Avid Bioservices Inc (CDMO)

[hutschi]

T-cell invigoration to tumour burden ratio associated with anti-PD-1 response.

Huang AC1,2,3,4, Postow MA5,6, Orlowski RJ1,2,3,4, Mick R3,4,7, Bengsch B2,4,8, Manne S2,8, Xu W1,3, Harmon S1,3, Giles JR2,4,8, Wenz B1,3, Adamow M9, Kuk D10, Panageas KS10, Carrera C5,11, Wong P9,12, Quagliarello F2,8, Wubbenhorst B1,3, D'Andrea K1,3, Pauken KE2,8, Herati RS1,2,3, Staupe RP2,8, Schenkel JM13, McGettigan S1,3, Kothari S1, George SM2,4,8, Vonderheide RH1,2,3,4, Amaravadi RK1,3, Karakousis GC3,14, Schuchter LM1,3, Xu X3,15, Nathanson KL1,3,4, Wolchok JD5,12, Gangadhar TC1,3, Wherry EJ2,3,4,8.

Author information

Abstract

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.


https://www.ncbi.nlm.nih.gov/pubmed/28397821