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，以治疗晚期宫颈癌， 一个长期的目标是更早地治疗 子宫颈发育不良的分期和评估对病原体人乳头瘤病毒（HPV）的免疫力。的 宫颈癌造成的痛苦和死亡的沉重负担不成比例地福尔斯在资源贫乏的妇女身上 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，需要在治疗方法上实现范式转变， 由这里提出的创新免疫剂。 IFx-Hu 2.1（SN 63/016，700）是一种乳膏型治疗性免疫调节剂，将针对稳定性进行优化， 性能我们的IFx-Hu 2家族包含质粒DNA（pDNA）原料药，其可通过以下方法生产： 只需要目前免疫疗法成本的一小部分。pDNA编码复合细菌抗原Emm 55。 当在肿瘤细胞表面表达时，Emm 55吸引抗原呈递细胞和先天性巨噬细胞的其他细胞。 免疫反应非自身表位如肿瘤和HPV抗原然后以这样的方式暴露， 多抗原细胞和体液适应性免疫反应。基于Emm 55的疗法诱导 个性化，多价，全身性和持续的免疫反应，并有可能治疗 通过增强的肿瘤识别、免疫激活和表位扩散来治疗广泛的癌症。 在多项动物研究中，病灶内注射IFx-Hu 2.0具有已确立的安全性特征， 在皮肤黑色素瘤、默克尔细胞癌和皮肤癌的1期人体临床试验中进行测试。 鳞状细胞癌我们的初步临床数据证实了临床前的观察结果，显示 激活T细胞和B细胞免疫应答并减少肿瘤，无短期或长期不良反应。 我们建议使用已建立的方法优化IFx-Hu 2.1制剂的温度稳定性， 模型体外评价，包括标准质量控制方法和人阴道上皮 癌模型，随后在小鼠中进行体内摄取、表达和疾病进展研究 子宫颈癌的模型。室温储存和自我管理将避免繁琐的诊所访问， 改善预后和保持生育能力。IFx-Hu 2.1乳膏制剂将提供无毒的癌症 治疗性治疗，支持性护理要求最低，具有独特的交付， 适用性/对服务不足人群的影响。通过完成这些研究获得的数据将定位 Morphogenesis，Inc.提交一份研究性新药申请，以便在一个 当地社区医院（低资源环境）和南非（LMIC）。这些试验将是 SBIR第二阶段提案。