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

项目概要/摘要联合治疗旨在利用细胞因子或细胞因子刺激协同免疫途径在癌症临床前模型中，免疫调节抗体通常比单一疗法更有效免疫疗法。然而，当全身给药时，这些联合治疗会产生高毒性。由于肿瘤外显率差，导致脱靶刺激以及肿瘤部位局部浓度低以及高清仓率。局部瘤内治疗是绕过一些挑战的可行方法与全身递送相关，但需要优化以促进治疗剂保留在注射部位并尽量减少泄漏到循环中。我们最近开发了一种方法来增强通过设计免疫原与常用佐剂氢氧化铝的结合来提高疫苗功效（明矾）通过位点特异性磷酸丝氨酸 (pSer) 肽标签。 pSer 部分经历配体交换与明矾表面的游离羟基发生反应，导致蛋白质稳定锚定在明矾上颗粒。我们在此建议在癌症背景下应用这种明矾锚定平台以保留有效的免疫肿瘤部位内的激动剂，以最小的毒性促进强大的全身免疫反应。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在肿瘤部位保留长达一个月，单次注射治疗即可激发强烈的抗肿瘤反应。我们计划通过以下具体目标来开发和优化这一转化策略：（1）使用in-cell 磷酸化产生磷酸丝氨酸标记的细胞因子和其他候选免疫激动剂以获得最佳效果明矾结合，(2) 确定这些肿瘤内明矾结合治疗剂的最佳治疗方案在多种肿瘤模型体内，（3）定义该疗法引起反应的作用机制， (4) 评估全身免疫反应并评估通过促进增强远隔效应的策略将免疫刺激有效负载转移到运动淋巴细胞，以运输到远端未经治疗的肿瘤。这些研究将建立一个强大的技术平台，能够安全地提供目前所看到的治疗方法毒性太大，通过解决现有局部治疗策略的关键限制