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

By Alexander C. Huang, M. Postow, R. Orlowski, R. Mick, Bertram Bengsch, Sasikanth Manne, Wei Xu, Shannon Harmon, Josephine R. Giles, Brandon M. Wenz and 24 more. Nature, 2017

1,506 citations recorded by the source corpus.

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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/02de24e31a93c9d40769251e100968e838e5d46f

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Citations in the corpus

Distinct cellular mechanisms underlie anti-CTLA-4 and anti-PD-1 checkpoint blockade (2017, positive): “Previous studies have demonstrated that PD-1 receptor occupancy by anti-PD-1 antibody can persist for months following therapy, despite a serum half-life of 2 to 3weeks of the antibody itself(Brahmer et al., 2010; Huang et al., 2017).”
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade–based immunotherapy (2018, neutral): “Additional IHC assays have been developed that measure protein markers of a cytolytic T cell environment, and evaluating their performance characteristics in conjunction with TMB in future studies may be useful (14, 35).”
Organoid modeling of the tumor immune microenvironment (2018, background): “organoid cells (including tumor epithelium) (Figure 6B), paralleling CD8 TIL expansion by anti-PD-1 within MC38 and B16 tumors in vivo and in patient peripheral blood (Huang et al., 2017; Kamphorst et al., 2017; Wei et al., 2017).”
Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms (2020, background): “Because Texint cells also convert to Texterm, these data also predict a potential replacement of Texterm in tumors with new Texint converting to Texterm cells after PD-1 blockade consistent with accumulation of Eomeshi Tex cells after blockade or loss of PD-1 (Huang et al., 2017; Odorizzi et al., 20”
Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications (2020, methodology): “To quantify these interpatient changes, we used a previously described dataset (46) to define the stability of populations of interest in healthy individuals over time.”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “These data are also consistent with a single, transient peak of T cell (re)invigoration in human melanoma patients treated with PD-1 blockade (26), suggesting that in the absence of epigenetic changes, the effects of reinvigoration by checkpoint blockade may not be durable at the cellular level.”