Biomarker Investigations for Clinical Trials

与上述特定的生物标记物目标相关，我们进行了各种研究来支持生物标记物驱动的早期药物开发：1.新的或新的生物标记物在高度独特的治疗药物的早期试验中的应用。A)我们支持Raffit Hassan博士使用我们之前开发的分析方法(JCO Precis Onol)对他的以间硫蛋白为靶标的新疗法进行的相关标记研究，包括传统的抗体药物结合疗法和T细胞疗法。DOI：10.1200/PO.17.00282,2018年)。在许多患者中看到了显著的反应，我们的肿瘤抗原测试几乎是实时进行的，以向研究人员提供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持续的生物标记物支持，并发表了一些工作(Girardi DM，临床癌症研究，DOI：10.1158/1078-0432)。2022年)。C)我们建立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、癌症基因分型和患者选择。我们支持Scott Norberg博士进行的HPV靶向治疗试验。最近的一些工作集中在利用NGS和游离DNA来对抗T细胞疗法的耐药机制。D)对染色体检测结果异常的孕妇进行游离DNA体细胞突变分析。在与NICHD的Christina Annunziata和Diana Bianci博士合作中，我们进行了一些开创性的工作，以揭示肿瘤特异性体细胞突变，为癌症的起源、常见的致病过程和治疗药物选择提供信息。中期结果展示了该领域的一些有意义的新知识，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了信息。2.新生物标志物的识别。A)在与Steven Pavletic博士的合作中，我们开发了新的细胞因子测试，用于研究移植物抗宿主疾病(Curtis LM血液)。137：896-907。2021年；戈克尔梅兹·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。与Christine Alewin博士的合作是为了更好地设计临床研究，并提高生物标记物研究的价值。其中一些研究已经发表(Zhang X，Transl Onol，DOI：10.1016/j.tran.2022.101440)。2022年)，其他国家也将效仿。3.分析方法的开发和验证。A)为了应对新冠肺炎大流行，我们为新冠肺炎开发了一种高性能的血清学检测方法。此外，我们还开发了一种测试来评估ACE2受体与各种SARS-CoV-2变异体的结合。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，对接受新冠肺炎或疫苗接种的捐赠者产生了广泛的临床数据(于勇，科学代表，12：2628。DOI：10.1038/s41598-022-06629-2。2022年)。4.新技术开发。A)我们专注于开发一种基于循环肿瘤DNA的技术，用于确定与治疗反应相关的癌症基因突变，并用于识别与耐药性相关的突变。我们成功地开发了新的基于NGS的分析方法，利用游离DNA检测涉及抗原呈递和T细胞反应过程的体细胞突变。这项工作是为了支持克里斯蒂安·辛里奇博士的试验，他的继任者是斯科特·诺伯格博士。B)在NICHD的Christina Annunziata博士和Diana Bianci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.