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• W3036768055 abstract "Background Checkpoint inhibitor (CPI) monotherapies, including pembrolizumab (KEYTRUDA®, pembro), avelumab and atezolizumab have demonstrated modest clinical benefit in chemotherapy-relapsed/refractory TNBC patients (pts) with ~5-10% response rate, median overall survival (mOS) of 7-9 months, and 1 year OS ~37-40%. TNBC, although more immunogenic relative to the other breast cancer subtypes, is also the most heterogenous, resulting in substantial variability in immune responses. There is a dire need for immunotherapeutic agents that could consistently induce anti-cancer immune responses. Methods The primary analyses of our Phase 2 study ( NCT02981303 ; collaboration with Merck & Co., Inc.) in 44 (intent-to-treat) chemotherapy-refractory/relapsed TNBC pts treated with Imprime PGG (Imprime), a novel yeast derived, Dectin-1 agonist β-glucan PAMP in combination with pembro has shown enhanced disease control rate (25%, N= 11;1 CR, 6 PR and 4 SD>24 weeks), 12-month OS rate (57.3%) and increased mOS (16.6 months) vs the respective endpoints in Keynote086 pts treated with pembro alone. As part of exploratory translational objectives, peripheral blood from pts receiving the combination in 3-week cycles were collected at various time points. Results from serum and cellular immunopharacodynamic (IPD) evaluations from 41 pts are presented. Results Peak levels of serum circulating immune complexes (~3 to 22-fold) and complement protein SC5b-9 (~1.4 to 41-fold) in stage 1 pts provided evidence for Imprime-anti beta glucan antibody immune complex formation. A significant increase in the frequency of HLA-DR+ myeloid cells was observed in the overall population (up to 7.4-fold). In pts showing disease control (N=11), a significant increase in complement function (CH50, ~0.8-4 fold range), select chemokines such as MCP-1 production (up to 1000-fold), CD86 expression on monocyte (~0.5-6-fold) and DC subsets (~0.8-11-fold), and increased frequency of Ki-67+, HLA-DR/PD-1+ CD8 T cells (~0.4-14-fold) was observed. Some IPD responses were associated with the 12-month landmark OS analyses. Additionally, enhanced mPFS (HR 0.51; p=0.03) and mOS (HR 0.13; p=0.0013) was observed in 18 pts with >1.25-fold increase in CD86 expression on classical monocytes. Greater than 2-fold increase in the frequency of Ki-67+, HLA-DR/PD-1+ CD8 T cells in 16 pts was also associated with enhanced mPFS (HR 0.395; p=0.01) and mOS (HR 0.183; p=0.008). Additionally, the gene expression profile of these IPD-responders were similar to the RECIST responders with >2-fold upregulation of several genes including IFNg, CD83, GZMA, GZMK, and CD3. Conclusions Overall, the strong association of the innate/adaptive IPD responses to the clinical responses are suggestive of interplay between the therapeutic mechanisms of Imprime and pembro combination. Ethics Approval The study was approved by central and local ethics committees depending on site requirements. The central IRB for the study is Western Institutional Review Board (WIRB), approval number 20162506; all sites received IRB approval before opening the study at the respective sites." @default.
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• W3036768055 date "2020-04-01" @default.
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• W3036768055 title "P859 Association of immunopharmacodynamic responses of imprime PGG plus pembrolizumab with clinical benefit in metastatic triple negative breast cancer (TNBC) subjects failing front-line chemotherapy" @default.
• W3036768055 doi "https://doi.org/10.1136/lba2019.13" @default.
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