Tam Y K, Klingemann H G
Section of Bone Marrow Transplantation, Rush Cancer Institute, Rush Medical College, Chicago, Illinois 60612, USA.
Biol Blood Marrow Transplant. 1999;5(4):231-42. doi: 10.1053/bbmt.1999.v5.pm10465103.
Myeloablative chemotherapy or radiation therapy supported by autologous stem cell transplantation (SCT) for the treatment of hematologic malignancies such as acute leukemia, lymphoma, and myeloma is associated with high rates of relapse. The reasons for this are 1) autologous transplantation lacks the in vivo graft-vs.-tumor (GVT) effect associated with allogeneic SCT, which is effective in controlling or eliminating residual malignant cells remaining in the body after high-dose therapy, and 2) contaminating malignant cells in the autologous graft are reinfused into the body. Some researchers have attempted to administer immunomodulatory cytokines to simulate a GVT effect, and although this has shown some efficacy, it has several disadvantages. These include high toxicity associated with systemic administration, a short in vivo half-life, and insufficient levels reaching the site of residual disease. As an alternative, we investigated whether delivery of the cytokine interleukin (IL)-2 to the bone marrow can exert an antileukemic effect while avoiding the problems associated with systemic administration. We describe the delivery of IL-2 to the bone marrow by transplantation of syngeneic bone marrow, retrovirally transduced with the gene for IL-2, into lethally irradiated mice. We were able to efficiently transduce murine bone marrow with the IL-2 gene without adversely affecting clonogenic output from hematopoietic progenitors, and we were able to achieve expression of the transgene in transplanted animals. However, IL-2 transduction inhibited hematopoietic reconstitution in lethally irradiated mice. Marrow transduced with high-titer, high-expressing IL-2 retrovirus failed to engraft, and a low-titer, low-expressing IL-2 retrovirus also demonstrated reduced engraftment, although engraftment was sufficient to support survival of transplanted mice. Long-term, low-level expression of the IL-2 transgene was detectable in these mice and was effective in exerting an antileukemic effect. Mice transplanted with control marrow and challenged with leukemic cells suffered 100% mortality within 70 days, whereas mice transplanted with IL-2-transduced marrow exhibited 50% survival over the 175-day duration of this study. The work shows that delivery of immunomodulatory cytokines to the bone marrow can be achieved by transplantation of genetically modified hematopoietic cells. Furthermore, low-level IL-2 expression can exert an antileukemic effect. These data suggest that this may be an effective immunotherapeutic strategy to reduce relapse after autologous transplantation, but the selection and expression of the cytokine must be carefully considered to minimize adverse effects on hematopoiesis.
由自体干细胞移植（SCT）支持的清髓性化疗或放射治疗用于治疗血液系统恶性肿瘤，如急性白血病、淋巴瘤和骨髓瘤，其复发率很高。原因如下：1）自体移植缺乏与异基因SCT相关的体内移植物抗肿瘤（GVT）效应，而异基因SCT在控制或消除高剂量治疗后体内残留的恶性细胞方面是有效的；2）自体移植物中污染的恶性细胞会重新注入体内。一些研究人员试图给予免疫调节细胞因子以模拟GVT效应，尽管这已显示出一些疗效，但也有几个缺点。这些缺点包括与全身给药相关的高毒性、体内半衰期短以及到达残留病灶部位的水平不足。作为一种替代方法，我们研究了将细胞因子白细胞介素（IL）-2递送至骨髓是否能在避免与全身给药相关问题的同时发挥抗白血病作用。我们描述了通过将用IL-2基因逆转录病毒转导的同基因骨髓移植到经致死性照射的小鼠体内，从而将IL-2递送至骨髓的方法。我们能够有效地用IL-2基因转导小鼠骨髓，而不会对造血祖细胞产生克隆形成能力产生不利影响，并且我们能够在移植动物中实现转基因的表达。然而，IL-2转导抑制了经致死性照射小鼠的造血重建。用高滴度、高表达的IL-2逆转录病毒转导的骨髓未能植入，而低滴度、低表达的IL-2逆转录病毒也显示植入减少，尽管植入足以支持移植小鼠的存活。在这些小鼠中可检测到IL-2转基因的长期低水平表达，并且其在发挥抗白血病作用方面是有效的。移植了对照骨髓并受到白血病细胞攻击的小鼠在70天内死亡率为100%，而移植了IL-2转导骨髓的小鼠在本研究的175天期间存活率为50%。这项工作表明，通过移植基因修饰的造血细胞可以实现将免疫调节细胞因子递送至骨髓。此外，低水平的IL-2表达可以发挥抗白血病作用。这些数据表明，这可能是一种有效的免疫治疗策略，可降低自体移植后的复发率，但必须仔细考虑细胞因子的选择和表达，以尽量减少对造血的不利影响。
