Project 3: Stem Cell Allografts for Lymphoid Malignancies

摘要-项目3 异基因造血细胞移植（HCT）提供了移植物抗肿瘤（GVT）反应， 晚期淋巴瘤患者。我们开发了一种耐受性良好、强度降低的预处理方案， 低剂量全身照射（TBI）（2戈伊）与氟达拉滨（FLU; 30 mg/m2 3），提供可靠的 用于来自HLA匹配的相关或无关供体的同种异体HCT的移植。这种疗法允许治疗 接近这些疾病中位发病年龄的老年患者或患有合并症的患者 耐受清髓性HCT大多数抗肿瘤活性来自移植后产生的GVT反应。 免疫抑制被撤销。近90%的HCT失败的原因是复发和移植物抗宿主病。主机 疾病（GVHD）相关的非复发死亡率（NRM）。复发风险取决于肿瘤组织学和肿瘤体积 在体积较大的患者中，HCT时复发风险最高，而侵袭性NHL不存在复发风险。 缓解和既往自体HCT失败的HL患者。需要更好的治疗来减少和 控制疾病直至GVT效应出现。通过以下方式增加非特异性、系统性条件反射的强度 在这一人群中增加TBI或化疗的耐受性较差，并增加NRM。 放射免疫疗法（RIT）使用与碘-131（131 I; γ和β-发射体）和钇-90（90 Y; β-发射体）与我们的FLU/TBI预处理方案相结合 已被证明是安全的;然而，长的路径长度，长的半衰期，和相对较低的能量，这些 放射性同位素可能无法提供足够的靶向辐射，并可能被循环水平的利妥昔单抗阻断 之前的治疗。我们建议用抗CD 45单克隆抗体与α- 放射性核素211 At。α发射体的短路径长度、高能量和短 半衰期可以减少早期毒性和晚期效应，如继发性癌症， 常规β发射极RIT。我们假设α颗粒抗CD 45 RIT可能提供额外的抗CD 45抗体， 肿瘤活性，以及降低植入障碍，而不大大增加NRM治疗 B和T细胞NHL和HL，单独使用FLU/TBI时复发风险高。具体目标1将 评价211 At抗CD 45 mAb与来自HLA匹配相关患者的低强度同种异体HCT联合使用 无关的捐赠者。为了将HCT的选择扩展到没有HLA匹配供体的患者， 服务于少数群体的患者，我们已经开发了一种降低强度的方案， 捐助者。虽然该方案耐受性良好，GVHD发生率低，但复发和免疫缺陷仍然存在 高，可能是由于HCT后使用环磷酰胺进行免疫抑制以控制GVHD。具体目标2 将使用供体NK细胞的过继免疫治疗和基因修饰供体的输注来解决这个问题。 T淋巴细胞表达可诱导的iCaspase-9基因，该基因可在肿瘤细胞中用二聚化剂消融。 严重GVHD的出现。我们假设这将减少HCT后的复发和免疫缺陷。

ABSTRACT - PROJECT 3 Allogeneic hematopoietic cell transplantation (HCT) provides graft-vs-tumor (GVT) reactions that may cure patients with advanced lymphoma. We developed a well tolerated, reduced intensity conditioning regimen with low-dose total body irradiation (TBI) (2 Gy) with fludarabine (FLU; 30 mg/m2 ¿ 3) that provides reliable engraftment for allogeneic HCT from HLA-matched related or unrelated donors. This regimen allows treatment of older patients nearer the median age of presentation for these diseases or those with comorbidities unable to tolerate myeloablative HCT. Most anti-tumor activity is from GVT responses that develop as post-grafting immunosuppression is withdrawn. Nearly 90% of the causes of HCT failure are relapse and graft-vs.-host disease (GVHD) related nonrelapse mortality (NRM). Relapse risk depends on tumor histology and tumor bulk at the time of HCT with the highest risk of relapse in patients with bulky disease, aggressive NHL not in remission, and HL patients who have failed prior autologous HCT. Better treatments are needed to reduce and control disease until GVT effects emerge. Increasing the intensity of nonspecific, systemic conditioning by increasing TBI or chemotherapy in this population has been poorly tolerated and increases NRM. Radioimmunotherapy (RIT) using anti-CD20 monoclonal antibodies (mAb) conjugated with iodine-131 (131I; gamma and beta-emitter) and yttrium-90 (90Y; beta-emitter) combined with our FLU/TBI conditioning regimen has been shown to be safe; however, the long path-length, long half-life, and relatively low-energy of these radioisotopes may not provide enough targeted radiation, and may be blocked by circulating levels of rituximab from prior therapy. We propose to augment transplant conditioning with anti-CD45 mAb coupled to the alpha- emitting radionuclide astatine-211 (211At). The short path length of the alpha-emitter, high energy, and short half-life may reduce both early toxicities and late effects, such as secondary cancers, associated with conventional beta-emitter RIT. We hypothesize that alpha particle anti-CD45 RIT may provide additional anti- tumor activity, as well as lower the barriers to engraftment without greatly increasing NRM for the treatment of both B and T-cell NHL and HL at a high risk of relapse using FLU/TBI alone. Accordingly, Specific Aim 1 will evaluate 211At anti-CD45 mAb in combination with reduced intensity allogeneic HCT from HLA-matched related and unrelated donors. In order to extend the option of HCT to patients without HLA-matched donors and better serve patients from minority groups, we have developed a reduced intensity regimen using HLA-haploidentical donors. While the regimen is well tolerated with a low rate of GVHD, relapse and immunodeficiency remain high, likely due to the post HCT immunosuppression with cyclophosphamide to control GVHD. Specific Aim 2 will address this using adoptive immunotherapy with donor NK cells and with infusions of gene modified donor T lymphocytes expressing an inducible iCaspase-9 gene that can be ablated with a dimerizing agent in the advent of severe GVHD. We hypothesize that this will reduce relapse and immunodeficiency post HCT.