Chan, Carlos Hou Fai

TPS276 Background: Immune checkpoint inhibitors have revolutionized the treatment of a number of cancers. In colorectal cancers, their efficacy is limited to mismatch repair deficient or microsatellite stability-high (dMMR/MSI-High) tumors only. These constitute only 4-5% of all metastatic colorectal cancers (mCRC). Novel approaches are needed to make immunotherapy a viable option for mismatch repair proficient or microsatellite stable (pMMR/MSS) tumors. Increasing exposure of neo-antigens to the immune system could be one potential strategy to enhance the response of immunotherapy. Yttrium 90-radioembolization (Y90-RE) in combination with immunotherapy may work synergistically to enhance efficacy of each other. Additionally, radiation can potentially make the tumor microenvironment conducive to effector T-cell recruitment and function. Therefore, we hypothesize and propose the clinical trial of combining immunotherapy with Y90-RE as a feasible and safe strategy that will improve outcomes in patients with mCRC with liver-predominant metastases. Methods: This clinical trial will be conducted as a single-center, open-label, Phase I/II trial to evaluate initially the feasibility and safety of Y90-RE in combination with a fixed dose of immunotherapy (durvalumab) in subjects with liver-predominant, mCRC (Table). It will be offered in the refractory setting. The trial will be performed in 18 subjects with mCRC with liver metastasis and the safety of immunotherapy (durvalumab) with Y90-RE will be investigated in an accelerated titration design. This would allow a maximum tolerated dose with the minimum number of subjects. Correlative studies pertaining to serial circulating tumor DNA (ctDNA - liquid biopsies) testing as well as immune-panel based profiling will be performed alongside pre- and post-biopsies to study changes in the tumor microenvironment. Clinical trial information: NCT04108481. [Table: see text]

763 Background: Non-invasive biomarkers with high sensitivity and specificity would be of great value for patients with Pancreatic Ductal Adenocarcinoma (PDAC). This would aid in early detection and serve other purposes that 'liquid biopsies' are being explored in. Besides circulating tumor DNA (ctDNA) and methylation markers, glycosylation markers hold great potential promise. We developed a novel workflow using high-resolution quantification of site-specific protein glycosylation by liquid chromatography and tandem mass spectrometry to evaluate the clinical utility of glycoprotemics signature for patients with PDAC. Methods: Serum samples from newly diagnosed PDAC patients and controls were obtained from a commercial biobank (Indivumed, Hamburg, Germany), and a panel of 504 glycan motifs, representing 73 previously reported proteomic markers, was determined. Age-adjusted generalized linear regression models were used to evaluate the differential abundance of each marker, and stepwise variable selection was used for model construction. Results: We analyzed 45 PDAC and 136 control samples. PDAC patients (60% male) had a mean age of 67 (±11) years. with 4.4%, 71.1%, 4.4%, and 20% at stage 1, 2, 3,4, respectively. Controls were women with benign histology after pelvic mass surgery; with a mean age of 61 (±11) years. Twenty-six glycoproteomic markers showed statistically highly significant differential abundance among cases and controls (p<1e-4 each) and were highly reproducible(Pearson’s r > 0.85), which were glycoforms in proteins that have previously been found to be associated with PDAC. Fourteen of these markers displayed >0.8 area under the curve of the receiver operating characteristic (AUC). Multivariate logistic regression modeling with backward selection yielded a classification model with an AUC of 0.94 (95% CI: 0.89-0.99), sensitivity of 91% (95% CI: 75-97%) and specificity of 86% (95% CI: 81-92%). Conclusions: Circulating glycoproteomic biomarkers may be useful in the early detection and clinical management of PDAC patients; offering a new platform to explore and validate.