Abstract 1126P
Background
Resistance to immune checkpoint inhibitors (ICIs) is still far from understood. Identifying clinical useful biomarkers might improve drug selection and patients’ therapy.
Methods
We analyzed the soluble immune checkpoints sPD1, sPDL1, sLAG3 and sTIM3 using ELISA in paired serum samples of 90 ICI treated melanoma patients before and 6 weeks after start of anti-PD1 +/- ipilimumab. FACS analysis on circulating T cells was performed in 48 of these patients. In a partially overlapping cohort of 76 patients, pre-treatment biopsies from melanoma metastases were stained for TIM3 and LAG3 by immunohistochemistry. Results were correlated with clinical parameters using univariate and multivariate regression analyses.
Results
Resistance to anti-PD1 treatment (n=48) was associated with high levels of sLAG3 (DCR: p=0.009; PFS: p=0.018; ROC cut off > 148 pg/mL) in pre-treatment serum samples but not sPD1, sPDL1 or sTIM3. In contrast, resistance to ipilimumab plus nivolumab (n=42) was associated with high sPD1 levels (DCR: p=0.019, PFS: p=0.046; ROC cut off > 167 pg/mL) but not sPDL1, sLAG3 or sTIM3. Both treatment regimens shared a profound increase of sPD1 serum levels with treatment (p=0.000). FACS analysis of the T cell subsets revealed reduced frequencies of CD3+CD8+PD1+ T cells (p=0.036) in PD1-resistant patients whereas, increased frequencies of CD3+CD4+LAG3+ T cells characterized patients resistant to ipilimumab plus nivolumab (p=0.034). Unlike anti-PD1 monotherapy, combination blockade significantly increased proliferating T cells (CD3+CD8+Ki67+ T cells; p=0.000) and eosinophils (p=0.02) in the peripheral blood. Interestingly, the concentration of sPD1 inversely correlated with lymphocyte counts and the frequency of PD1+ T cells, and positively correlated with the frequency of TIM3+ and LAG3+ T cells. In melanoma metastases, an increased infiltration with TIM3+ or LAG3+ T cells in the tumor microenvironment correlated with a shorter PFS to anti-PD1 (TIM3: p=0.024, LAG3: p=0.027).
Conclusions
Different soluble immune checkpoints characterized checkpoint inhibitor resistant melanoma. Measuring these serum markers is easy and has the potential to be used in clinical routine.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors (JC Hassel).
Funding
BMS.
Disclosure
J.C. Hassel: Advisory/Consultancy: MSD, Pierre Fabre, Sunpharma; Honoraria (self): BMS, MSD, Novartis, Roche; Honoraria (institution): BMS, Novartis; Research grant/Funding (institution): BMS; Travel/Accommodation/Expenses: BMS, Pierre Fabre. All other authors have declared no conflicts of interest.