Project 3: Localized microneedle-directed combination immunotherapy for cSCC

项目3：局部微针定向联合免疫治疗cSCC

• 批准号: 10270233
• 负责人: Louis D Falo
• 金额: $ 36.39万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270233
• 关键词: 3-Dimensional; Adverse effects; Agonist; Antigen-Presenting Cells; Antigens; Autoimmune Diseases; Biotechnology; CD8-Positive T-Lymphocytes; Cell Death; Cells; Chronic; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cutaneous Melanoma; Cutaneous T-cell lymphoma; Data; Development; Devices; Dose; Doxorubicin; Drug Delivery Systems; Epitope spreading; FDA approved; Future; Generations; Goals; Heterogeneity; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunocompetent; Immunomodulators; Immunosuppression; Immunotherapy; In Situ; Inflammatory; Injections; Kinetics; Laboratories; Malignant Neoplasms; Needles; Organ Transplantation; Pathologic; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Phase Ib/II Clinical Trial; Positioning Attribute; Recurrence; Risk; STING agonists; Safety; Skin; Skin Cancer; Skin Neoplasms; Solid; Solid Neoplasm; Source; Stimulator of Interferon Genes; T-Lymphocyte; Technology; Therapeutic immunosuppression; Toxic effect; Translating; Transplant Recipients; Transplantation; Tumor Antigens; Tumor Immunity; Work; anti-PD1 antibodies; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinical application; clinical efficacy; cohort; fitness; flexibility; immune clearance; immunogenic; immunogenic cell death; immunosuppressed; immunotherapy clinical trials; improved; neoplasm immunotherapy; neoplastic cell; next generation; novel; novel therapeutic intervention; patient population; peripheral blood; pre-clinical; preclinical study; prevent; programs; response; safety study; skin squamous cell carcinoma; tumor; tumor eradication; tumor heterogeneity; tumor microenvironment; virtual

Project Summary/Abstract: Project 3 This project evaluates a novel combination immunotherapy approach applicable to a broad range of accessible skin cancers. Specifically, we will target both a potent chemotherapeutic agent to induce immunogenic cell death and an innate immune stimulant specifically to the 3D space of the tumor microenvironment (TME) of cutaneous squamous cell carcinomas (cSCCs). This strategy is enabled by a dissolvable microneedle array (MNA) device developed and produced in our laboratories. These studies represent the first tumor immunotherapy clinical trials utilizing spatially and kinetically controlled delivery of a synergistically acting combination therapy. This approach uniquely enables individualized patient-specific immunotherapy through low dose localized drug delivery, obviating obstacles related to tumor and antigen heterogeneity and reducing/preventing adverse effects associated with systemic exposure. Thus, the strategy could be applicable to a large patient population, including those who are immunosuppressed or have or are at risk for autoimmune diseases, as well as a broad range of skin cancers through a completely non-specific and generalizable MNA “band-aid”-like delivery platform. Our hypothesis is that in situ MNA-directed immunotherapy (MNA-IT) will kill tumor cells locally and induce a proinflammatory TME, enabling immune elimination of the treated tumor while potentially inducing durable systemic immunity. It is supported by both preclinical studies and results from our own clinical trials. To evaluate MNA-IT in patients with cSCCs, we will perform an iterative phase Ib/II clinical trial evaluating MNA-IT single and combination therapies utilizing dissolving MNAs to deliver doxorubicin, a STING agonist, or both directly to the TME of cSCCs. This will be evaluated in both immunocompetent patients and in immunosuppressed transplant recipients. We will evaluate safety, clinical, and pathologic responses, and explore therapy-induced changes in the TME and peripheral blood before, during, and after therapy. Through forward reaching pre-clinical studies, we will develop a “next-generation” combination MNA- IT to achieve sustained release of immune checkpoint inhibitors in the TME to support a sustained pro- inflammatory TME favoring the induction of systemic tumor immunity.

项目摘要/摘要：项目3 该项目评估了一种适用于广泛可访问的新型组合免疫疗法方法 皮肤癌。特别是，我们将靶向有效的化学治疗剂来诱导免疫原性细胞 死亡和先天免疫刺激剂专门针对肿瘤微环境（TME）的3D空间 皮肤鳞状细胞癌（CSCC）。可溶解的微针阵列启用了此策略 （MNA）在我们的实验室中开发和生产的设备。这些研究代表了第一个肿瘤 通过空间和动力学控制协同作用的免疫疗法临床试验 联合疗法。这种方法独特地通过 低剂量的局部药物输送，消除了与肿瘤和抗原异质性有关的障碍 减少/防止与全身暴露有关的不良影响。那策略可能适用 对于大量的患者人群，包括免疫抑制或有或有自身免疫风险的患者 疾病以及通过完全非特异性且可推广的MNA的广泛的皮肤癌 “创可贴”类似的交付平台。我们的假设是原位MNA指导的免疫疗法（MNA-IT）将杀死 肿瘤细胞局部并诱导促炎性TME，使治疗肿瘤的免疫进化，同时 潜在诱导的耐用全身免疫力。临床前研究和我们的结果都得到了支持 自己的临床试验。为了评估CSCC患者的MNA-IT，我们将进行迭代期IB/II临床 使用溶解MNA评估MNA-IT单一和组合疗法以递送阿霉素，A 刺痛的激动剂，或直接到CSCC的TME。这将在两种免疫能力中进行评估 患者和免疫抑制的移植受者。我们将评估安全，临床和病理学 反应，并探索治疗引起的TME和外周血的变化之前，之中和之后 治疗。通过向前进行临床前研究，我们将开发一个“下一代”组合MNA- 它可以在TME中持续释放免疫定位抑制剂 有利于诱导全身性肿瘤免疫的炎症性TME。