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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：
10469637
负责人：
Louis D Falo
金额：
$ 37.8万
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/10469637
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 immune stimulant 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