Project 2: Anti-PR1 Immune Therapy for Myeloid Leukemia

项目2：髓系白血病的抗PR1免疫治疗

基本信息

批准号：
10006813
负责人：
JEFFREY J MOLLDREM
金额：
$ 23.22万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-05 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006813
关键词：
Action Potentials Acute Myelocytic Leukemia Address Adoptive Cell Transfers Affinity Agreement Allogenic Animal Model Antibodies Antibody Therapy Antigen Targeting Antigen-Presenting Cells Antigens Apoptosis Avidity B-Lymphocytes Biological Assay Bispecific Antibodies Blood Bone Marrow Cells Cancer Center Caring Cells Clinic Clinical Clinical Research Clinical Trials Companions Complex Cross Presentation Cytotoxic T-Lymphocytes Dendritic Cells Development Disease remission Disease-Free Survival Doctor of Medicine Dose Dose-Limiting Down-Regulation Drug Kinetics Drug resistance Enrollment Frequencies Goals Grant HLA-A2 Antigen Hematopoietic Hematopoietic stem cells Human IgG1 Immune Tolerance Immune response Immunoglobulin Idiotypes Immunotherapeutic agent Immunotherapy In Vitro Industry Knowledge Leukocyte Elastase Maximum Tolerated Dose Measures Mediating Methodology Modality Modeling Modification Molecular Monkeys Monoclonal Antibodies Morbidity - disease rate Myeloid Leukemia Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Phase Pre-Clinical Model Predisposition Proteinase 3 Refractory Relapse Resistance Safety Source Specificity Stem cell transplant Surface Antigens T-Cell Receptor T-Lymphocyte Testing Texas Therapeutic Time Toxic effect Translating Umbilical Cord Blood Universities Vaccination Vaccines Work alpha-beta T-Cell Receptor alternative treatment base bi-specific T cell engager chemotherapy chimeric antigen receptor T cells effective therapy first-in-human improved in vivo incomplete Freund&apos s adjuvant leukemia leukemic stem cell multicatalytic endopeptidase complex novel novel strategies novel therapeutics overexpression phase I trial pre-clinical resistance mechanism response safety study targeted treatment therapy resistant treatment strategy tumor vaccine trial validation studies

Action Potentials Acute Myelocytic Leukemia Address Adoptive Cell Transfers Affinity Agreement Allogenic Animal Model Antibodies Antibody Therapy Antigen Targeting Antigen-Presenting Cells Antigens Apoptosis Avidity B-Lymphocytes Biological Assay Bispecific Antibodies Blood Bone Marrow Cells Cancer Center Caring Cells Clinic Clinical Clinical Research Clinical Trials Companions Complex Cross Presentation Cytotoxic T-Lymphocytes Dendritic Cells Development Disease remission Disease-Free Survival Doctor of Medicine Dose Dose-Limiting Down-Regulation Drug Kinetics Drug resistance Enrollment Frequencies Goals Grant HLA-A2 Antigen Hematopoietic Hematopoietic stem cells Human IgG1 Immune Tolerance Immune response Immunoglobulin Idiotypes Immunotherapeutic agent Immunotherapy In Vitro Industry Knowledge Leukocyte Elastase Maximum Tolerated Dose Measures Mediating Methodology Modality Modeling Modification Molecular Monkeys Monoclonal Antibodies Morbidity - disease rate Myeloid Leukemia Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Phase Pre-Clinical Model Predisposition Proteinase 3 Refractory Relapse Resistance Safety Source Specificity Stem cell transplant Surface Antigens T-Cell Receptor T-Lymphocyte Testing Texas Therapeutic Time Toxic effect Translating Umbilical Cord Blood Universities Vaccination Vaccines Work alpha-beta T-Cell Receptor alternative treatment base bi-specific T cell engager chemotherapy chimeric antigen receptor T cells effective therapy first-in-human improved in vivo incomplete Freund&apos s adjuvant leukemia leukemic stem cell multicatalytic endopeptidase complex novel novel strategies novel therapeutics overexpression phase I trial pre-clinical resistance mechanism response safety study targeted treatment therapy resistant treatment strategy tumor vaccine trial validation studies

