Developmental Therapeutics

发育治疗学

• 批准号: 7078596
• 负责人: Guido J. Tricot
• 金额: $ 33.07万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7078596
• 关键词: autologous transplantation; cytogenetics; gene expression profiling; graft versus host disease; hematopoietic tissue transplantation; histocompatibility typing; homologous transplantation; human subject; human therapy evaluation; multiple myeloma; natural killer cells; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; prognosis; stem cell transplantation

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.

高剂量化疗联合自体干细胞移植显着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（高危骨髓瘤）患者中尚未观察到这种改善。因此，这些患者需要一种完全不同的方法。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性骨髓瘤。因此，基于这些观察，我们假设通过免疫操作增强自体移植治疗可以改善高危骨髓瘤的结果。发展治疗计划将探索三种创新治疗策略：目标1将评估细胞遗传学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 异常。目标 2 将评估在先前治疗过的骨髓瘤细胞中表达这些基因的患者中，在自体移植前后接种 NY-ESO-1 或 MAGE-A3 肽是否可以改善 EFS 和 OS。目标3将评估KIR配体的应用是否不匹配 单倍体供体自然杀伤 (NK) 细胞输注，然后进行自体移植 改善移植后复发或患有高风险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 GVHD 的发生，尽管它对于控制疾病是必要的，但会导致相当大的发病率和死亡率。其他两种方法（目标 2 和 3）试图在不发生 GVHD 的情况下实现类似的有效杀死骨髓瘤细胞的效果。在每项研究中，EFS 和 OS 都将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 30% 或以上的研究才会被认为值得在随机研究中进行。有效的免疫学方法与自体移植相结合，应提供优越的治疗效果。 高风险骨髓瘤患者的疾病控制，一旦证明优越性，这些策略将应用于标准风险患者，以进一步改善他们的结果。