Peripheral immunological response to treatment with a novel bifunctional anti-PD-L1/TGFβRII agent in recurrent/metastatic nasopharyngeal carcinoma.

person Ngar Woon Kam Laboratory for Synthetic Chemistry and Chemical Biology, InnoHK, Hong Kong, China info_outline Ngar Woon Kam, Jeffrey Yan Ho Lau, Wei Dai, Chi Leung Chiang, Chi Ming Che, Victor Ho-Fun Lee, Dora Lai Wan Kwong

Authors person Ngar Woon Kam Laboratory for Synthetic Chemistry and Chemical Biology, InnoHK, Hong Kong, China info_outline Ngar Woon Kam, Jeffrey Yan Ho Lau, Wei Dai, Chi Leung Chiang, Chi Ming Che, Victor Ho-Fun Lee, Dora Lai Wan Kwong Organizations Laboratory for Synthetic Chemistry and Chemical Biology, InnoHK, Hong Kong, China, The University of Hong Kong, Hong Kong, NA, Hong Kong, Department of Clinical Oncology, University of Hong Kong, Hongkong, China, Hongkong, Hong Kong, Department of Clinical Oncology, The University of Hong Kong, Hong Kong, Hong Kong, Laboratory of Synthetic Chemistry and Chemical Biology Limited, Hong Kong, NA, Hong Kong, The University of Hong Kong, Hong Kong, Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong Abstract Disclosures Research Funding Other Health and Medical Research Fund Background: Anti-programmed cell death protein-ligand 1 (PD-L1) monotherapy has not shown promising anti-tumor effects in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) in first-line settings. Consequently, second-generation checkpoint inhibitors via targeting multiple pathways are urgently needed. Bintrafusp alfa (also known as M7824) is one of such agents that targets both the transforming-growth factor beta (TGF-β) and PD-L1 pathways. As T cells are the major immune cell subset responsible for tumor destruction, we focus on the peripheral memory T-cell subsets. Through the evaluation of peripheral biomarker analysis and their correlation with clinical outcomes, we have characterized blood-based dynamic phenotypes that predict responses to M7824 in NPC. Methods: Biomarker analysis was performed as part of a phase II clinical trial (NCT04396886) in patients with treatment-refractory histologically confirmed recurrent NPC (n=32) who received M7824. Peripheral blood samples were obtained at baseline before treatment (D0) and every 2 weeks during treatment. Samples collected at D0 and at time of best response assessment (DR) were analysed using multicolor flow cytometry. Patients with complete/partial response or stable disease for at least 6 months were considered responders (R), those with stable disease less than 6 months or progressive disease were considered non-responders (NR). Results: Peripheral T cells between R (n=10) and NR (n=22) patients were compared. While the overall percentage of memory T-cell subsets was similar in both groups after treatment, R patients displayed a significantly lower amount of prototype cell death receptor, CD95, among terminally differentiated effector memory (TEMRA; CD45RA + CD62L + ) T cells (CD45 + CD3 + and CD45 + CD3 + CD4 + : p<0.0001; CD45 + CD3 + CD8 + : p=0.0047) (CD95 DR /RvsNR) as compared to patient in NR group. Besides, reduced expression of CD95 DR on TEMRA CD4 T cells was significantly associated with longer overall survival (OS), regardless of response status (median OS: 16.26 months for patients with lower CD95 levels; median OS: 5.29 months for patients with higher CD95 levels [p < 0.0001]). Notably, we noticed that R patients displayed a lower frequency of CD95-expressing TEMRA at the baseline (CD95 D0 /Rvs NR) as compared to NR group. Conclusions: The apoptotic response of peripheral blood TEMRA CD4 T cells (CD95 DR /R vsNR) may be a useful surrogate biomarker for predicting prognosis to M7824 therapy in NPC. The finding of a lower frequency of CD95 D0 TEMRA in R patients suggesting that CD95 may potentially act as a biomarker for predicting treatment response as well as reveal a possible target for guiding therapeutic strategy for R/M NPC. Percentage of CD95 + TEMRA. Subsets Response groups Median of cell number (%) CD3 + NR 9.53 R 4.61 CD3 + CD4 + NR 10.2 R 7.10 CD3 + CD8 + NR 3.21 R 0.985

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