Slavin S, Nagler A
Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
Cancer J Sci Am. 1997 Dec;3 Suppl 1:S59-67.
Relapse remains a major problem following treatment of hematologic malignancies and metastatic solid tumors with allogeneic and autologous bone marrow transplantation (alloBMT and autoBMT). Our goal was to introduce posttransplantation immunotherapy for eradication of tumor cells that escape high-dose chemoradiotherapy prior to transplantation.
Murine B-cell leukemia in BALB/c mice was used to develop a preclinical model to study the role of cytokine-mediated immunotherapy and allogeneic cell-mediated immunotherapy with donor lymphocytes in minimal residual disease (MRD). Based on these studies, a clinical trial was initiated to investigate the safety and efficacy of treating lymphoma patients with recombinant interleukin-2 (rIL-2) and interferon-alpha (IFN-alpha) at the stage of MRD following autoBMT. The clinical application of donor lymphocyte infusion (DLI) was also investigated for treatment and prevention of relapse following alloBMT. Patients in relapse following alloBMT who were resistant to DLI were treated with DLI plus rIL-2 in an attempt to activate the alloreactive potential of immunocompetent donor lymphocytes.
High-dose rIL-2 was effective against MRD in BALB/c mice, and the combination of rIL-2 and IFN-alpha resulted in synergistic effects even at doses of rIL-2 that were ineffective when given alone. In this animal model, graft-versus-leukemia/lymphoma (GVL) effects were induced by DLI after alloBMT and could be potentiated by coadministration of rIL-2. In clinical studies, rIL-2 plus IFN-alpha significantly improved relapse rate and survival in lymphoma patients treated after autoBMT. Relapse following alloBMT was successfully treated with DLI, and a proportion of patients who failed to respond to DLI could be salvaged with a combination of DLI and low-dose rIL-2.
Following autoBMT, GVL effects may be induced with a combination of rIL-2 and IFN-alpha, resulting in a reduced rate of relapse. The combination of both allogeneic donor lymphocytes and rIL-2 seemed synergistic. Because DLI plus rIL-2 was effective, even following failure of myeloablative conditioning, future strategies for treatment of leukemia should be based on T-cell-dependent immunotherapy rather than high-dose chemoradiotherapy.
对于接受异基因和自体骨髓移植（alloBMT和autoBMT）治疗的血液系统恶性肿瘤和转移性实体瘤患者，复发仍然是一个主要问题。我们的目标是引入移植后免疫疗法，以根除在移植前逃避大剂量放化疗的肿瘤细胞。
利用BALB/c小鼠的鼠B细胞白血病建立一个临床前模型，以研究细胞因子介导的免疫疗法和供体淋巴细胞介导的异基因细胞免疫疗法在微小残留病（MRD）中的作用。基于这些研究，启动了一项临床试验，以研究在autoBMT后的MRD阶段用重组白细胞介素-2（rIL-2）和干扰素-α（IFN-α）治疗淋巴瘤患者的安全性和有效性。还研究了供体淋巴细胞输注（DLI）在alloBMT后治疗和预防复发中的临床应用。对DLI耐药的alloBMT后复发患者接受DLI加rIL-2治疗，试图激活具有免疫活性的供体淋巴细胞的同种异体反应潜能。
高剂量rIL-2对BALB/c小鼠的MRD有效，rIL-2和IFN-α联合使用即使在单独使用无效剂量的rIL-2时也产生协同作用。在这个动物模型中，alloBMT后DLI诱导了移植物抗白血病/淋巴瘤（GVL）效应，并且通过联合使用rIL-2可以增强这种效应。在临床研究中，rIL-2加IFN-α显著提高了autoBMT后治疗的淋巴瘤患者的复发率和生存率。alloBMT后的复发通过DLI成功治疗，一部分对DLI无反应的患者可以通过DLI和低剂量rIL-2联合挽救。
autoBMT后，rIL-2和IFN-α联合使用可能诱导GVL效应，从而降低复发率。异基因供体淋巴细胞和rIL-2联合使用似乎具有协同作用。由于DLI加rIL-2有效，即使在清髓性预处理失败后，未来白血病的治疗策略应基于T细胞依赖性免疫疗法而非大剂量放化疗。
