Integrating Low-Cost Paper-Based Devices and Personalized Immunotherapeutics to Treat Triple Negative Breast Cancer

整合低成本纸基设备和个性化免疫疗法来治疗三阴性乳腺癌

• 批准号: 10707347
• 负责人: Brian Richard McNaughton
• 金额: $ 37.03万
• 依托单位: DELAWARE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707347
• 关键词: Affect; Affinity; African American; African American population; Antibodies; Antineoplastic Agents; Appointment; Binding; Biological Markers; Biological Products; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer cell line; Cell Surface Proteins; Cell Surface Receptors; Cell surface; Cells; Childhood; Clinic; Combination immunotherapy; Combined Modality Therapy; Complex; Delaware; Development; Devices; Diagnostic Equipment; Disease; Disparity; Drug Costs; Drug usage; Effectiveness; Epidermal Growth Factor Receptor; Escherichia coli; Estrogen Receptors; Excretory function; Generations; Goals; High Risk Woman; Hormone Receptor; Human; Immune; Immune mediated destruction; Immune system; Immunotherapeutic agent; Immunotherapy; Incidence; Left; Localized Disease; Low income; Malignant Neoplasms; Mammalian Cell; Marketing; Mastectomy; Measures; Mental association; Methods; Minority Groups; Monitor; Monoclonal Antibodies; Mutate; Operative Surgical Procedures; Outcome; Paper; Patient-Focused Outcomes; Patients; Phage Display; Pharmaceutical Preparations; Population; Production; Progesterone Receptors; Proteins; Radiation; Reporter; Research; Serum; Signal Transduction; Source; Techniques; Technology; Testing; Therapeutic; Tissues; Trastuzumab; Trauma; Treatment Efficacy; Treatment outcome; Vaccination; Woman; Work; aggressive breast cancer; antibody-dependent cell cytotoxicity; cancer cell; cancer immunotherapeutics; cancer immunotherapy; cancer subtypes; clinically significant; cost; design; diagnostic platform; drug discovery; experimental study; health equity; hormone receptor-positive; hormone therapy; improved; in vivo; malignant breast neoplasm; member; nanobodies; new technology; novel strategies; personalized approach; personalized medicine; personalized therapeutic; precision drugs; receptor; recruit; side effect; survival outcome; targeted treatment; triple-negative invasive breast carcinoma; tumor; virtual

Integrating Low-Cost Paper-Based Devices and Personalized Immunotherapeutics to Treat Triple Negative Breast Cancer Summary After a breast cancer patient has an initial appointment with her clinician, one possible outcome is that the cancer tests positive for one or more clinically significant cell surface “biomarkers”, most notably estrogen receptor (ER), progesterone receptor (PR), or HER2. In this relatively good scenario, the patient would likely be prescribed a personalized therapy such as a hormone therapy (in the case of ER+ and/or PR+ cancers) or with drugs that specifically target HER2+ cells (e.g. the monoclonal antibody, mAb, Herceptin™). These personalized drugs are less toxic than general anti- cancer drugs such as chemotherapeutic cocktails. In a different, and relatively dire scenario, a patient is told she has “triple negative” breast cancer (ER-, PR-, HER2-), meaning her cancer cells lack hormone receptors like ER or PR, and lack HER2. Triple negative breast cancer (TNBC) represents 15-20% of all breast cancer cases, and disproportionately affects minority populations. Without personalized therapies, this patient is now left to suffer through treatment with non-targeted and toxic drugs (chemotherapeutics) that come with a host of debilitating side effects. Commonly, drastic measures, such as mastectomy, are required in order to fully remove all tissue that could serve as a source of, or substrate for, new tumors. The five-year survival outcomes of populations that test positive for HR and/or HER2, and TNBC patients substantially differs as well. For patients who test positive for HR and/or HER2 with regional breast cancer, five-year survival is ~82-89%, but 65% for TNBC. Clearly, new technologies and approaches are required to target TNBC and provide these patients the same therapeutic opportunities that patients that test positive for HR or HER2 biomarkers have. Here, we propose a fundamentally different approach to personalized medicine, which will dramatically change how we treat TNBC, particularly in lower income minority populations. We will evolve small proteins to selectively bind a patient’s breast cancer cells, irrespective of the specific changes to the cell surface that have occurred as a result of breast cancer. These proteins will be fused to other proteins that provide stability in the body, and recruit antibodies from the patient’s serum to TNBC cells, resulting in their targeted destruction. We will pair our TNBC-targeting immunotherapies (drugs that use the immune system to destroy TNBC cells) with a low-cost paper-based platform, which will allow simple, accessible, and routine assessment of our TNBC-targeting proteins, and allow clinicians to select which members should make up a combination therapy. The diagnostic platform will also allow clinicians to monitor the effectiveness of each member of the cocktail over the course of treatment (as cancer cells mutate), and select alternative members and/or replacements when necessary. Collectively, this work represents necessary and exciting advances in the integration of low-cost approaches to TNBC-targeting, and personalized, drug discovery, and the optimization and monitoring of these immunotherapeutic cocktails over the course of treatment.

