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：
10247505
负责人：
JEFFREY J MOLLDREM
金额：
$ 27.24万
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/10247505
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 Modification Molecular Monkeys Monoclonal Antibodies Morbidity - disease rate Myeloid Leukemia Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Phase Phase 1/1b Clinical Trial 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 antibody test 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 leukemia relapse leukemic stem cell multicatalytic endopeptidase complex novel novel strategies novel therapeutic intervention overexpression patient derived xenograft model phase I trial pre-clinical resistance mechanism response safety study targeted treatment therapy resistant treatment strategy tumor vaccine trial validation studies

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.

项目概要我们的长期目标是开发针对母细胞中异常表达的蛋白酶的免疫疗法白血病干细胞 PR1 肽 (VLQELNVTV) 是一种源自白血病相关抗原的肽。蛋白酶 3 (P3) 和中性粒细胞弹性蛋白酶 (NE)，呈递于 HLA-A2 至 PR1 特异性细胞毒性 T 淋巴细胞 (PR1-CTL) 在最后的资助期间，我们证明 PR1 是由树突状细胞交叉呈递的。 (DC) 和 B 细胞，我们展示了蛋白酶体裂解外源 P3 和 NE 所需的机制在 SPORE 资助的前几年，我们进行了 I-II 期 PR1 疫苗。在 66 名 AML、CML 和 MDS 患者中进行试验，观察到 58% 的患者对 PR1 疫苗有免疫反应。仅在 11 名 (16%) 患者中观察到临床客观缓解，并且这些患者仅限于病情低的患者我们发现，虽然 PR1-CTL 表达高亲合力，但其具有高度的细胞溶解性。一些患者在接种 PR1 疫苗后，PR1/HLA-A2 的 T 细胞受体 (TCR-αβ) 增加，他们接受了表达高 PR1/HLA-A2 表面抗原的白血病细胞凋亡，导致免疫耐受此外，尽管可以从脐带中分离出高亲合力 PR1-CTL。脐带血（CB）单位，它们很难在体外扩增足够数量以用作过继细胞治疗，从而限制了它们的治疗潜力，因此，需要一种新的替代治疗方法来靶向治疗。 PR1，我们生产了针对 PR1/HLA-A2 的 TCR 样单克隆抗体（8F4）。 8F4 (h8F4) 对 PR1/HLA-A2 具有高亲和力 (KD=7.8 nM)，我们表明 h8F4 消除了 AML 和与临床前模型中的白血病干细胞而非正常人类造血干细胞一致。从支持 h8F4 生产的行业来看，我们已经生产了足够的临床级 h8F4，这表明在体外和体内介导 AML 和 LSC 的 ADCC 和细胞凋亡，并开发了 PK 配套测定法，此外，我们还建立了AML的PDX模型进行平行检测。因此，该提案的目标是（1）转化这部小说的发现。 h8F4 单克隆抗体在 AML 的首次人体 I 期试验中进入临床 (2) 以确定药代动力学，毒性和作用方式；并描述作用机制、潜在耐药机制和使用基于 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，克服潜在的治疗耐药性。