Efficacy and safety of novel CD80 IL15 IL15Ra expressing autologous AML vaccines

新型表达 CD80 IL15 IL15Ra 的自体 AML 疫苗的功效和安全性

基本信息

批准号：
8512024
负责人：
KARIN L GAENSLER
金额：
$ 20.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-06 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512024
关键词：
Acute Myelocytic Leukemia Address Adult Acute Myeloblastic Leukemia Agonist Allogenic Antigen Presentation Antigens Autoimmune Responses Autologous Binding Biological Biological Assay Blast Cell Blood Circulation Bone Marrow CD28 gene CD80 gene CD8B1 gene Cell Death Cells Cellular Immunity Chimeric Proteins Clinical Clinical Research Clinical Trials Coculture Techniques Combined Vaccines Comorbidity Complex Cytotoxic T-Lymphocytes Dendritic Cells Disease remission Donor person Effector Cell Elderly Engineering Future Genetic Engineering Goals Granulocyte-Macrophage Colony-Stimulating Factor Half-Life Hematopoietic stem cells Human IL2 gene Immune Immune response Immune system Immunity Immunosuppressive Agents Immunotherapy In Vitro Individual Infusion procedures Interleukin-15 Interleukin-2 Lentivirus Vector Leukocytes Link Lymphocyte Mediating Membrane Memory Modeling Mus Natural Killer Cells Nature Neutropenia Outcome Pathway interactions Patients Peripheral Blood Mononuclear Cell Phase Phase I Clinical Trials Population Production Property Proteins Randomized Regulatory T-Lymphocyte Relapse Relative (related person)Remission Induction Residual Neoplasm Residual Tumors Safety Secondary to Side Specificity Stem cell transplant Subfamily lentivirinae Sushi Domain T memory cell T-Lymphocyte Testing Tissues Toxic effect Tumor Immunity Vaccination Vaccine Design Vaccines Whole Cell Vaccine age related aged base cellular transduction chemotherapy cytokine cytotoxic design effective therapy extracellular genetically modified cells graft vs leukemia effect head-to-head comparison immunogenicity improved in vivo leukemia novel older patient preclinical study public health relevance receptor resistance mechanism response safety testing senescence tumor vector vector control

项目摘要

DESCRIPTION (provided by applicant): Our goal is to improve survival in older acute myeloid leukemia (AML) patients using optimized, genetically engineered, autologous AML cell vaccines. Compelling evidence for the efficacy of immunotherapy in eliminating minimal residual disease (MRD) is provided by the superior outcomes of allogeneic hematopoietic stem cell transplants (HSCT) and donor leukocyte infusion (DLI) due to graft vs leukemia (GVL) effects. However, patients > 60 yo are often ineligible for allo-HSCT, due to co-morbidities or lack of a donor, and have dismal outcomes. Our hypothesis is that co-expression of IL-15 and IL-15R¿ by autologous AML vaccines combined with CD80 expression, will elicit potent anti-leukemic responses that will improve relapse-free survival in older patients after remission induction. Mechanisms of resistance to immunotherapy include ineffective presentation of leukemia-specific or -associated antigens and inadequate effector cell activation. Previous efforts to improve antigen presentation of AML cells by in vitro differentiation into AML-derived dendritic cells were unsuccessful. However, transduction of AML to co-express the missing CD80 co-stimulator, and IL2 or GM-CSF, efficiently stimulates specific anti-leukemic immunity in murine AML and in human ex vivo assays. Despite approval in the UK, of a Phase-I trial using a CD80/IL2 expressing irradiated AML vaccines, concerns remain that IL2 expression may stimulate not only the activation of cytolytic T and NK cells, but also immune inhibitory T regulatory cells (Treg). Recently IL15, a ?c chain cytokine that shares with IL2 the ability to stimulate NK and CD8+ memory T cells, has shown unique properties suited to stimulating anti-tumor immunity. IL15 is primarily trans-presented by cells expressing IL-15 receptor alpha (IL15R¿) to responding cells expressing IL15R subunits (IL2/15R¿ and ? common (?c) sub-units). IL15 improves memory CD8+ T cell expansion, shows less Treg induction than IL2, and can protect immune effectors from Treg suppression. Unlike IL2, IL15 does not cause activation induced cell death in stimulated T cells. Co-expression of IL15 with membrane-bound IL15R¿ (mIL-15R¿), as a secreted complex (IL15/sIL15R¿), or as an IL15/IL15R¿ fusion protein, greatly increases IL15 stability and efficacy. We have generated and will test tricistronic lentiviral vectors expressing CD80 and either 1) IL15/mIL-15R¿, 2) IL-15/sIL-15R¿, or 3) IL-15/IL-15R¿ fusion protein to determine which is optimal for clinical trial. Ex vivo studies in Aim 1 will provde a head-to-head comparison of the specificity as well as the nature, and magnitude of anti-leukemia responses induced by co-culture of human immune effectors with irradiated, autologous AML cells, transduced with the test human IL-15 lentiviral vectors vs a control vector expressing human CD80/IL-2. In vivo studies in Aim 2 will test the safety, toxicity, and efficacy of parallel vaccines transduced with murine IL-15 vectors vs the IL-2 control vector against murine 32Dp210 leukemia. The AML vaccine with best safety and survival outcomes will then be tested in aged mice that recapitulate features of immune senescence. Studies will directly inform the design of a Phase 1 clinical AML vaccine trial at UCSF for patients >60, ineligible for HSCT.

