Biomarker Investigations for Clinical Trials

与上述特定生物标志物目标相关，我们进行了各种研究以支持 生物标志物驱动的早期药物开发：1.新的或新颖的生物标志物在 高度独特的治疗药物的早期试验。A）我们支持相关标记 Raffit哈桑博士对他的间皮素靶向新疗法的研究，包括 传统的抗体药物缀合物疗法和T细胞疗法，使用我们 先前已经开发了（JCO Precis Oncol. doi：10.1200/PO.17.00282，2018）。显著 在许多患者中观察到反应，我们的肿瘤抗原检测在近 真实的时间，以及时向研究者提供关于缓解和进展的信息。（B） 我们为Andrea Apolo博士和一些研究人员的临床试验提供了持续的生物标志物支持。 发表了工作（Girardi DM，Clin Cancer Res，doi：10.1158/1078-0432. 2022年）。C）我们 开发了宫颈癌的无细胞DNA检测，并将其用于治疗监测， 最小残留疾病（MRD）检测，癌症基因分型，用于患者选择。我们支持 Scott Norberg博士的HPV靶向治疗试验。最近的一些工作集中在使用 具有无细胞DNA的NGS用于针对T细胞疗法的抗性机制。D）体细胞突变 染色体检查结果异常孕妇的游离DNA分析。在 与NICHD的Christina Annunziata和Diana比安奇博士合作， 致力于揭示肿瘤特异性体细胞突变，为癌症起源提供信息， 致病过程和治疗药物选择。中期结果显示， 可能影响患者临床管理的领域中的重要新知识， 并告知使用染色体非整倍体进行癌症筛查的可行性。2. 鉴定新的生物标志物。A）在与Steven Pavletic博士的合作中，我们开发了新的 用于研究移植物抗宿主病的细胞因子试验（Curtis LM Blood. 137：896-907。 2021; Goklemez S骨髓移植。doi：10.1038/s41409-021-01419-2。2021年）。（B） 动物模型中肿瘤生物标志物的临床前研究。和克莉丝汀医生一起工作 Alewine是为了更好地设计临床研究，提高生物标志物的价值， 调查一些研究已发表（Zhang X，Transl Oncol，doi： 10.1016/j.transon.2022.101440。#20222;，其他人也跟着。3.检测方法开发和 验证。A）为应对COVID-19疫情，我们开发了一种高效的血清学检测方法， 为COVID-19。此外，我们还开发了一种测试来评估用于评估ACE 2的测定法。 各种SARS-cov-2变体的受体结合。我们生成了大量的临床数据， 与美国国立卫生研究院临床研究所的卡米尔·韦斯特博士合作， Center（Yu Y，Sci Rep，12：2628. doi：10.1038/s41598-022-06629-2。2022年）。4.新技术 发展A）我们专注于开发基于循环肿瘤DNA的技术， 确定与治疗反应相关的癌症基因突变，以及 鉴定与耐药性相关的突变。我们成功开发了新的 检测抗原呈递过程中涉及的体细胞突变的基于NGS的测定 和T细胞反应。这项工作是为了支持克里斯蒂安博士的试验 Hinrichs，由Scott Norberg博士继任。B）我们正在进行无细胞DNA测试， NIPT试验异常孕妇潜在肿瘤形成的调查 由NICHD的Christina Annunziata博士和Diana比安奇博士领导的一项试验得出了这一结果。

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.