Localized immunotherapy using alum-binding therapeutics

使用明矾结合疗法的局部免疫疗法

基本信息

批准号：
10686236
负责人：
Darrell J Irvine
金额：
$ 51.84万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686236
关键词：
Abscopal effect Address Adjuvant Adsorption Affinity Agonist Aluminum Hydroxide Antibodies Antigens Antitumor Response Bilateral Binding Bypass Cells Circulation Combination immunotherapy Combined Modality Therapy Diffusion Disease Distal Dose Engineering Extravasation Genetically Engineered Mouse Human Immune Immune response Immunity Immunologic Stimulation Immunophenotyping Immunotherapeutic agent Immunotherapy In Vitro Injections Interleukin-12 Interleukin-2 Lesion Licensing Ligands Lymphocyte Malignant Neoplasms Mediating Metabolic Clearance Rate Modeling Modification Pathway interactions Penetrance Peptides Pharmaceutical Preparations Phosphorylation Phosphoserine Population Positioning Attribute Pre-Clinical Model Production Proteins Reaction Recombinant Proteins Research Personnel Role Route Signal Transduction Site Stretching Surface System T-Lymphocyte Testing Therapeutic Therapeutic Agents Therapeutic Index Toxic effect Treatment Efficacy Treatment Protocols Tumor Immunity Vaccination Vaccine Adjuvant Vaccine Antigen Vaccines aluminum sulfate anti-tumor immune response cancer immunotherapy cell motility cytokine design efficacy evaluation hydroxyl group immunoregulation improved in vivo lymphocyte trafficking melanoma novel strategies optimal treatments particle response technology platform translational approach tumor tumor microenvironment uptake vaccine efficacy

项目摘要

Project Summary/Abstract Combination treatments aiming to stimulate synergistic immune pathways employing cytokines or immunomodulatory antibodies are generally more effective than monotherapies in preclinical models of cancer immunotherapy. However when given systemically, these combination treatments suffer from high toxicity from on-target off-tumor stimulation as well as low local concentrations at the tumor site due to poor tumor penetrance and high clearance rates. Local intratumoral therapy is a viable approach to bypass some of the challenges associated with systemic delivery, but requires optimization to promote retention of the therapeutic agent at the injection site and minimize leakage into the circulation. We have recently developed an approach to enhance vaccine efficacy by engineering the binding of immunogens to the commonly used adjuvant aluminum hydroxide (alum) via a site-specific phosphoserine (pSer) peptide tag. The pSer moieties undergo a ligand-exchange reaction with free hydroxyl groups on the surface of alum leading to stable anchoring of proteins on alum particles. We propose here to apply this alum-anchoring platform in the context of cancer to retain potent immune agonists within the tumor site, promoting a robust systemic immune response with minimal toxicity. Our preliminary results show that this simple approach can be used to load stimulatory cytokines onto alum for retention at the tumor site up to a month, stimulating a strong anti-tumor response from a single shot treatment. We plan to develop and optimize this translational strategy through the following specific aims: (1) use in-cell phosphorylation to produce phosphoserine-tagged cytokines and other candidate immune agonists for optimal alum binding, (2) determine optimal treatment regimens for these intratumoral alum-bound therapeutic agents in vivo in multiple tumor models, (3) define the mechanism of action through which this therapy elicits a response, (4) evaluate the systemic immune response and assess strategies to enhance abscopal effects by promoting the transfer of immunostimulatory payloads to motile lymphocytes for trafficking to distal untreated tumors. These studies will establish a robust technology platform capable of safely delivering treatments currently viewed as too toxic, by addressing key limitations in existing localized therapeutic strategies

项目摘要/摘要旨在刺激使用细胞因子或在癌症的临床前模型中，免疫调节抗体通常比单一疗法更有效免疫疗法。但是，当系统地给出时，这些组合治疗的毒性很高由于肿瘤的渗透率较差，因此在肿瘤部位的靶向外肿瘤刺激以及局部浓度较低和高间隙率。局部肿瘤内疗法是绕过一些挑战的可行方法与系统性交付相关，但需要优化以促进在注射部位并最大程度地减少泄漏中的泄漏。我们最近开发了一种增强的方法通过设计疫苗功效，使免疫原与常用辅助铝氧化物的结合结合（明矾）通过位点特异性磷酸盐（PSER）肽标签。 PSER部分经历了配体交换与明矾表面上的游离羟基反应，导致蛋白质稳定在明矾上颗粒。我们在这里建议在癌症的背景下应用这个明矾锚定平台，以保留有效的免疫力肿瘤部位内的激动剂，促进毒性最小的全身免疫反应。我们的初步结果表明，这种简单的方法可用于将刺激性细胞因子加载到明矾上长达一个月的肿瘤部位保留率，刺激了一次射击治疗的强烈抗肿瘤反应。我们计划通过以下特定目的制定和优化这种翻译策略：（1）使用单元格磷酸化以产生磷酸碱标记的细胞因子和其他候选免疫激动剂，以获得最佳明矾结合，（2）确定这些肿瘤内明矾结合的治疗剂的最佳治疗方案多种肿瘤模型中的体内，（3）定义了该疗法引起反应的作用机理，（4）评估系统性免疫反应并评估策略以通过促进免疫刺激有效载荷转移到运动淋巴细胞以进行运输到远端未治疗的肿瘤。这些研究将建立一个强大的技术平台，能够安全地提供当前查看的治疗由于毒性过多，通过解决现有局部治疗策略中的关键限制