CASPALLO: A PHASE I STUDY EVALUATING THE USE OF ALLODEPLETED T CELLS TRANSDUCED

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在T细胞去除的干细胞移植（SCT）后，供体T细胞的回加可以加速免疫重建并有效对抗复发性恶性肿瘤。在单倍相合SCT后，移植物抗宿主病（GvHD）的高风险基本上排除了这种选择。因此，我们一直在使用CD 25免疫毒素耗尽供体T细胞的同种异体反应性前体细胞。我们的方法似乎是有效的，并且少至5 x 104/kg的同种异体耗尽的单倍体相合供体细胞实质上加速了受体中的抗病毒免疫恢复，而不增加GvHD（Blood Plenary Paper[1]）。 给予更高剂量的细胞对于获得抗白血病效果是必要的，并且几乎不可避免的是，在一些患者中，这些剂量的细胞将足以触发GvHD，即使在同种异体耗竭之后。 因此，我们建议通过将自杀基因，诱导型胱天蛋白酶9（iCasp 9），在同种异体耗竭的T细胞，允许他们的破坏，应该管理有不良反应，以增加我们的方法的安全性。 iCasp 9由促凋亡分子人胱天蛋白酶9与人FK 506结合蛋白衍生的药物结合结构域连接组成;添加小分子合成药物导致胱天蛋白酶9同源二聚化，激活胱天蛋白酶途径，并在24小时内使转导细胞凋亡。 AP 1903二聚反应器已成功完成人类志愿者的安全性测试。 我们已经产生了编码iCasp 9和选择性标记（截短的CD 19）的逆转录病毒载体，以使转导的细胞能够富集至>90%纯度。我们计划注入递增剂量的iCasp 9表达的同种异体耗竭细胞，从即使对未修饰的同种异体耗竭细胞也安全的剂量开始。我们的假设是，由于基因修饰的同种异体耗竭细胞的破坏，在较高剂量水平下发生的任何GVHD将对AP 1903的施用产生应答 如果我们的假设是正确的，这种方法将能够安全地给予更大和更有效剂量的供体细胞，以在大多数情况下实现最佳的抗肿瘤和抗病毒免疫重建，同时确保少数发生GVHD的人可以得到有效治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GvHD) had essentially precluded this option. We have therefore been depleting donor T cells of alloreactive precursor cells, using a CD25 immunotoxin. Our method appeared effective and as few as 5 x 104/kg allodepleted haploidentical donor cells substantially accelerated anti-viral immune recovery in the recipient, without increasing GvHD (Blood Plenary Paper[1]). Administration of higher doses of cells will be necessary to obtain an antileukemic effect, and it is almost inevitable that in some patients, these doses of cells will be sufficient to trigger GvHD even after allodepletion. We therefore propose to increase the safety of our approach by incorporating a suicide gene, inducible caspase 9 (iCasp9), in the allodepleted T cells, permitting their destruction should administration have adverse effects. iCasp9 consists of a pro-apoptotic molecule, human caspase 9, joined to a drug-binding domain derived from human FK506-binding protein; addition of a small molecule synthetic drug leads to homodimerization of caspase 9, activation of the caspase pathway and apoptosis of the transduced cells within 24 hours. The dimerizer, AP1903, has successfully completed safety-testing in human volunteers. We have generated a retroviral vector encoding iCasp9 and a selectable marker (truncated CD19) to enable enrichment of transduced cells to >90% purity. We plan to infuse escalating doses of iCasp9-expressing allodepleted cells, starting at doses that are safe even for unmodified allodepleted cells. Our hypothesis is that any GVHD that develops at higher dose levels will respond to administration of AP1903 because of destruction of the gene-modified allodepleted cells If our hypothesis is correct, this approach will enable safe administration of larger and more effective doses of donor cells for optimal anti-tumor and anti-viral immune reconstitution in the majority, while ensuring that the minority who develop GVHD can be effectively treated.