Developmental Therapeutics

大剂量化疗联合自体干细胞移植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，对于这些患者来说，需要一种完全不同的方法。AII型供者T细胞可以通过移植物抗骨髓瘤效应根除耐化疗的骨髓瘤。因此，基于这些观察，我们假设高危骨髓瘤的预后可以通过加强免疫操作的自体移植治疗来改善，开发治疗计划中将探索三种创新的治疗策略：AIM 1将评估在细胞遗传学异常患者进行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基因的患者在自体移植前后接种NY-ESO-1或MAGE-A3多肽是否可以改善EFS和OS。目标3将评估KIR-配体的应用是否错配 半相合供者自然杀伤(NK)细胞输注后进行自体移植可以 改善移植后复发或患有高危骨髓瘤的患者的预后。非清髓性同种异体移植(目标1)的主要问题是移植物抗宿主病的发展，虽然这对疾病控制是必要的，但会导致相当大的发病率和死亡率。另外两种方法(目标2和目标3)试图在不发展GVHD的情况下实现类似的有效杀灭骨髓瘤细胞。在每一项研究中，EFS和OS将与与适当预后因素相匹配的历史对照进行比较。只有那些在24个月时将EFS延长到与历史对照相同或超过30%的研究才被认为是值得在随机研究中继续进行的。有效的免疫学方法，与自体移植相结合，应该会提供更好的 在高危骨髓瘤患者中进行疾病控制，一旦优势被证明，这些策略将被应用于标准风险患者，以进一步改善他们的预后。

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.