Allogeneic HCT for Hematologic Malignancies: Immune Manipulations

同种异体 HCT 治疗血液系统恶性肿瘤：免疫操作

• 批准号: 7585357
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 24.04万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585357
• 关键词: Acute; Acute Graft Versus Host Disease; Acute Myelocytic Leukemia; Address; Adoptive Immunotherapy; Affect; Age; Allogenic; Allografting; Ambulatory Care; Antitumor Response; Area; Busulfan; Calcineurin inhibitor; Canis familiaris; Categories; Cell Transplantation; Cells; Chimerism; Clinic; Clinical Trials Design; Comorbidity; Comorbidity Index; Cyclophosphamide; Cyclosporine; Cyclosporins; Data Analyses; Decitabine; Disease; Disease remission; Donor Lymphocyte Infusion; Dose; Dysmyelopoietic Syndromes; Effectiveness; Engraftment; Future; Graft Rejection; Graft-Versus-Tumor Induction; Grant; Health Benefit; Hematologic Neoplasms; Hematological Disease; Hematopoietic; Immune; Immunosuppression; Immunosuppressive Agents; Infection; Infusion procedures; Malignant - descriptor; Malignant Neoplasms; Morbidity - disease rate; Myeloproliferative disease; Natural Killer Cells; Outcome; Patients; Pentostatin; Pharmaceutical Preparations; Phase II Clinical Trials; Phase III Clinical Trials; Principal Investigator; Protocols documentation; Public Health; Randomized; Randomized Controlled Clinical Trials; Recovery; Recurrent disease; Relapse; Reproducibility; Risk; Severities; Sirolimus; Stem cells; Survival Rate; Tacrolimus; Translating; Transplantation; Treatment Protocols; Validation; Whole-Body Irradiation; base; chronic graft versus host disease; conditioning; cytotoxic; ethnic minority population; flu; fludarabine; graft vs host disease; high risk; improved; indexing; mortality; mycophenolate mofetil; novel strategies; older patient; pre-clinical; prognostic; programs; prospective; response; trial comparing; tumor eradication

PROJECT 3: ALLOGENEIC HCT FORHEMATOLOGIC MALIGNANCIES: IMMUNE MANIPULATIONS We have translated a novel approach at allogeneic hematopoietic cell transplantation (HCT) into the clinic to treat patients with hematologic malignancies. The approach uses 2 Gy total body irradiation (TBI) with or without fludarabine (Flu;90 mg/m2) before and immunosuppression with mycophenolate mofetil and cyclosporine (CSP), after HCT for control of both engraftment and graft-versus-host disease (GVHD). With this approach, the burden of tumor eradication has been shifted from the conventional high-dose cytotoxic conditioning to the HCT donors' immune cells (graft-versus-tumor [GVT] effect). Impressive antitumor responses have been seen among almost all of the disease categories studied. However, relapse of disease continues to be a major contributor to poor outcomes in high risk patients. The tempo of donor natural killer (NK) cell recovery after HCT appeared correlated with relapse risk. This finding has influenced the design of trials in Specific Aim 1 proposing donor NK cell infusions to reduce relapse. Encouraged by results inHLA- matched related and unrelated HCT, we have expanded the donor pool to include HLA-haploidentical donors. This, in combination with NK cell infusions, should provide for GVT effects. Specific Aim 2 addresses the issue of nonrelapse mortality (NRM). Retrospective findings of increased NRM in patients given Flu are being addressed in a phase III trial to determine whether Flu is needed in addition to 2 Gy TBI to condition heavily pretreated patients. GVHD and its extended treatment with immunosuppressive drugs also caused NRM. In order to reduce GVHD, tacrolimus has been substituted for CSP in a phase II study, and early results look promising. For acute myelocytic leukemias, outcomes in elderly patients and those with comorbidities were not different from concurrently transplanted younger patients given myeloablative conditioning regimens. Based on these findings, we have initiated a phase III study comparing myeloablative and nonmyeloablative conditioning in younger patients with myeloid malignancies (Specific Aim 3). During the last grant period, we assessed the impact of comorbidities on survival and cure. After initially using the Charlson Co-morbidity Index, we developed a hematopoietic cell transplantation-specific index (HCT-Cl), which seemed to have higher discriminative capacity. In order to validate the HCT-Cl, we propose to address multi-center issues, as well as inter-rater reproducibility in future studies (Specific Aim 4). The public health benefits of this Project are that patients with various malignant blood disorders who otherwise would have been excluded because of age and comorbidities have benefited from treatment by allogeneic HCT. In addition, the use of HLA-haploidentical donors will extend the option of HCT to a greater number of patients, including ethnic minorities.

项目3：同种异体HCT FROHATOLOGIC恶性肿瘤：免疫操纵 我们已经在同种异体造血细胞移植（HCT）中翻译了一种新的方法 治疗血液学恶性肿瘤的患者。该方法使用或使用2 Gy全身照射（TBI）或 没有氟达拉滨（流感； 90 mg/m2），并与霉酚酸酯莫菲尔和 HCT后，环孢菌素（CSP）控制了植入和移植物抗宿主病（GVHD）。和 这种方法，消除肿瘤的负担已从常规的高剂量细胞毒性转移 适应HCT供体的免疫细胞（移植物及脉冲[GVT]效应）。令人印象深刻的抗肿瘤 在研究的几乎所有疾病类别中都看到了反应。但是，疾病复发 继续成为高风险患者不良结果的主要贡献者。捐助者天然杀手的节奏 （NK）HCT后的细胞恢复与复发风险相关。这一发现影响了 特定目标的试验1提出供体NK细胞输注以减少复发。受到结果的鼓励 匹配的相关和无关的HCT，我们将供体池扩展到包括HLA-HAPLOIDENTIL 捐助者。与NK细胞输注结合使用，应提供GVT效应。特定目标2地址 非勒索死亡率（NRM）的问题。感染患者NRM增加的回顾性发现是 在第三阶段试验中解决，以确定除2 Gy TBI以外是否还需要流感 大量预处理患者。 GVHD及其对免疫抑制药物的扩展治疗也引起 NRM。为了减少GVHD，他克莫司在II期研究中已被CSP取代，并早期 结果看起来很有希望。对于急性骨髓细胞性白血病，老年患者的结局和 合并症与同时移植的年轻患者没有差异 调理方案。基于这些发现，我们开始了一项III期研究，比较了骨髓性 和患有髓样恶性肿瘤患者的年轻患者（特定AIM 3）的非乳不公动调理。期间 最后一个赠款期，我们评估了合并症对生存和治愈的影响。最初使用 Charlson合并症指数，我们开发了造血细胞移植特异性指数（HCT-CL）， 似乎具有更高的歧视能力。为了验证HCT-CL，我们建议解决 在未来的研究中，多中心问题以及评估者间的可重复性（特定目的4）。公共卫生 该项目的好处是，患有各种恶性血液疾病的患者本来会有 由于年龄和合并症而被排除在外，因此受益于同种异体HCT的治疗。在 此外，使用HLA-HAPloidentical供体将将HCT的选择扩展到更多的患者， 包括少数民族。