This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development–analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).
Purpose
Myeloid-derived suppressor cells (MDSC) one of the major contributors to immune suppression in cancer. We recently have demonstrated in preclinical study that MDSC are sensitive to TRAIL receptor 2 (TRAIL-R2) agonist. The goal of this study was to clinically test the hypothesis that targeting TRAIL-R2 can selectively eliminate MDSC.
Experimental Design
The TRAIL-R2 agonistic antibody (DS-8273a) has been tested in 16 patients with advanced cancers enrolled in a phase 1 trial. The antibody (24 mg/kg) was administered IV once every 3 weeks till disease progression, unacceptable toxicities, or withdrawal of consent. The safety and the presence of various populations of myeloid and lymphoid cells in peripheral blood and tumor tissues were evaluated.
Results
The treatment was well tolerated with only mild to moderate adverse events attributable to the study drug. Treatment with DS-8273a resulted in reduction of the elevated numbers of MDSC in the peripheral blood of most patients to the levels observed in healthy volunteers. However, in several patients, MDSC rebounded back to the pre-treatment level by day 42. In contrast, DS-8273a did not affect the number of neutrophils, monocytes, and other populations of myeloid and lymphoid cells. Decrease in MDSC inversely correlated with the length of progression-free survival. In tumors, DS-8273a treatment resulted in a decrease of MDSC in 50% of the patients who were able to provide pre- and on-treatment biopsies.
Conclusion
Targeting TRAIL-R2 resulted in elimination of different populations of MDSC without affecting mature myeloid or lymphoid cells. These data support the use of this antibody in combination immmunotherapy of cancer.
Trial registration
ClinicalTrials.gov NCT02076451.
Multiple modifiable factors were associated with ureteroenteric anastomotic strictures following robot assisted radical cystectomy. Surgical revision can provide a definitive management with comparable outcomes for open and robotic repairs.
Colonic distention and preparation at CT colonography were significantly improved by using supine and prone scanning in combination, and results correlated directly with improved sensitivity of polyp detection.
We have developed a user-friendly nomogram that uses easily recognized variables to calculate the likelihood of upgrade for ADH. The nomogram could assist the treating surgeon in decision-making, particularly when the patient is at risk for surgical intervention.
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