Biomarker Investigations for Clinical Trials

与上述具体目标相关，我们进行了各种研究以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)我们参与了James Gulley博士对双功能免疫靶向剂M7824的第一阶段人体研究的生物标记物研究。我们的数据是关于该制剂作用机制的第一个数据。我们的数据还提供了有关剂量-反应关系的第一组信息，这是药物剂量选择所必需的(临床试验)。癌症研究24：1287-1295,2018)。我们将继续支持后续工作。B)我们在Vladimir Valera博士的一项试验中进行了生物标记物的研究，该试验结合免疫疗法对EpCAM抗体vicdium进行了研究。在这项研究中，我们开发了药物的PD和PK分析，并为试验进行了免疫细胞因子分析。我们的结果提供了第一个关于维拉宁的信息性PK数据，试验仍在进行中。C)我们建立了宫颈癌的无细胞DNA检测方法，并将其用于治疗监测、MRD检测、癌症基因分型等。其中一些工作已经发表(临床癌症研究23：6856-6862,2017)。我们目前支持克里斯蒂安·亨利克斯博士进行的大约5项试验。D)我们通过研究药物对血管生成和炎症的影响来支持安德里亚·阿波罗博士的标志性研究。这项研究最近发表在《柳叶刀》杂志上。DOI：2020年/S1470-30202(20)10.1016)。2)新生物标志物的识别。A)我们与Brid Ryan博士在生物标记物发现工作方面进行了合作，并在多个出版物上取得了成果(癌症流行病学生物标记物Prev，DOI：10.1158/1055-9965,2019年；J Thorac Onol)。2019年14：1192-1203)。这些测试涉及高度复杂的临床级别分析，涉及数千个样本，产生了超过10万个测试结果。B)我们与Ira Pastan博士和Raffit Hassan博士合作，发现了用于治疗监测和反应预测的生物标记物。早期结果发表在(JCO Precis Oncol.DOI：10.1200/PO.17.00282,2018年)，我们继续支持由Hassan博士和Alewin博士进行的多项NCI关于间硫内酯靶向药物的试验。C)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(Am J Hematol)。DOI：10.1002/ajh.25717,2020年)。3)测试开发和验证。A)我们开发了一种新的肿瘤抗原测试，并进行了广泛的分析和临床验证，导致NCI Biomarker Committee批准了NCI赞助的多个多中心试验(J Appl Lab Med)的应用。2018年3：166-177)。我们目前进行了三项多中心试验，以评估其对治疗监测和患者选择的能力。B)我们开发了一种无细胞DNA，用于过继T细胞疗法中HPV阳性癌症患者的患者选择和治疗监测。我们已经与Kite Pharma进行了联合检测验证，并将检测转移到他们的手术中，用于治疗监测和患者选择。C)为了响应新冠肺炎，我们发起了一项血清学检测开发工作。根据我们的初步数据，我们的检测结果可能与罗氏和雅培的检测结果相当。然而，与这两种方法相比，我们的检测方法的一个潜在优势是能够检测病毒中和所需的抗体。我相信，这将有助于解决未来的问题，如免疫、免疫和重复感染。这项工作不包括在2020财年的时间分配中。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。我们目前的工作是分析HPV阳性肿瘤逃脱过继T细胞免疫治疗。这项工作是为了支持克里斯蒂安·辛里奇博士的试验。B)在克里斯蒂娜·安农齐亚塔博士的一项试验中，我们致力于无细胞DNA测试，以支持孕妇的癌症诊断。

Related to the specific 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 were involved the biomarker studies for the first in phase Ia human study of a dual function immune-targeting agent M7824 by Dr. James Gulley. Our data was the first for the mechanism of action of this agent. Our data also provided the first set of information on the dose-response relationship, which is necessary for drug dose selection (Clin. Cancer Res. 24: 1287-1295, 2018). We continue to support the follow up work. B) We conduct the biomarkers studies in a trial by Dr. Vladimir Valera on an EpCAM antibody, vicinium, in combination with immunotherapy. In the study, we develop both PD and PK assays for the drug, as well as conduct immune cytokine profiling for the trial. Our results provided the first informative PK data on vicinium and the trial is on-going. C) We developed a cell free DNA detection for cervical cancer and use it for treatment monitoring, MRD detection, cancer genotyping for patient selection. Some of the work was published (Clin Cancer Res. 23:6856-6862, 2017). We are currently support about 5 trials by Dr. Christian Henrichs. D) We support marker investigation of Dr. Andrea Apolo by investigating the drugs effects on angiogenesis and inflammation. The work was recently published (Lancet Oncol. doi: 10.1016/S1470-2045(20)30202-3, 2020). 2) Identification of new biomarkers. A) We collaborate with Dr. Brid Ryan in biomarker discovery work, and work results in several publications (Cancer Epidemiol Biomarkers Prev, doi: 10.1158/1055-9965, 2019; J Thorac Oncol. 14:1192-1203, 2019). The tests involved highly plex clinical grade assays with thousands of samples, produced over 100,000 test results. B) We worked with Dr. Ira Pastan and Raffit Hassan to uncover biomarkers for treatment monitoring and response prediction. The early results were published (JCO Precis Oncol. doi: 10.1200/PO.17.00282, 2018), and we continuously support a number of NCI trials by Dr. Hassan and Dr. Alewine on mesothelin-targeted agents. C) In working with Dr. Steven Pavletic, we developed new cytokine tests for the investigation of graft vs host disease (Am J Hematol. doi: 10.1002/ajh.25717, 2020). 3) Assay development and validation. A) We developed a new tumor antigen test and carried extensive analytic and clinical validation, leading to the approval of the test by NCI Biomarker Committee for applications of multiple NCI-sponsored multicenter trials (J Appl Lab Med. 3: 166-177, 2018). We currently three multicenter trials with this test to assess its ability for treatment monitoring and patient selection. B) We developed a cell free DNA for patient selection and treatment monitoring of HPV positive cancer patients on adoptive T cell therapies. We have conducted a joint assay validation with Kite Pharma and have the assay transfer to their operation for treatment monitoring and patient selection. C) In response to COVID-19, we initiated a serology assay development effort. Based on our preliminary data, our assay would likely have the performance comparable to these by Roche and Abbott. However, a potential advantage of our assay over these two is the ability to detect antibodies required for virus neutralization. I believe that this would allow to address future issues such as immunization, immunity, and repeat infections. This work is not included in the time allocation of FY2020. 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. Our current work is on the analysis of HPV positive tumors escaping from adoptive T cell immunotherapies. The work is to support trials by Dr. Christian Hinrichs. B) We work on cell free DNA test to support cancer diagnosis in pregnant women in a trial by Dr. Christina Annunziata.