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志物驱动的早期药物开发：1）在高度独特的治疗剂的早期试验中应用新的或新颖的生物标志物。A）我们参与了James Gulley博士的双功能免疫靶向剂M7824的首次Ia期人体研究的生物标志物研究。我们的数据是第一个为这种代理的作用机制。我们的数据还提供了关于剂量-反应关系的第一组信息，这是药物剂量选择所必需的（Clin. Cancer Res. 24：1287-1295，2018）。我们将继续支持后续工作。B）我们在弗拉基米尔瓦莱拉博士对EpCAM抗体vicinium与免疫疗法组合的试验中进行生物标志物研究。在这项研究中，我们开发了药物的PD和PK测定，并为试验进行了免疫细胞因子分析。我们的结果提供了关于Vicinium的第一个信息性PK数据，该试验正在进行中。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，MRD检测，癌症基因分型以供患者选择。部分研究成果已发表（Clin Cancer Res. 23：6856-6862，2017）。我们目前正在支持Christian Henrichs博士的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Andrea Apolo博士的标志物研究。这项工作最近发表（Lancet Oncol。doi：10.1016/S1470-2045（20）30202-3，2020）。2)鉴定新的生物标志物。A）我们与Brid Ryan博士合作进行生物标志物发现工作，并在几篇出版物中获得了工作成果（Cancer Epidemiol Biomarkers Prev，doi：10.1158/1055-9965，2019; J Thorac Oncol. 14：1192-1203，2019）。这些测试涉及数千个样本的高度复杂的临床级检测，产生了超过100，000个测试结果。B）我们与伊拉帕斯坦博士和拉菲特哈桑博士合作，发现用于治疗监测和反应预测的生物标志物。早期结果已发表（JCO Precis Oncol. doi：10.1200/PO.17.00282，2018），我们持续支持哈桑博士和Alewine博士关于间皮素靶向药物的多项NCI试验。C）在与Steven Pavletic博士的合作中，我们开发了用于研究移植物抗宿主病的新的细胞因子测试（Am J Hematol. doi：10.1002/ajh.25717，2020）。3)试验开发和验证。A）我们开发了一种新的肿瘤抗原检测方法，并进行了广泛的分析和临床验证，导致NCI生物标志物委员会批准该检测方法用于多项NCI申办的多中心试验（J Appl Lab Med. 3：166-177，2018）。我们目前进行了三项多中心试验，以评估其用于治疗监测和患者选择的能力。B）我们开发了无细胞DNA，用于接受过继性T细胞疗法的HPV阳性癌症患者的患者选择和治疗监测。我们与Kite Pharma进行了联合试验验证，并将试验转移至其操作，用于治疗监测和患者选择。C）为应对COVID-19，我们启动了血清学检测开发工作。根据我们的初步数据，我们的检测试剂盒的性能可能与罗氏和雅培的检测试剂盒相当。然而，我们的检测方法相对于这两种方法的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，如免疫接种、免疫和重复感染。该工作不包括在2020财政年度的时间分配内。4)新技术开发。A）我们专注于开发基于循环肿瘤DNA的技术，用于确定与治疗反应相关的癌症基因突变，以及鉴定与耐药性相关的突变。我们目前的工作是分析逃避过继性T细胞免疫治疗的HPV阳性肿瘤。这项工作是为了支持Christian Hinrichs博士的试验。B）我们在Christina Annunziata博士的试验中致力于无细胞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.