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

基本信息

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
项目类别：
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

项目摘要

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型联合免疫治疗方法，适用于广泛的可及性具体来说，我们将针对一种有效的化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）是通过可溶解的微针阵列实现的。我们的实验室开发和生产的 (MNA) 设备代表了第一个肿瘤。利用空间和动力学控制递送协同作用的免疫治疗临床试验这种方法独特地通过个体化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相关的障碍减少/预防与全身暴露相关的不良反应因此，该策略可能适用。大量患者群体，包括那些免疫抑制或患有自身免疫性疾病或有自身免疫性疾病风险的患者通过完全非特异性和通用的 MNA 来诊断疾病以及广泛的皮肤癌我们的假设是，原位 MNA 定向免疫疗法 (MNA-IT) 会杀死患者。局部肿瘤细胞并诱导促炎性 TME，从而能够通过免疫消除治疗的肿瘤，同时临床前研究和我们的结果都支持这一点。为了评估 cSCC 患者的 MNA-IT，我们将进行迭代 Ib/II 期临床试验。评估 MNA-IT 单一疗法和联合疗法的试验，利用溶解的 MNA 传递阿霉素，一种 STING 激动剂，或两者直接作用于 cSCC 的 TME 这将在免疫功能健全的情况下进行评估。我们将评估安全性、临床和病理学。反应，并探索治疗前、治疗中和治疗后 TME 和外周血的变化通过前瞻性的临床前研究，我们将开发“下一代”组合MNA- IT 实现 TME 中免疫检查点抑制剂的持续释放，以支持持续的亲和治疗炎症性 TME 有利于诱导全身肿瘤免疫。