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项目摘要

Project Summary Our long-term goal is to develop immune therapies that target aberrantly expressed proteases in blasts and leukemia stem cells. PR1 peptide (VLQELNVTV) is a peptide derived from the leukemia-associated antigens proteinase 3 (P3) and neutrophil elastase (NE), which is presented on HLA-A2 to PR1-specific cytotoxic T lymphocytes (PR1-CTL). During the last grant period, we showed that PR1 is cross-presented by dendritic cells (DCs) and B cells, and we showed the mechanism required proteasome cleavage exogenous P3 and NE taken up by antigen-presenting cells. In previous years of the SPORE grant, we conducted a Phase I-II PR1 vaccine trial in 66 patients with AML, CML, and MDS, and observed immune responses to PR1 vaccine in 58%. However, objective clinical responses were observed in only 11 (16%) patients, and these were limited to patients with low leukemia burden (<10% blasts). We showed that, although highly cytolytic PR1-CTL that expressed high avidity T cell receptors (TCR-αβ) for PR1/HLA-A2 increased after PR1 vaccination in some patients, they underwent apoptosis by leukemia that expressed high PR1/HLA-A2 surface antigen, resulting in immune tolerance by deletion of high avidity PR1-CTL. Furthermore, although high avidity PR1-CTL could be isolated from umbilical cord blood (CB) units, they are difficult to expand in sufficient quantity ex vivo to be useful as an adoptive cell therapy, thus limiting their therapeutic potential. Therefore, in a novel alternative treatment approach to target PR1, we produced a TCR-like monoclonal antibody (8F4) against PR1/HLA-A2. We have produced a humanized 8F4 (h8F4) with high affinity (KD=7.8 nM) to PR1/HLA-A2 and we showed that h8F4 eliminated AML and leukemia stem cells but not normal human hematopoietic stem cells in preclinical models. With an agreement from industry that supported manufacturing of h8F4, we have produced sufficient clinical grade h8F4, showed it mediated ADCC and apoptosis of AML and LSC in vitro and in vivo, and developed companion assays for PK, anti-idiotype and anti-drug antibody testing. Moreover, we have established PDX models of AML for parallel studies to support a clinical trial. Thus, the goals of this proposal are to (1) translate the discovery of this novel h8F4 monoclonal antibody to the clinic in a first-in-human phase I trial in AML; (2) to determine pharmacokinetics, toxicity, and mode of action; and to characterize the mechanism of action, potential resistance mechanisms and to test novel strategies with an h8F4-based bispecific antibody and an h8F4 chimeric antigen receptor (CAR) T cells to increase the potency of 8F4 to overcome potential treatment resistance.

项目摘要我们的长期目标是开发免疫疗法，该疗法的靶向异常表达的蛋白酶在爆炸和白血病干细胞。 Pr1 Pepperide（VLQELNVTV）是源自白血病相关的抗原的胡椒蛋白酶3（P3）和中性粒细胞弹性酶（NE），在HLA-A2上呈现至PR1特异性细胞毒性T 淋巴细胞（PR1-CTL）。在最后一个赠款期间，我们表明PR1由树突细胞交叉出现（DC）和B细胞，我们显示了所需的蛋白酶裂解外源性P3和NE的机制由抗原呈递细胞向上。在孢子赠款的前几年，我们进行了I-II期PR1疫苗在66例AML，CML和MDS的患者中试用，并观察到58％的PR1疫苗的免疫回报。然而，仅在11例（16％）患者中观察到客观的临床反应，这些反应仅限于白血病Burnen（<10％爆炸）。我们表明，虽然表达高流行的高胞溶液PR1-CTL PR1/HLA-A2的T细胞受体（TCR-αβ）在某些患者的PR1疫苗接种后增加，他们接受了白血病凋亡表达高PR1/HLA-A2表面抗原，从而导致免疫耐受性删除高流行病PR1-CTL。此外，尽管可以从脐带中分离出高的pr1-ctl 脐带血（CB）单位，它们很难在体内扩展足够数量，无法作为被采用的单元治疗，从而限制其治疗潜力。因此，在一种新颖的替代方法中 PR1，我们生产了针对PR1/HLA-A2的TCR样单克隆抗体（8F4）。我们已经生产了人源化 8F4（H8F4）具有高亲和力（KD = 7.8 nm）的PR1/HLA-A2，我们表明H8F4消除了AML和临床前模型中的白血病干细胞，但不是正常的人造血干细胞。达成协议从支持H8F4制造的行业，我们已经生产了足够的临床H8F4 在体外和体内介导的AML和LSC的ADCC和凋亡，并开发了PK的伴侣测定法抗IDiotype和抗药物抗体测试。此外，我们已经建立了AML的PDX模型支持临床试验的研究。这是该提议的目标是（1）翻译这本小说的发现在AML的第一阶段I试验中，H8F4单克隆抗体对诊所的抗体；（2）确定药代动力学，毒性和作用方式；并表征作用机理，潜在的抵抗机制和用基于H8F4的双特异性抗体和H8F4嵌合抗原受体（CAR）T测试新策略细胞增加8F4的效力以克服潜在的治疗抗性。