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（由适用提供）：我们的目标是使用优化的，基因设计的自体AML细胞疫苗来改善较老的急性髓样白血病（AML）患者的生存率。令人信服的证据证明免疫疗法消除最小残留疾病（MRD）的效率是由同种异体造血干细胞移植（HSCT）和供体白细胞输注（DLI）提供的优势结果，该结果是Graft VS vs deraft vs derukemia（GVL）效应。然而，由于合并症或缺乏供体，患者通常不符合Allo-HSCT的资格，并且结果令人沮丧。我们的假设是自体AML疫苗与CD80表达的自体AML疫苗对IL-15和IL-15R的共表达，将引起潜在的抗白血病反应，这些反应将改善缓解诱导后老年患者的无中继生存。对免疫疗法的耐药性机制包括表现为白血病特异性或相关抗原的无效和效应细胞激活不足。以前通过体外分化为AML衍生的树突状细胞来改善AML细胞抗原呈递的努力失败了。然而，AML转换以表达缺失的CD80共刺激器，以及IL2或GM-CSF，有效地刺激了鼠AML和人体实体分析中的特定抗白血病免疫。尽管在英国获得了批准，但使用表达辐照的AML疫苗的CD80/IL2进行了I期试验，仍然担心IL2表达不仅会刺激细胞溶解T和NK细胞的激活，还可以刺激免疫学抑制性T调节细胞（TREG）。最近，IL15是与IL2共享刺激NK和CD8+记忆T细胞能力的A？C链细胞因子，已显示出适合刺激抗肿瘤免疫史地性的独特特性。 IL15主要由向表达IL15R亚基（IL2/15r¿和？common（？c）亚基）的响应细胞表达IL-15受体α（IL15R¿）的细胞跨表现。 IL15改善了记忆CD8+ T细胞的扩展，比IL2显示出较少的Treg诱导，并且可以保护免疫效应免受TREG抑制。与IL2不同，IL15不会引起激活诱导的刺激T细胞中的细胞死亡。 IL15与膜结合的IL15R¿（MIL-15R¿）共表达，作为分泌的复合物（IL15/SIL15R¿），或作为IL15/IL15R¿融合蛋白，大大提高IL15的稳定性和效率。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？确定哪种是最佳临床试验的IL-15/SIL-15R¿或3）IL15/MIL-15R¿，2）IL15/MIL-15R？的三生型植物载体了。 AIM 1中的离体研究将对人类免疫效应的共文化与辐射的自体AML细胞引起的抗白血病反应的特异性，性质和幅度进行面对面的比较，并用测试的人IL-15静脉病毒毒素vectors vs vs vs表达人类CD80/IL-il-il-il-il-il-il-il-il-il-il-il-il-il-il-il iL-15。 AIM 2中的体内研究将测试用鼠IL-15载体与IL-2控制载体转移的平行疫苗的安全性，毒性和效率。随后，具有最佳安全性和生存结果的AML疫苗将在概括免疫纪念特征的老年小鼠中进行测试。研究将直接告知UCSF的1期临床AML疫苗试验的设计，> 60例，不符合HSCT的资格。