描述（由申请人提供）：我们的目标是使用优化的基因工程自体 AML 细胞疫苗提高老年急性髓性白血病 (AML) 患者的生存率，提供令人信服的证据证明免疫疗法在消除微小残留病 (MRD) 方面的功效。由于移植物抗白血病 (GVL) 效应，同种异体造血干细胞移植 (HSCT) 和供体白细胞输注 (DLI) 取得了优异的结果。然而，由于合并症或缺乏供体，> 60 岁的患者通常不适合接受同种异体造血干细胞移植，并且结果不佳。我们的假设是 IL-15 和 IL-15R 共表达。通过自体 AML 疫苗与 CD80 表达相结合，将引发有效的抗白血病反应，从而改善老年患者在缓解诱导后的无复发生存率。免疫治疗的耐药机制包括白血病特异性或相关抗原的无效呈递和效应细胞不足。先前通过体外分化为 AML 衍生树突状细胞来改善 AML 细胞抗原呈递的努力并未成功。尽管英国批准了一项使用表达 CD80/IL2 的辐照 AML 疫苗的 I 期试验，但共刺激剂和 IL2 或 GM-CSF 可有效刺激小鼠 AML 和人类离体测定中的特异性抗白血病免疫。人们仍然担心，IL2 的表达不仅会刺激溶细胞性 T 细胞和 NK 细胞的激活，而且还会刺激免疫抑制性 T 调节细胞 (Treg) 的激活。最近，IL15 是一种与 IL2 具有相同能力的 βc 链细胞因子。刺激 NK 和 CD8+ 记忆 T 细胞，已显示出适合刺激抗肿瘤免疫的独特特性 IL15 主要由表达 IL-15 受体 α (IL15R¿) 的细胞反式呈递。 ) 对表达 IL15R 亚基（IL2/15R¿ 和 ? 常见 (?c) 亚基）的细胞产生反应，IL15 可以改善记忆 CD8+ T 细胞的扩增，显示出比 IL2 更少的 Treg 诱导作用，并且与 IL2 不同，可以保护免疫效应子免受 Treg 抑制。，IL15 不会在受刺激的 T 细胞中引起激活诱导的细胞死亡。IL15 与膜结合的 IL15R 共表达。 (mIL-15R¿)，作为分泌复合物 (IL15/sIL15R¿)，或作为 IL15/IL15R¿融合蛋白，大大提高了 IL15 的稳定性和功效，我们已经生成并将测试表达 CD80 和 1) IL15/mIL-15R¿ , 2) IL-15/sIL-15R¿ ，或 3) IL-15/IL-15R¿目的 1 中的离体研究将提供对人类免疫共培养物诱导的抗白血病反应的特异性、性质和程度的头对头比较。目标 2 中的体内研究将测试用受测试的人 IL-15 慢病毒载体与表达人 CD80/IL-2 的对照载体转导的经过辐射的自体 AML 细胞的效应器。然后，将在老年小鼠中测试用小鼠 IL-15 载体与 IL-2 对照载体转导的平行疫苗针对小鼠 32Dp210 白血病的毒性和功效，以概括免疫衰老的特征。将直接为 UCSF 针对 60 岁以上、不适合 HSCT 的患者进行 AML 疫苗临床试验的设计提供信息。