射1200 mg/m²环磷酰胺（CTX），随后在第2 - 28天给予CsA和α - 干扰素，采用连续三步的I期剂量递增方案。每周对患者进行两次评估，以寻找移植物抗宿主（GVH）反应的临床证据。在治疗前、出现临床GVH反应时、第21天和第28天采集外周血单个核细胞（PBMC），并分析其auto - CTL、自然杀伤（NK）细胞和淋巴因子激活的杀伤（LAK）细胞活性。患者在出现临床GVH反应时或第21天还接受了皮肤穿刺活检，以确定GVH的组织学证据。14例患者完成治疗，可进行免疫学研究和抗肿瘤反应评估。未观察到auto - CTL、NK细胞或LAK细胞活性增加。未出现GVH反应的临床或组织学证据。我们得出结论，这种骨髓抑制剂量的CTX联合CsA和IFN无法产生自身GVH反应的临床或免疫学证据。基于auto - BMT临床获益的初步结果，有必要进一步努力评估其他产生具有抗肿瘤活性的auto - CTL的治疗尝试。
