Biomarker Investigations for Clinical Trials

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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.