Anit-PR1 Immune Therapy for Myeloid Leukemia

Anit-PR1 粒细胞白血病免疫治疗

• 批准号: 8499745
• 负责人: JEFFREY J MOLLDREM
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499745
• 关键词: Acute Myelocytic Leukemia; Animal Model; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Binding; Biological; Blast Cell; Blood Cells; Bone Marrow; Bone Marrow Cells; CD34 gene; Cell Therapy; Cells; Chronic Myeloid Leukemia; Clinical; Clinical Treatment; Clinical Trials; Complement-Dependent Cytotoxicity; Cytolysis; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dysmyelopoietic Syndromes; Engraftment; Epitopes; Extramedullary; Goals; Grant; Growth; HLA-A2 Antigen; Hematopoietic; Hematopoietic stem cells; Human; Immune response; Immunity; Immunotherapy; Instruction; Leukocyte Elastase; Maximum Tolerated Dose; Mediating; Modality; Modeling; Monoclonal Antibodies; Mus; Myeloid Leukemia; Myeloproliferative disease; NOD/SCID mouse; Outcome; Patients; Peptide Hydrolases; Peptide Vaccines; Peptides; Phase; Phase I Clinical Trials; Proteinase 3; Relapse; Specificity; Stem cell transplant; Stem cells; Surface; T-Cell Receptor; Therapeutic; Therapeutic Monoclonal Antibodies; Toxic effect; Toxicology; Transgenic Mice; Transgenic Organisms; Transplant Recipients; University of Texas M D Anderson Cancer Center; Vaccines; Xenograft procedure; base; cell growth; granulocyte; improved; in vivo; leukemia; leukemic stem cell; mouse model; multicatalytic endopeptidase complex; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; progenitor; response; safety study; validation studies

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- speclfic 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. We completed a phase 2 PRI peptide vaccine trial that showed immune responses in 58% and clinical responses in 16%, but responses were limited to patients with low leukemia burden. We developed a strategy to adoptively transfer donor- derived PR1-CTL to stem cell transplant recipients to treat high leukemia burden. As an alternate strategy, we identified a T cell receptor (TCR)-like monoclonal antibody (8F4) with specificity for a conformational epitope of PR1 bound to the HLA-A2 molecule. 8F4 induces complement-dependent cytotoxicity (CDC) of AML and LSC and inhibits AML progenitor cell growth but not normal bone marrow progenitors, which supports further study of 8F4 as a potential therapeutic monoclonal antibody (mAb) for AML. Our preliminary data show that 8F4 prevents AML engraftment and reduced or eliminated established primary human AML xenografts in vivo. 8F4 also significantly reduced or eliminated leukemia stem cells (LSCs) in mouse models. We produced a humanized 8F4 (Hu8F4) and showed it significantly reduced (>95%) established human AML xenografts. Thus, 8F4 is the first TCR-like mAb that inhibits growth of AML and LSC and eliminates AML in vivo. In prior years of this grant, we have used a PRI peptide vaccine to induce immunity in patients with AML, CML, and MDS and more recently we initiated two adoptive cell therapy trials with PRI-specific CTL in AML and CML, respectively. In this proposal, we will characterize the 8F4 mAb as a novel therapeutic modality for leukemia. Our central hypothesis is that immune therapy targeting surface PR1/HLA-A2 molecules can selectively eliminate leulfemia and leuliemia stem cells, but not normal hematopoietic cells. To investigate the therapeutic potential of this novel antibody to improve the outcome of patients with myeloid malignancies, we will pursue the following Specific Aims 1) characterize the activity of HU-8F4 against human AML, 2) perform pre-clinical treatment validation and safety studies of Hu-8F4, and 3) conduct a first-in-human phase 1 clinical trial with Hu8F4 in patients with relapsed AML. RELEVANCE (See instructions): Successful completion of these studies will provide the biological, pre-clinical and clinical bases for exploring the therapeutic potential of a highly novel TCR-like antibody (8F4) to treat leukemia. 8F4 eliminates leukemia and leukemia stem cells in mouse models of primary human leukemia without eliminating normal blood cells or normal hematopoietic stem cells. Therefore, 8F4 shows promise as a highly AML-specific agent with low potential for toxicity. We will conduct a first-in-human clinical trial with this antibody in AML.

我们的长期目标是开发针对异常表达的蛋白酶In的免疫疗法