Combining Targeted RIT and Synergistic Novel Agents to Eradicate AML

结合靶向 RIT 和协同新型药物来根除 AML

基本信息

批准号：
10409679
负责人：
Johnnie Jose Orozco
金额：
$ 28.55万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10409679
关键词：
90Y Acute Myelocytic Leukemia Allogeneic Bone Marrow Transplantation Allogenic Antibodies Antibody Specificity Apoptosis Apoptotic Astatine BCL2 gene Behavior Therapy Bispecific Antibodies Bone Marrow Bone Marrow Transplantation Cell Line Cells Cesium Chimerism Chromosome abnormality Clinical Research Clinical Trials Combination Drug Therapy DNA Damage DNA Repair DNA Sequence Alteration Data Disease Disease remission Engraftment Enrollment Funding Genetic Variation Grant Hematologic Neoplasms Hematology Hematopoietic Neoplasms I131 isotope Immunocompetent In Vitro Infrastructure Label Leukemic Cell Lymphoma Modeling Monoclonal Antibodies Multiple Myeloma Mus Non-Hodgkin&apos s Lymphoma Normal tissue morphology Oral Organ Outcome PTPRC gene Pathway interactions Patients Pharmacologic Substance Pre-Clinical Model Preparation Prior Chemotherapy Prior Therapy Radiation Radiation Dose Unit Radiation therapy Radioimmunoconjugate Radioimmunotherapy Radioisotopes Radiolabeled Regimen Relapse Reporting Research Personnel Site Spleen Supportive care Surface Antigens Systemic Therapy Systemic disease Technology Tissues Toxic effect Translating Transplantation Treatment Efficacy Treatment Failure United States National Institutes of Health Whole-Body Irradiation Xenograft procedure antibody conjugate base chemotherapy conditioning curative treatments donor stem cell dosimetry ethnic minority population hematopoietic cell transplantation high risk improved improved outcome inhibitor interest irradiation leukemia leukemia treatment mouse model multidisciplinary new therapeutic target novel patient subsets post-transplant pre-clinical preclinical study response small molecule small molecule inhibitor synergism targeted agent targeted treatment tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Potentially curative treatments for acute myeloid leukemia (AML) are limited to intensive systemic chemotherapy with or without allogeneic bone marrow transplantation (BMT). However, not every patient is healthy enough to tolerate intensive treatments, and not every patient may have a suitably HLA-matched stem cell donor, especially patients from ethnic minority groups. Targeted agents have recently been approved to treat AML, but these usually require intensive systemic chemotherapy to optimize efficacy. Furthermore, AML is genetically heterogeneous with distinct genetic mutations and chromosomal alterations that makes targeted- agent monotherapy unlikely to be curative. AML, like most hematologic malignancies, is very sensitive to radiation therapy but even involved field radiation may be too toxic and ineffective for disseminated systemic disease. However, radioimmunotherapy (RIT) mitigates the off-target toxicity by using monoclonal antibodies conjugated to radioactive isotopes to deliver radiation payloads directly to sites of disease by virtue of the antibody specificity. We have shown that RIT using 90Y- and 131I-radiolabeled anti-CD45 antibody targets radiation to sites of leukemia while minimizing radiation to uninvolved organs. We have improved upon our approach without increasing toxicity by targeting higher energy alpha-emitting radionuclides (astatine-211; 211At) to sites of disease and by developing a pre-targeted RIT (PRIT) approach using bispecific antibodies targeting CD45 and 90Y-DOTA. Using preclinical murine models, we now propose to identify synergistic combinations of 211At- and 90Y-anti- CD45 RIT with novel targeted therapies that interfere with DNA repair or promote apoptosis. We will do this by first assessing for synergy between alpha- or beta-emitting radionuclides (211At- and 90Y-) employed in anti- CD45 directly labeled RIT with recently approved targeted agents (PARP and BCL2 inhibitors) in both disseminated syngeneic and xenograft leukemia murine models. Second, we will improve therapeutic efficacy of anti-CD45 PRIT via bispecific antibody constructs targeting CD45 and 90Y-DOTA by assessing for synergy with targeted therapies (PARP and BCL2 inhibitors) in leukemia murine models. We will characterize the extent of DNA damage achieved with these two approaches as a means to elucidate the mechanism of efficacy. Finally, we will compare these two approaches as part of conditioning prior to allogeneic BMT using haploidentical, or partially matched donors, as all patients should have haploidentical donors. These preclinical studies should readily translate into clinical trials given our infrastructure for NIH funded and pharmaceutical-sponsored clinical trials, using anti-CD45 RIT prior to bone marrow transplantation for aggressive hematologic malignancies. These studies will add effective, well-tolerated treatment options for patients with AML by identifying synergistic combinations of targeted agents with anti-CD45 RIT approaches and by identifying the optimal RIT approach prior to haploidentical BMT.

项目摘要/摘要急性髓样白血病（AML）的潜在治愈方法仅限于密集型系统性具有或没有同种同种异体骨髓移植（BMT）的化学疗法。但是，并非每个病人都是健康足以容忍密集型治疗，并不是每个患者都有适当的HLA匹配茎细胞供体，尤其是来自少数民族群体的患者。目标代理最近已被批准治疗AML，但这些通常需要强化的全身化疗来优化疗效。此外，AML 在遗传上具有异质性，具有明显的遗传突变和染色体改变，这使得有针对性药剂单一疗法不太可能治愈。与大多数血液系统恶性肿瘤一样，AML对辐射疗法，甚至涉及场辐射可能过于毒性和无效，无法进行全身传播疾病。但是，放射免疫疗法（RIT）通过使用单克隆抗体来减轻靶向毒性与放射性同位素共轭以直接将辐射有效载荷传递到疾病部位抗体特异性。我们已经证明了使用90Y和131i-Radiolabel的抗CD45抗体靶标的RIT 对白血病部位的辐射，同时最大程度地减少对不参与器官的辐射。我们已经改善了我们的通过靶向较高的能量α发射放射性核素（Astatine-211; 211AT）到疾病部位，并通过使用双特异性抗体开发预先定位的RIT（PRIT）方法靶向CD45和90Y-DOTA。使用临床前鼠模型，我们现在建议确定211at-和90y-anti-的协同组合 CD45 RIT具有干扰DNA修复或促进凋亡的新型靶向疗法。我们将通过首先评估α或β发射放射性核素（211at-和90y-）之间的协同作用 CD45直接标记为RIT，并在两者中都标有最近认可的靶向剂（PARP和BCL2抑制剂）散布的同源性和异种移植白血病鼠模型。第二，我们将提高治疗功效通过双特异性抗体构建体靶向CD45和90Y-DOTA的抗CD45 PRIT，通过评估协同作用白血病模型中的靶向疗法（PARP和BCL2抑制剂）。我们将表征程度通过这两种方法实现的DNA损伤，以阐明功效机理。最后，我们将在同种异体BMT之前比较这两种方法作为调节的一部分单倍型或部分匹配的捐助者，因为所有患者都应有单倍型供体。鉴于我们用于NIH资助的基础设施和药物赞助的临床试验，在骨髓移植之前使用抗CD45 RIT进行侵略性血液学恶性肿瘤。这些研究将为通过鉴定针对靶向药物的协同组合使用抗CD45 RIT方法，患有AML的患者并通过在单倍性BMT之前识别最佳RIT方法。