Developmental Therapeutics

自体干细胞移植的高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结局;然而，在细胞遗传学异常的患者（高危骨髓瘤）中没有观察到这种改善。因此，需要对这些患者采取完全不同的方法。同种异体供体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，我们假设高危骨髓瘤的结局可以通过免疫学操作增强自体移植治疗来改善，将在发展治疗计划中探索三种创新治疗策略：目标1将评估细胞遗传学异常患者单次自体移植后计划的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NY-ESO-1或MAGE-A3肽的先前治疗的患者中，在自体移植之前和之后，通过接种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KIR配体错配的应用是否 单倍相合供体自然杀伤（NK）细胞输注后进行自体移植， 改善移植后复发或高危骨髓瘤患者的预后。非清髓性同种异体移植（目的1）的主要问题是GVHD的发展，尽管GVHD对疾病控制是必要的，但会导致相当大的发病率和死亡率。其他两种方法（目的2和3）试图实现类似的有效杀死骨髓瘤细胞而不发展GVHD。在每项研究中，将EFS和OS与匹配适当预后因素的历史对照进行比较。只有那些在24个月时EFS比历史对照延长等于或大于30%的研究才被认为值得在随机研究中进行。有效的免疫学方法，结合自体移植，应提供上级 在高危骨髓瘤患者中进行疾病控制，一旦证明了优越性，这些策略将应用于标准风险患者，以进一步改善其结局。

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.