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

• 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
• 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

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。由于移植物抗白血病（GVL）效应，异基因造血干细胞移植（HSCT）和供体白细胞输注（DLI）的上级结局提供了免疫治疗在消除微小残留病（MRD）方面有效性的有力证据。然而，由于合并症或缺乏供体，> 60岁的患者通常不适合进行allo-HSCT，并且具有令人沮丧的结果。 我们的假设是，IL-15和IL-15 R通过自体AML疫苗的共表达与CD 80表达相结合，将引起有效的抗白血病应答，这将改善缓解诱导后老年患者的无复发生存率。对免疫疗法的抗性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活化不足。先前通过体外分化成AML衍生的树突状细胞来改善AML细胞的抗原呈递的努力是不成功的。然而，转导AML以共表达缺失的CD 80共刺激因子和IL 2或GM-CSF，在鼠AML和人离体测定中有效地刺激特异性抗白血病免疫。尽管在英国批准了使用表达CD 80/IL 2的经辐照的AML疫苗的I期试验，但仍然存在以下问题：IL 2表达不仅可能刺激溶细胞性T和NK细胞的活化，而且可能刺激免疫抑制性T调节细胞（Treg）的活化。 15、A？与IL 2共享刺激NK和CD 8+记忆T细胞的能力的C链细胞因子已经显示出适合于刺激抗肿瘤免疫的独特性质。IL-15主要由表达IL-15受体α（IL-15 R <$）的细胞反式呈递给表达IL-15 R亚单位（IL-2/15 R <$和？common（？（c）次级单位）。IL 15改善记忆性CD 8 + T细胞扩增，显示出比IL 2更少的Treg诱导，并且可以保护免疫效应物免受Treg抑制。与IL 2不同，IL 15在刺激的T细胞中不引起活化诱导的细胞死亡。IL 15与膜结合IL 15 R <$（mIL-15 R <$）的共表达，作为分泌复合物（IL 15/sIL 15 R <$）或作为IL 15/IL 15 R <$融合蛋白，大大增加了IL 15的稳定性和功效。 我们已经产生并将测试表达CD 80和1）IL-15/mIL-15 R <$，2）IL-15/sIL-15 R <$，或3）IL-15/IL-15 R <$融合蛋白的三顺反子慢病毒载体，以确定哪一种最适合临床试验。目的1中的离体研究将提供人免疫效应物与经辐照的自体AML细胞共培养诱导的抗白血病应答的特异性以及性质和幅度的头对头比较，所述经辐照的自体AML细胞用测试人IL-15慢病毒载体与表达人CD 80/IL-2的对照载体转导。目的2中的体内研究将测试用鼠IL-15载体与IL-2对照载体转导的平行疫苗针对鼠32 Dp 210白血病的安全性、毒性和功效。具有最佳安全性和存活结果的AML疫苗将在重现免疫衰老特征的老年小鼠中进行测试。这些研究将直接为UCSF的1期临床AML疫苗试验的设计提供信息，该试验适用于>60岁、不适合HSCT的患者。