O'Shaughnessy J A, Cowan K H, Nienhuis A W, McDonagh K T, Sorrentino B P, Dunbar C E, Chiang Y, Wilson W, Goldspiel B, Kohler D
St. Jude Children's Research Hospital.
Hum Gene Ther. 1994 Jul;5(7):891-911. doi: 10.1089/hum.1994.5.7-891.
Patients with metastatic breast cancer will receive 4-5 cycles of induction chemotherapy on one of the ongoing Medicine Branch protocols. Patients achieving at least a partial response, and who do not have evidence of bone marrow involvement and who do not have metastatic bone disease, will undergo PBSC and bone marrow harvest when hematologic recovery has occurred. Patients who have not achieved a PR, but who are responding to therapy, may be treated with additional cycles of therapy in an attempt to achieve a PR. Such patients will be eligible for transplant if a PR is obtained. 70% of the bone marrow and PBSC will be cryopreserved. The CD34+ subpopulation from the remaining 30% of the bone marrow and PBSC harvest will be obtained using an anti-CD34+ antibody and immunoabsorption column. The bone marrow and peripheral blood CD34 cells will be transduced with a retroviral vector expressing the human MDR-1 cDNA. Patients with positive bone scans or histologic evidence of bone marrow involvement will be excluded from the gene transfer component of the protocol. The MDR-1 transduced CD34 cells will be reinfused along with the non-transduced bone marrow and PBSC into patients following high dose ICE chemotherapy. Serial peripheral blood and bone marrow samples will be obtained to study hematopoietic reconstitution with MDR-1 transduced cells. Patients with residual or progressive disease after ABMT will be treated with taxol or vinblastine. In these relapsed patients, peripheral blood and bone marrow samples will be obtained to study whether chemotherapy amplifies the proportion of hematopoietic cells containing the MDR-1 provirus. We will monitor the nadir blood counts of each patient receiving salvage chemotherapy for evidence of myeloprotection and correlate this data with changes in the mean proviral copy number. Sites of relapsed tumor will be biopsied to test for the presence of the MDR-1 provirus.
转移性乳腺癌患者将按照医学科正在进行的方案之一接受4 - 5个周期的诱导化疗。至少获得部分缓解、无骨髓受累证据且无转移性骨病的患者，在血液学恢复后将接受外周血干细胞采集和骨髓采集。未达到部分缓解但对治疗有反应的患者，可能会接受额外周期的治疗以试图达到部分缓解。若获得部分缓解，此类患者将有资格接受移植。70%的骨髓和外周血干细胞将被冷冻保存。使用抗CD34 +抗体和免疫吸附柱从剩余30%的骨髓和外周血干细胞采集中获取CD34 +亚群。骨髓和外周血CD34细胞将用表达人MDR - 1 cDNA的逆转录病毒载体进行转导。骨扫描阳性或有骨髓受累组织学证据的患者将被排除在该方案的基因转移部分之外。经MDR - 1转导的CD34细胞将与未转导的骨髓和外周血干细胞一起在大剂量ICE化疗后回输给患者。将获取系列外周血和骨髓样本以研究经MDR - 1转导细胞的造血重建情况。自体骨髓移植后有残留或进展性疾病的患者将接受紫杉醇或长春碱治疗。在这些复发患者中，将获取外周血和骨髓样本以研究化疗是否会增加含有MDR - 1原病毒的造血细胞比例。我们将监测每位接受挽救性化疗患者的最低血细胞计数，以获取骨髓保护的证据，并将该数据与平均原病毒拷贝数的变化相关联。对复发肿瘤部位进行活检以检测MDR - 1原病毒的存在。
