Project 3: Stem Cell Allografts for Lymphoid Malignancies

项目 3：干细胞同种异体移植治疗淋巴恶性肿瘤

• 批准号: 8742472
• 负责人: DAVID G MALONEY
• 金额: $ 26.37万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-31 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742472
• 关键词: 90Y; Address; Adoptive Immunotherapy; Age; Allogenic; Allografting; Alpha Particles; Ambulatory Care; Antibodies; Astatine; Autologous; B-Lymphocytes; Bulky Disease; CASP9 gene; CSF3 gene; Cell Therapy; Cells; Child; Chimerism; Comorbidity; Coupled; Cyclophosphamide; Development; Disease; Disease remission; Dose; Engraftment; Enrollment; Failure; Gamma Rays; Gene-Modified; Genes; Graft vs Tumor Effect; Grant; Half-Life; Hematopoietic; Histology; I131 isotope; Immune; Immunologic Deficiency Syndromes; Immunologics; Immunosuppression; Indolent; Infusion procedures; Label; Late Effects; Length; Life; Lymphoid; Lymphoma; MS4A1 gene; Malignant Neoplasms; Malignant lymphoid neoplasm; Marrow; Minority Groups; Monoclonal Antibodies; Multicenter Trials; Natural Killer Cells; Outcome; PTPRC gene; Parents; Patients; Peripheral Blood Stem Cell; Population; Prior Therapy; Proliferating; Radiation; Radioimmunotherapy; Radioisotopes; Reaction; Recurrent disease; Regimen; Relapse; Risk; Second Primary Cancers; Siblings; Spleen; Stem cell transplant; Stem cells; System; T-Lymphocyte; Testing; Time; Toxic effect; Transplantation; Whole-Body Irradiation; aging population; antibody conjugate; cancer cell; caspase-9; chemotherapy; conditioning; disorder control; fludarabine; graft vs host disease; granulocyte; hematopoietic cell transplantation; high risk; improved; in vivo; irradiation; lymph nodes; mortality; older patient; prospective; public health relevance; rituximab; suicide gene; tumor

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.

摘要 - 项目3 同种异体造血细胞移植（HCT）提供了可能治愈的移植物-VS肿瘤（GVT）反应 晚期淋巴瘤患者。我们开发了一种耐受性良好的，降低的强度调节方案 低剂量的总体照射（TBI）（2 Gy），氟达拉滨（流感； 30 mg/m2€3），可提供可靠 来自HLA匹配的相关供体或无关供体的同种异体HCT的植入。该方案允许治疗 这些疾病的年龄较大患者的中位年龄或无法合并症的患者 耐受髓质的HCT。大多数抗肿瘤活性来自GVT的反应，这些反应是作为植根后发展的 免疫抑制被撤回。 HCT失败的原因近90％是缓解和移植物。 疾病（GVHD）相关的非恢复死亡率（NRM）。复发风险取决于肿瘤组织学和肿瘤大量 在HCT时，患有笨重疾病的患者的救济风险最高，侵略性NHL不参加 缓解和先前自体HCT失败的HL患者。需要更好的治疗来减少和 控制疾病，直到出现GVT。通过 该人群中TBI或化学疗法的增加的耐受性较差，NRM增加。 使用抗CD20单克隆抗体（MAB）与碘131（131i; 伽玛和β发电机）和yttrium-90（90y; beta-emitter）与我们的流感/TBI调节方案相结合 已被证明是安全的；但是，这些长的长路径长度，长的半衰期和相对较低的能量 放射性同位素可能无法提供足够的靶向辐射，并且可以通过利妥昔单抗的循环水平阻止 从先前的疗法。我们建议用抗CD45 mAb耦合到α-增强移植调节 发射放射性助理助理211（211AT）。 α-发射器的短路径长度，高能量和短路 半衰期可能会降低早期毒性和晚期作用，例如次要癌症 常规的β发射极端。我们假设α粒子抗CD45 RIT可能会提供额外的抗 肿瘤活性，以及​​降低植入障碍而没有大大增加NRM的治疗 仅使用流感/TBI，B和T-Cell NHL和HL都具有高继电器风险。彼此之间，特定的目标1将 评估211AT抗CD45 MAB，结合降低的HLA匹配相关强度同种异体HCT 和无关的捐助者。为了将HCT的选择扩展到没有HLA匹配捐助者和更好的患者 使用少数群体的患者，我们使用HLA-HAPLOCINEDICE制定了强度降低的强度方案 捐助者。虽然该方案的耐受性良好，而GVHD的速率较低，但继电器和免疫缺陷仍然存在 高，可能是由于HCT后与环磷酰胺的HCT免疫抑制作用来控制GVHD。具体目标2 将使用供体NK细胞的自适应免疫疗法和基因改性供体的输注来解决此问题 表达诱导型ICaspase-9基因的T淋巴细胞，该基因可以用二聚剂在 严重GVHD的出现。我们假设这将减少HCT后的救济和免疫缺陷。