Intratumoral immunotherapy with formulated resiquimod for metastatic melanoma

使用制剂瑞喹莫特治疗转移性黑色素瘤的瘤内免疫疗法

基本信息

批准号：
9888355
负责人：
Yen Tun Wang
金额：
$ 97.5万
依托单位：
CUREBIOTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-06 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888355
关键词：
Acute Agonist Antigen Presentation Antigens Antiviral Response Blood Businesses CD8B1 gene Cancer Patient Canis familiaris Cessation of life Clinical Clinical Oncology Clinical Trials Cutaneous T-cell lymphoma Data Dendritic Cells Development Dimethyl Sulfoxide Distant Dose Drug Kinetics Enhancers Exhibits FDA approved Formulation Foundations Frequencies Funding Generations Goals Grant Growth Health High Pressure Liquid Chromatography Human Human Resources Hyaluronic Acid Hydrogels Imiquimod Immune Immune Tolerance Immune response Immune system Immunologic Adjuvants Immunotherapeutic agent Immunotherapy Incidence Injectable Insurance Carriers Intellectual Property Legal patent Leukocytes Mainstreaming Malignant Neoplasms Manufacturer Name Maximum Tolerated Dose Measures Melanoma Vaccine Metastatic Melanoma Metastatic Neoplasm to Lymph Nodes Modeling Molecular Weight Mus Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma PD-1/PD-L1 PTPRC gene Patients Penetration Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacotherapy Phase Phase I Clinical Trials Plasma Play Poloxamer 188 Price Privatization RNA Viruses Rattus Receptor Activation Regimen Safety Sales Serum Signal Transduction Site Skin Cancer Small Business Innovation Research Grant Solid Spleen Supervision Symptoms TLR7 gene Testing Therapeutic Agents Therapeutic Effect Time Tissues Toll-like receptors Topical agent Toxic effect Toxicokinetics Toxicology Treatment Efficacy Treatment-related toxicity Tumor Antigens Tumor Tissue anti-CTLA-4 therapy anti-CTLA4 anti-PD-1 anti-PD1 therapy base cancer cell cytokine design effective therapy effector T cell efficacy testing experimental study fight against good laboratory practice immune-related adverse events immunoreaction in vivo medical specialties melanoma mouse model novel therapeutics pharmacokinetics and pharmacodynamics preclinical study resiquimod response skin disorder skin irritation success therapeutic evaluation tumor tumor growth

项目摘要

PROJECT SUMMARY Malignant melanoma is one of the most aggressive types of skin cancer, causing a large majority of skin-cancer related deaths worldwide. The combination of anti-PD-1 and anti-CTLA-4 is FDA approved for metastatic melanoma and shows better efficacy than any single agent alone. Unfortunately, the incidence of high-grade immune-related adverse events (irAEs) due to anti-CTLA-4 is approaching 50%. There is a pressing clinical need to develop therapeutic agents that may enhance the therapeutic effect of anti-PD1 therapy without significantly increasing toxicity in cancer patients. CureBiotech is aimed to develop an efficacious intratumoral immunotherapeutic drug that can treat metastatic melanoma by itself and in combination with anti-PD1 therapy. Resiquimod is a toll-like receptors (TLR) 7 and 8 agonist. It is a second generation imidazoquinoline that is 100 time more potent than imiquimod (Aldara). Using a phase I SBIR grant, CureBiotech has developed two proprietary hydrogel based injectable formulations for resiquimod. The formulations were designed to confine resiquimod locally in the tumor to decrease systemic cytokine release symptoms;; and to be penetrate better fibrotic tumor stroma to allow a stronger host immune response. Our preliminary data demonstrates that resiquimod treatment not only inhibited melanoma growth, but also suppressed lymph node metastasis. Resiquimod increases the number of intra-tumoral CD45+ leukocytes and enhances the proliferation and function of tumor antigen recognizing CD8+ effector T-cells. Resiquimod shows synergistic effect in inhibiting melanoma growth when combined with anti-PD1 therapy. This SBIR phase II project is aimed to 1) study PD/PK of the formulated injectable resiquimod in melanoma mouse models;; 2) optimize dose/frequency/timing of formulated resiquimod in combination with anti-PD1 therapy for melanoma;; 3) perform non-clinical IND enabling studies using formulated injectable resiquimod. The deliverables proposed in this SBIR grant represent the jumping stone towards (i) submission of FDA IND application of an injectable resiquimod formulation and (ii) attracting private equity funding to support Phase I clinical trial of injectable resiquimod in patients with metastatic melanoma. CureBiotech has the business development expertise, proper intellectual property and scientific and personnel capability to achieve these aims quickly and meticulously. Results from this proposal will lay a solid foundation for FDA IND submission that will ultimately bring a novel and effective therapy to clinicians and patients in their fight against melanoma.

项目摘要恶性黑色素瘤是皮肤癌最具侵略性的类型之一，导致大型全世界大多数与皮肤癌相关的死亡。抗PD-1和抗CTLA-4的组合是否批准FDA用于转移性黑色素瘤并显示出比任何单一药物更好的功效独自的。不幸的是，由于高度免疫相关事件（IRAE）的发生率抗CTLA-4接近50％。有紧迫的临床需要发展治疗可能增强抗PD1治疗的治疗作用的药物而没有显着癌症患者的毒性增加。 Curebiotech的目的是发展高效肿瘤内免疫治疗药物可以单独治疗转移性黑色素瘤结合抗PD1治疗。 Resiquimod是Toll样受体（TLR）7和8激动剂。它是第二代Imidazoquinoline，比咪喹莫德（Imiquimod）多100次（Aldara）。使用I期SBIR赠款，Curebiotech开发了两个专有水凝胶可重置的注射公式。该公式被设计为限制Resiquimod 在肿瘤中局部降低全身细胞因子释放症状；并变得更好纤维化肿瘤基质，使宿主免疫反应更强。我们的初步数据证明重生治疗不仅抑制了黑色素瘤的生长，而且还抑制抑制淋巴结转移。 resiquimod增加了肿瘤内CD45+的数量白细胞和增强识别CD8+的肿瘤抗原的增殖和功能效应子T细胞。重二胺在抑制黑色素瘤生长中显示出协同作用结合抗PD1治疗。 SBIR II期项目的目的是1）研究的PD/PK 在黑色素瘤小鼠模型中配制的可注射式resiquimod； 2）优化剂量/频率/时机与抗PD1疗法结合使用黑色素瘤； 3）使用配制的注射式resiquimod进行非临床IND支持研究。此SBIR赠款代表中提出的送货服务（i）提交FDA IND应用可注射的Resiquimod公式和（ii）吸引力私募股权资金以支持I阶段的I期临床试验转移性黑色素瘤。 Curebiotech具有业务发展专业知识，专有的知识分子财产，科学和个人能力实现这些目标的目标。该提案的结果将为FDA IND提交奠定坚实的基础，最终将在与黑色素瘤作斗争中为临床医生和患者带来一种新颖有效的疗法。