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.

这个项目的目标是提供一种负担得起的免疫疗法来治疗晚期宫颈癌