A low-cost topical immunotherapy formulation suitable for treating cervical cancer in low and middle income countries and low-resource settings in the U.S.

一种低成本局部免疫治疗制剂，适用于低收入和中等收入国家以及美国资源匮乏地区的宫颈癌治疗。

• 批准号: 10252242
• 负责人: Michael J Shamblott
• 金额: $ 40万
• 依托单位: MORPHOGENESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252242
• 关键词: Adverse effects; Animal Model; Animals; Antigen-Presenting Cells; Antigens; Area; B-Lymphocytes; Bacterial Antigens; Biodistribution; Carcinoma; Cell Survival; Cell surface; Cells; Cervical; Cervical dysplasia; Cessation of life; Clinic Visits; Clinical Data; Clinical Trials; Cold Chains; Community Hospitals; Complex; Cream; Cutaneous Melanoma; DNA Maintenance; Data; Disease Progression; Early treatment; Environment; Epidemiology; Epitope spreading; Epitopes; Equilibrium; Equipment; Evaluation; Excipients; Family; Female; Formulation; Future; Goals; Human; Human Papillomavirus; Human papillomavirus 16; Image; Immune response; Immunity; Immunohistochemistry; Immunology; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In Vitro; Infrastructure; Innate Immune Response; Intralesional Injections; Investigation; Investigational New Drug Application; Luciferases; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Merkel cell carcinoma; Methods; Modeling; Monitor; Morphogenesis; Mus; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Positioning Attribute; Probability; Prognosis; Quality Control; Research Personnel; Resources; Safety; Self Administration; Serious Adverse Event; Small Business Innovation Research Grant; South Africa; Specialist; Superhelical DNA; Supportive care; T-Cell Activation; Temperature; Testing; Therapeutic; Tissues; Training; Transfection; Transgenic Organisms; Underserved Population; Vagina; Viscosity; Vulvar Squamous Cell Carcinoma; Woman; adaptive immune response; animal imaging; barrier to care; base; cancer immunotherapy; cancer type; cervicovaginal; cost; enhanced green fluorescent protein; falls; fertility preservation; imaging study; immune activation; improved; in vivo; innovation; low and middle-income countries; mouse model; neoplastic cell; plasmid DNA; pre-clinical; product development; protein expression; reproductive; skin squamous cell carcinoma; success; time use; tumor; uptake

The goal of this project is to deliver an affordable immunotherapy to treat advanced cervical cancer in low- and middle-income countries (LMICs) and low-resource settings in the U.S. A longer-term goal is to treat earlier stages of cervical dysplasia and assess immunity to the causative agent, human papillomavirus (HPV). The heavy burden of suffering and death from cervical cancer disproportionately falls on women in resource poor settings. Overcoming barriers to treatment, i.e. lack of infrastructure, trained specialists, specialized equipment, cold chain, and financial resources, requires a paradigm shift in the approach to treatment that can be achieved by the innovative immunotherapeutic agent proposed here. IFx-Hu2.1 (SN63/016,700) is a cream-based therapeutic immunomodulator that will be optimized for stability and performance. Our IFx-Hu2 family contains a plasmid DNA (pDNA) bulk drug substance, which can be produced for a fraction of the cost of current immunotherapies. The pDNA encodes a complex bacterial antigen, Emm55. When expressed on the tumor cell surface, Emm55 attracts antigen presenting cells and other cells of the innate immune response. Non-self-epitopes such as tumor and HPV antigens are then exposed in such a way as to set up multi-antigenic cellular and humoral adaptive immune responses. Emm55-based therapies induce personalized, multivalent, systemic, and sustained immune responses and have the potential to treat a broad range of cancers through enhanced tumor recognition, immune activation and epitope spreading. Intralesional injection of IFx-Hu2.0 has an established safety profile in multiple animal studies and is currently being tested in Phase 1 human clinical trials for cutaneous melanoma, Merkel cell carcinoma and cutaneous squamous cell carcinoma. Our preliminary clinical data corroborate pre-clinical observations, showing the activation of T- and B-cell immune responses and tumor reduction, with no short or long-term adverse effects. We propose to optimize the IFx-Hu2.1 formulation for temperature stability using established methods and models. In vitro evaluation, to include standard quality control methods and a human vaginal epithelium carcinoma model, will be followed by in vivo uptake, expression, and disease progression studies in a mouse model of cervical cancer. Room temperature storage and self-administration will circumvent onerous clinic visits, improve prognosis and preserve fertility. IFx-Hu2.1 cream formulation will provide a non-toxic cancer therapeutic treatment with minimal supportive care requirements, featuring unique delivery, and high applicability/impact to underserved populations. The data obtained by completing these studies will position Morphogenesis, Inc. to submit an Investigational New Drug application to conduct a clinical trial for women in a local community hospital (low-resource setting) and in South Africa (LMIC). These trials will be the objective of an SBIR Phase 2 proposal.

该项目的目标是提供一种负担得起的免疫疗法，以治疗低死亡率的晚期宫颈癌。 和中等收入国家 (LMIC) 以及美国的资源匮乏地区。长期目标是尽早治疗 宫颈发育不良的阶段并评估对病原体人乳头瘤病毒（HPV）的免疫力。这 宫颈癌带来的痛苦和死亡的沉重负担不成比例地落在资源匮乏的妇女身上 设置。克服治疗障碍，即缺乏基础设施、训练有素的专家、专门设备、 冷链和财政资源需要治疗方法的范式转变才能实现 通过这里提出的创新免疫治疗剂。 IFx-Hu2.1 (SN63/016,700) 是一种基于乳膏的治疗性免疫调节剂，将针对稳定性和 表现。我们的 IFx-Hu2 系列包含质粒 DNA (pDNA) 原料药，可用于生产 成本仅为当前免疫疗法的一小部分。 pDNA 编码复杂的细菌抗原 Emm55。 当在肿瘤细胞表面表达时，Emm55 会吸引抗原呈递细胞和其他先天性细胞。 免疫反应。然后将非自身表位（例如肿瘤和 HPV 抗原）暴露出来，以设定 提高多抗原细胞和体液适应性免疫反应。基于 Emm55 的疗法诱导 个性化、多价、系统性和持续的免疫反应，并有可能治疗 通过增强肿瘤识别、免疫激活和表位扩散来治疗广泛的癌症。 病灶内注射 IFx-Hu2.0 在多项动物研究中已确定安全性，目前正在研究中 正在针对皮肤黑色素瘤、默克尔细胞癌和皮肤癌的 1 期人体临床试验进行测试 鳞状细胞癌。我们的初步临床数据证实了临床前观察结果，表明 激活 T 细胞和 B 细胞免疫反应并减少肿瘤，并且没有短期或长期副作用。 我们建议使用既定方法优化 IFx-Hu2.1 配方的温度稳定性， 模型。体外评估，包括标准质量控制方法和人类阴道上皮 癌症模型，随后将在小鼠中进行体内摄取、表达和疾病进展研究 宫颈癌模型。室温储存和自我管理将避免繁重的就诊， 改善预后并保留生育能力。 IFx-Hu2.1乳膏配方将提供无毒的抗癌效果 具有最低支持护理要求的治疗性治疗，具有独特的交付方式和高 对服务不足人群的适用性/影响。通过完成这些研究获得的数据将定位 Morphogenesis , Inc .将提交研究性新药申请，以对女性进行临床试验 当地社区医院（资源匮乏的环境）和南非（LMIC）。这些试验的目标将是 SBIR 第 2 阶段提案。