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.

项目概要/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。具体而言，我们将靶向一种有效的化疗剂，以诱导免疫原性细胞， 死亡和先天免疫刺激剂，特异性地针对肿瘤微环境（TME）的3D空间， 皮肤鳞状细胞癌（cSCC）。该策略通过可溶解的微针阵列实现 (MNA)在我们的实验室开发和生产的设备。这些研究代表了第一个 利用空间和动力学受控递送协同作用的免疫治疗临床试验 联合治疗这种方法独特地使个体化的患者特异性免疫疗法， 低剂量局部药物递送，避免与肿瘤和抗原异质性相关的障碍， 减少/预防与全身接触相关的不良反应。因此，该战略可以适用 大的患者人群，包括那些免疫抑制或有自身免疫性疾病或有自身免疫性疾病风险的患者 疾病，以及广泛的皮肤癌，通过一个完全非特异性和普遍性的MNA “创可贴”式的配送平台。我们的假设是，原位MNA-directed免疫疗法（MNA-IT）将杀死 肿瘤细胞局部和诱导促炎性TME，使免疫消除治疗的肿瘤，同时 潜在地诱导持久的全身免疫。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患者中的MNA-IT，我们将进行迭代Ib/II期临床试验， 一项评估MNA-IT单一和联合疗法的试验，该疗法利用溶解的MNAs来递送阿霉素， STING激动剂，或两者直接与cSCC的TME结合。这将在两种免疫活性 患者和免疫抑制移植受者。我们将评估安全性、临床和病理 反应，并探索治疗前，期间和之后TME和外周血中的治疗诱导的变化 疗法通过前瞻性临床前研究，我们将开发“下一代”组合MNA- IT在TME中实现免疫检查点抑制剂的持续释放，以支持持续的亲 炎性TME有利于诱导全身肿瘤免疫。