Biomarker Investigations for Clinical Trials

与上述特定的生物标志物目标相关，我们进行了各种研究来支持生物标志物驱动的早期药物开发：在高度独特的治疗药物的早期试验中应用新的或新颖的生物标志物。A)我们支持Raffit Hassan博士的间皮素靶向新疗法的相关标记研究，包括传统的抗体药物偶联疗法和T细胞疗法，使用我们之前开发的检测方法（JCO Precis Oncol）。doi: 10.1200/PO.17.00282, 2018)。在许多患者中发现了显著的反应，我们的肿瘤抗原检测几乎实时进行，为研究人员提供了有关反应和进展的及时信息。B)我们为Andrea Apolo博士的临床试验提供了持续的生物标志物支持，并发表了部分工作（Girardi DM, clinycancer Res, doi: 10.1158/1078-0432）。2022)。C)我们开发了一种宫颈癌的无细胞DNA检测方法，并将其用于治疗监测、最小残留病（MRD）检测、癌症基因分型以供患者选择。我们支持斯科特·诺伯格博士的hpv靶向治疗试验。最近的一些工作集中在使用NGS与细胞游离DNA对抗T细胞治疗的抗性机制。D)染色体检测结果异常孕妇的体细胞突变与游离DNA分析。在与NICHD的Christina Annunziata和Diana Bianchi博士的合作中，我们进行了一些开创性的工作，揭示了肿瘤特异性的体细胞突变，为癌症的起源、常见的致病过程和治疗药物的选择提供了信息。中期结果提供了一些重要的新知识，这些知识可能会影响患者的临床管理，并为利用染色体非整倍体进行癌症筛查的可行性提供信息。2. 鉴定新的生物标志物。A)与Steven Pavletic博士合作，我们开发了用于移植物抗宿主病研究的新的细胞因子试验（Curtis LM Blood. 137:896-907）。2021年;骨髓移植。doi: 10.1038 / s41409 - 021 - 01419 - 2。2021)。B)肿瘤生物标志物在动物模型中的临床前研究。Christine Alewine博士的工作是更好地设计临床研究，提高生物标志物研究的价值。部分研究成果已发表（张欣，译Oncol， doi: 10.1016/j.t anon.2022.101440）。2022年)，其他国家也将效仿。3. 试验开发和验证。（一）为应对2019冠状病毒病大流行，我们开发了高效的COVID-19血清学检测方法。此外，我们还开发了一种测试方法来评估各种SARS-cov-2变体的ACE2受体结合情况。我们与美国国立卫生研究院临床中心的卡米尔·韦斯特博士合作，与患有COVID-19或接种疫苗的捐赠者一起生成了广泛的临床数据（Yu Y, Sci Rep, 12:2628）。doi: 10.1038 / s41598 - 022 - 06629 - 2。2022)。4. 新技术的发展。A)我们专注于开发基于循环肿瘤DNA的技术，以确定与治疗反应相关的癌症基因突变，并鉴定与耐药性相关的突变。我们成功开发了新的基于ngs的检测方法，利用细胞游离DNA检测抗原呈递和T细胞反应过程中涉及的体细胞突变。这项工作是为了支持Christian Hinrichs博士的试验，他的继任者是Scott Norberg博士。B)在NICHD的Christina Annunziata博士和Diana Bianchi博士领导的一项试验中，我们正在进行无细胞DNA测试，以调查NIPT测试结果异常的孕妇的潜在肿瘤。

Related to the specific biomarker goals above, we conducted various studies to support biomarker driven early-stage drug development: 1. Application of new or novel biomarkers in early-stage trials of highly unique therapeutic agents. A) We supported correlative marker investigations of Dr. Raffit Hassan on his mesothelin-targeted novel therapies, including traditional antibody drug conjugate therapies, and T cell therapies, using the assay that we have previously developed (JCO Precis Oncol. doi: 10.1200/PO.17.00282, 2018). Significant responses were seen in many patients, where our tumor antigen tests were performed in near real time to provide investigators with timely information on responses and on progression. B) We provided continues biomarker support of clinical trials by Dr. Andrea Apolo and some of the work was published (Girardi DM, Clin Cancer Res, doi: 10.1158/1078-0432. 2022). C) We developed a cell free DNA detection for cervical cancer and use it for treatment monitoring, minimum residue disease (MRD) detection, cancer genotyping for patient selection. We support HPV-targeted therapy trials by Dr. Scott Norberg. Some of the recent work was focused on using NGS with cell free DNA for resistance mechanisms against T cell therapies. D) Somatic mutation analysis with cell free DNA in pregnant women with abnormal chromosome test results. In working with Christina Annunziata and Dr. Diana Bianchi of NICHD, we performed some pioneer work to uncover tumor specific somatic mutation informing on cancer origins, on common pathogenic processes, and on treatment drug options. Interim results presented some significant novel knowledge in the field which could impact the patient clinical management, and inform on the feasibility of using chromosome aneuploidy for cancer screening. 2. Identification of new biomarkers. A) In working with Dr. Steven Pavletic, we developed new cytokine tests for the investigation of graft vs host disease (Curtis LM Blood. 137:896-907. 2021; Goklemez S Bone Marrow Transplant. doi: 10.1038/s41409-021-01419-2. 2021). B) Preclinical investigation of tumor biomarker in animal models. The work with Dr. Christine Alewine is to better design the clinical study and to improve the value of the biomarker investigation. Some of the research was published (Zhang X, Transl Oncol, doi: 10.1016/j.tranon.2022.101440. 2022), with others to follow. 3. Assay development and validation. A) In response to COVID-19 pandemic, we developed a high-performance serology test for COVID-19. In addition, we also developed a test to evaluate an assay to evaluate the ACE2 receptor binding of various SARS-cov-2 variants. We generated extensive clinical data with donors who had COVID-19 or vaccination in collaboration with Dr. Kamille West of NIH Clinical Center (Yu Y, Sci Rep, 12:2628. doi: 10.1038/s41598-022-06629-2. 2022). 4. New technology development. A) We focus on the development of a circulating tumor DNA based technology for determining cancer gene mutations associated with treatment responses, and for the identification of mutations associated with resistance. We successfully developed new NGS-based assays to examine somatic mutations involved in the process of antigen presentation and T cell response using cell free DNA. The work is to support trials by Dr. Christian Hinrichs, who was succeeded by Dr. Scott Norberg. B) We are working on cell free DNA test for the investigation of potential neoplasia in pregnant women presented with abnormal NIPT test results in a trial led by Dr. Christina Annunziata and Dr. Diana Bianchi of NICHD.