Developmental Therapeutics

自体干细胞移植的大剂量化疗显著改善了中期细胞遗传学正常的骨髓瘤患者的预后；然而，在异常细胞遗传学（高危骨髓瘤）患者中没有观察到这种改善。因此，这些患者需要一种完全不同的治疗方法。同源供体t细胞可以通过移植物抗骨髓瘤效应根除化疗耐药骨髓瘤。因此，基于这些观察结果，我们假设高风险骨髓瘤的预后可以通过免疫操作增强自身移植治疗来改善。发育治疗学项目将探索三种创新的治疗策略：目的1将评估细胞遗传学异常患者在单次自身移植后计划进行非清髓性同种异体移植的疗效。目的2将评估在骨髓瘤细胞中表达其中一种基因的既往治疗患者，在自体移植前后接种NY-ESO-1或MAGE-A3肽是否可以获得改善的EFS和OS。目的3将评估ir -配体的应用是否错配

High-dose chemotherapy with autologous stem cell transplants has significantly improved the outcome of myeloma patients with normal metaphase cytogenetics; however, no such improvement has been observed in patients with abnormal cytogenetics (high-risk myeloma). Therefore, an entirely different approach is required for these patients. AIIogeneic donor T-cells can eradicate chemotherapy-resistant myeloma through a graft-versus-myeloma effect. Thus, based on these observations, we hypothesize that the outcome of high-risk myeloma can be improved upon by augmenting autotransplant therapy with immunologic manipulations, Three innovative treatment strategies will be explored in the Developmental Therapeutics Program: Aim 1 will evaluate the efficacy of a planned non-myeloablative allotransplant following a single autotransplant in patients with cytogenetic abnormalities. Aim 2 will evaluate whether improved EFS and OS can be obtained via vaccination with NY-ESO-1 or MAGE-A3 peptides prior to and after autotransplantation in previously treated patients expressing either of these genes in their myeloma cells. Aim 3 will evaluate whether the application of KIR-ligand-mismatched haploidentical donor natural killer (NK) cell infusions followed by an autotransplant can improve outcome in patients who have either relapsed after transplantation or have high risk myeloma. The major problem with non-myeloablative allotransplants (Aim 1) is the development of GVHD, which, although necessary to exert disease control, results in considerable morbidity and mortality. The other two approaches (Aims 2 and 3) try to accomplish a similar effective killing of myeloma cells without the development of GVHD. In each of these studies, EFS and OS will be compared to that of historical controls matched for the appropriate prognostic factors. Only those studies extending EFS byequal to or more than 30% at 24 months over that of historical controls will be considered worthwhile pursuing in a randomized study. Effective immunologic approaches, in combination with autotransplantation, should provide superior disease control in high-risk myeloma patients, and once superiority has been demonstrated, these strategies will be applied to standard-risk patients to further improve their outcome.