集成低成本的纸质设备和个性化 三阴性乳腺癌的免疫治疗 总结 在乳腺癌患者与她的临床医生初次预约后， 可能的结果是，癌症对一种或多种临床试验呈阳性。 重要的细胞表面“生物标志物”，最显著的是雌激素受体（ER）， 孕酮受体（PR）或HER 2。在这种相对较好的情况下，患者可能会被处方 个性化治疗，如激素治疗（在ER+和/或PR+癌症的情况下）或药物治疗 特异性靶向HER 2+细胞（例如单克隆抗体，mAb，Herceptin™）。这些个性化 药物的毒性较一般抗癌药物如鸡尾酒式化疗药物为低。 在一个不同的、相对可怕的场景中，一个病人被告知她患有“三阴性”乳腺癌。 (ER-、PR-、HER 2-），这意味着她的癌细胞缺乏激素受体如ER或PR，并且缺乏HER 2。三重 阴性乳腺癌（TNBC）占所有乳腺癌病例的15-20%， 影响少数民族。如果没有个性化的治疗，这个病人现在只能忍受 使用非靶向和有毒药物（化疗药物）进行治疗，这些药物具有许多使人衰弱的副作用 方面的影响.通常，为了完全去除所有组织，需要采取激烈的措施，例如乳房切除术 可以作为新肿瘤的来源或基质。人群的5年生存结果 HR和/或HER 2检测阳性的患者与TNBC患者也有很大不同。的患者 HR和/或HER 2检测呈阳性的局部乳腺癌，五年生存率约为82- 89%，但HR和/或HER 2检测呈阳性的局部乳腺癌，五年生存率为65% TNBC。显然，需要新的技术和方法来靶向TNBC并为这些患者提供治疗。 与HR或HER 2生物标志物检测阳性的患者具有相同的治疗机会。 在这里，我们提出了一种从根本上不同的个性化医疗方法， 这将极大地改变我们对待TNBC的方式，特别是在低收入的少数群体中。我们将 进化出小的蛋白质来选择性地结合患者的乳腺癌细胞，而不管具体的变化如何。 乳腺癌的细胞表面。这些蛋白质将融合到其他 蛋白质在体内提供稳定性，并从患者血清中招募抗体到TNBC细胞， 从而有针对性地摧毁它们。我们将配对我们的TNBC靶向免疫疗法（使用 免疫系统摧毁TNBC细胞），这将允许简单， 我们的TNBC靶向蛋白的可访问和常规评估，并允许临床医生选择 会员应组成一个联合治疗。该诊断平台还将允许临床医生 在治疗过程中监测鸡尾酒中每个成员的有效性（如癌细胞 突变），并在必要时选择替代成员和/或替换。 总的来说，这项工作代表了低成本集成的必要和令人兴奋的进步 TNBC靶向和个性化药物发现的方法，以及优化和监测 这些免疫鸡尾酒在治疗过程中。