C Survival curves for the metastatic melanoma validation cohort 6, 7 of patients treated with anti-PD1 drugs with high (green) or low (orange) pre-treatment TIL/Tc clonality ( n = 106, cut-off = 0.10, log-rank P = 0.0039), D predictive effect of TIL/Tc clonality on the relative hazard of death in the same cohort (univariate Cox regression P = 0.0225). The blue curves represent the HR function and “Rug plots” on curves show the density of the predictor (univariate Cox regression P = 0.0193) pointwise 95% confidence bands (shadowed area) are also shown. Y-axis: log of relative hazard a hazard ratio (HR) of 1 corresponds to 0, upper values correspond to HR > 1, and lower values correspond to HR < 1. 1C, D).Ī Survival curves for our metastatic melanoma training cohort of patients treated with anti-PD1 drugs with high (green) or low (orange) pre-treatment TIL/Tc clonality ( n = 16, cut-off = 0.06, log-rank P = 0.0003), B predictive effect of TIL/Tc clonality on the relative hazard for death in the same cohort as A. Here again, better OS correlated with higher TIL/Tc TCR clonality ( P = 0.0225, external validation C-index = 0.582, 95% confidence interval = 0.501–0.664 Fig. We validated our findings using published data from 106 metastatic melanoma patients biopsied prior to treatment with PD1 or sequential PD1/CTLA4 blockade 6, 7. However, we did find better OS and reduced death hazard (Cox regression P = 0.0401, hazard ratio = 4.8 × 10 −14, C-index = 0.88) correlated to high TCR clonality in these pre-treatment tumor samples (Fig. We also did not find significant correlation between patient overall survival (OS) and baseline peripheral serum lactic dehydrogenase levels, total number of TIL/Tc, number of TIL/Tc clones, TCR diversity, the number of non-synonymous single-nucleotide variants (SNVs), or PD-L1 staining (Supplementary Table 1). 1a–d), suggesting that the lymph-node microenvironment did not affect tumor infiltration by T cells. There were no differences in total TIL/Tc numbers, the number of TIL/Tc clones, or the diversity and clonality of the TCR when comparing lymph-node tumors and tumors from extranodal sites (Supplementary Fig. To determine how the TCR repertoire of TIL/Tc influenced PD1 CPB outcome, we analyzed pre-treatment biopsies from 16 metastatic melanoma patients who received anti-PD1 agents in Manchester, Padova, and Meldola (Table 1). Pre-treatment TIL/Tc clonality is predictive for CPB benefit Here we examine whether the TCR repertoire metrics in tumor-infiltrating T lymphocytes (TIL/Tc) can also identify which patients will benefit from CPB prior to commencement of therapy. This approach therefore allows patient responses to be monitored using minimally invasive liquid biopsies early during treatment. We recently reported that immune checkpoint inhibition with PD1 CBP can increase the clonality or the diversity of the TCR in peripheral T cells after 3 weeks of treatment, and importantly this bifurcated reaction only occurs in patients who respond to treatment 5. The highly variable complementarity determining region 3 (CDR3) of the beta chain of the T cell receptor (TCR) is unique to individual T cell clones and can therefore be used to monitor the dynamics of T cell repertoire responses to CPB 4. The first biomarker strategies to emerge focused on the quantification of the tumor mutational burden and the expression of PD1 ligand (PD-L1) in the tumor microenvironment, but additional tools are needed to improve accuracy and the distinction between prognostic and predictive biomarkers 2, 3. Moreover, in the adjuvant setting, tools are needed to select patients at lower risk of disease recurrence who have been cured by surgery so that they can be spared the risk of CPB-associated toxicity. Unfortunately, the identification of the patients who will benefit from treatment remains an unmet need, so to refine patient care predictive biomarkers are required to identify metastatic patients with better chances of responding to CPB. Immunotherapy with programmed death 1 (PD1) checkpoint blockade (CPB) is increasingly utilized to treat solid tumors in the metastatic setting, where the response rate is 20–55% 1, and also as an adjuvant or neoadjuvant approach for locally advanced disease.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |