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: 9342665
• 负责人: DAVID G MALONEY
• 金额: $ 25.76万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 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/9342665
• 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; Dimerization; Disease; Disease remission; Dose; Engraftment; Enrollment; Failure; 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; Lymphoid; Lymphoma; MS4A1 gene; Malignant Neoplasms; Malignant lymphoid neoplasm; Marrow; Minority Groups; Monoclonal Antibodies; Monoclonal Antibody CD20; Multicenter Trials; Natural Killer Cells; PTPRC gene; Parents; Patient risk; 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; chemotherapy; conditioning; dimer; disorder control; ethnic diversity; fludarabine; granulocyte; hematopoietic cell transplantation; high risk; improved outcome; in vivo; irradiation; lymph nodes; mortality; older patient; prospective; public health relevance; relapse risk; 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 异基因造血细胞移植(HCT)提供移植物抗肿瘤(GVT)反应，可能治愈 晚期淋巴瘤患者。我们开发了一种耐受性良好的降低强度的调节方案 使用氟达拉滨(Flu；30 mg/m2�3)进行低剂量全身照射(2GY)，可提供可靠的 移植人类白细胞抗原相合的亲缘或非亲缘供者的异基因血细胞移植。这种养生法允许治疗 接近这些疾病的发病年龄中位数的老年患者或那些没有能力 耐受清髓性红细胞压积。大多数抗肿瘤活性来自移植后形成的GVT反应 免疫抑制被撤销。近90%的红细胞移植失败的原因是复发和移植物对宿主 疾病(GVHD)相关的无复发死亡率(NRM)。复发风险取决于肿瘤组织学和肿瘤体积 在巨大疾病患者中复发风险最高的HCT时，侵袭性NHL不在 缓解，以及之前未通过自体HCT的HL患者。需要更好的治疗方法来减少和 控制疾病，直到出现GVT效应。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或化疗的耐受性很差，并增加了NRM。 放射免疫治疗(RIT)使用抗CD20单抗(单抗)与碘-131(131I； 伽马和贝塔发射体)和Y-90(90Y；贝塔发射体)与我们的Flu/TBI调节方案相结合 已经被证明是安全的；然而，长路径长度、长半衰期和相对低能量的这些 放射性同位素可能不能提供足够的靶向辐射，并可能被循环中的利妥昔单抗水平所阻断。 从先前的治疗中。我们建议用抗CD45单抗偶联到α-CD45来增强移植条件。 发射放射性核素-211(211 At)。阿尔法发射器的短路径长度、高能量和短 半衰期可能会减少早期毒性和晚期效应，如与以下疾病相关的继发性癌症 传统的贝塔发射器RIT。我们假设α粒子抗CD45RIT可能提供额外的抗CD45RIT 肿瘤活性，以及降低植入障碍，而不大幅增加NRM用于治疗 B和T细胞性非霍奇金淋巴瘤和霍奇金淋巴瘤有很高的复发风险，单独使用流感/脑损伤。因此，具体目标1将 211At抗CD45单抗联合低强度同种异体血细胞移植的评价 和无血缘关系的捐赠者。为了将HCT的选择扩大到没有匹配的供者和更好的患者 为少数民族患者服务，我们开发了一种使用人类白细胞抗原半相合的降低强度方案 捐赠者。虽然该方案耐受性良好，移植物抗宿主病的发生率很低，但复发和免疫缺陷仍然存在。 高，可能是因为红细胞移植后用环磷酰胺抑制免疫以控制移植物抗宿主病。具体目标2 将通过对捐赠者NK细胞进行过继免疫治疗和输注转基因捐赠者来解决这个问题 表达可诱导的iCaspase-9基因的T淋巴细胞可用二聚体消融 严重的移植物抗宿主病来临。我们假设这将减少HCT后的复发和免疫缺陷。