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: 10683759
• 负责人: Louis D Falo
• 金额: $ 36.97万
• 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/10683759
• 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 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; 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; 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; immune modulating agents; immune stimulant; immunogenic; immunogenic cell death; immunosuppressed; immunotherapy clinical trials; improved; local drug delivery; melanoma; 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 该项目评估了一种新的联合免疫治疗方法，适用于广泛的可获得的 皮肤癌。具体地说，我们将针对两种有效的化疗药物来诱导免疫原性细胞 死亡和一种针对肿瘤微环境(TME)3D空间的先天性免疫刺激剂 皮肤鳞状细胞癌。这种策略是由可溶解的微针阵列实现的 我们实验室开发和生产的(MNA)装置。这些研究代表了第一种肿瘤 利用空间和运动控制递送协同作用的免疫治疗临床试验 联合疗法。这种方法通过以下方式独特地实现了个性化的患者特异性免疫治疗 低剂量局部给药，消除与肿瘤和抗原异质性有关的障碍 减少/预防与系统性暴露相关的不良影响。因此，该策略可能是适用的。 对于大量的患者，包括那些免疫抑制的人，或有或处于自身免疫风险的人 疾病，以及广泛的皮肤癌，通过一个完全非特定和可概括的MNA “创可贴”式的投放平台。我们的假设是，原位MNA定向免疫疗法(MNA-IT)将杀死 肿瘤细胞局部并诱导促炎TME，使治疗的肿瘤能够免疫消除，同时 潜在地诱导持久的系统免疫。它得到了临床前研究和我们的研究结果的支持 自己的临床试验。为了评估CSCC患者的MNA-IT，我们将进行迭代的Ib/II期临床试验。 利用溶解的MNAs传递阿霉素的MNA-IT单一疗法和联合疗法的试验评估 刺激剂，或两者兼而有之，直接作用于CSCCs的TME。这将在两个免疫活性中进行评估 患者和免疫抑制的移植受者。我们将评估安全性、临床和病理学。 反应，并探讨治疗前、中、后TME和外周血的变化 心理治疗。通过前瞻性的临床前研究，我们将开发一种“下一代”的MNA组合-- 它实现了免疫检查点抑制剂在TME中的持续释放，以支持持续的亲- 炎症性TME有利于诱导全身肿瘤免疫。