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Sally Chui Mei Lau
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P14 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Immuno-Biology (ID 153)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P14.09 - Early Expansion of M-MDSCs and High Plasma TSLP levels as Predictors of Primary Resistance to PD1 Inhibitors in Metastatic NSCLC (ID 1866)
00:00 - 00:00 | Presenting Author(s): Sally Chui Mei Lau
- Abstract
Introduction
Elevation of peripheral myeloid cell populations has been associated with poor response to PD-1 inhibitors in metastatic non-small cell lung cancer (mNSCLC). The mechanisms underlying this relationship remain poorly understood. Thymic stromal lymphopoietin (TSLP), a cytokine involved in T-cell maturation, has been implicated in a complex feedback loop leading to expansion of myeloid populations and tumor growth. We hypothesized that TSLP levels directly correlate with the expansion of myeloid derived suppressor cell (MDSC) populations and sought to explore their association with response to PD-1 inhibitors in mNSCLC.
Methods
mNSCLC patients treated with PD-1 inhibitors underwent baseline and serial blood collection. Patients who received combination therapy with CTLA-4 inhibitors or chemotherapy were excluded from this analysis. Peripheral blood mononuclear cells (PBMCs) were analyzed by high-dimensional flow cytometry using validated panels to evaluate T/B/NK-cell, Treg and myeloid populations. Plasma cytokines including TSLP were analyzed using ELISA and Luminex assays. Cox and logistic regressions were utilized to correlate biomarkers with progression-free survival (PFS), overall survival (OS) and radiographic response.
Results
30 mNSCLC patients treated with single-agent PD-1 inhibitors were included in the analysis. Higher pre-treatment TSLP levels were significantly associated with a 2-fold increase of monocytic(M)-MDSCs (CD33+/HLA-DR-/CD14+) in response to ICI treatment (p=0.02). M-MDSC frequency after a median of 20 days (IQR 17-24 days) of ICI treatment was significantly associated with progressive disease (PD), shorter PFS and OS (all p<0.05) in the entire cohort including the subset of patients with PD-L1 expression ≥50% (n=24). No correlation was seen with baseline M-MDSC frequency. However, patients with a doubling of M-MDSCs (n=11) after treatment had a primary PD rate of 64% vs 24% (OR 7.0, p=0.04), significantly worse median PFS (2.5 vs 7.8 months; HR 2.6; p=0.04) (Figure 1) and a trend to worse median OS (7.7months vs NR; HR 3.7; p=0.08). Even after adjusting for PD-L1 expression, a doubling of M-MDSCs remained an independent predictor of poor PFS (multivariate HR 2.5; 95%CI 1.01-6.44; p=0.05). RNAseq of FACS-sorted myeloid populations is in progress.
Conclusion
Early expansion of circulating M-MDSCs after treatment with PD-1 inhibitors is associated with elevated baseline TSLP levels and primary disease progression in mNSCLC. These findings suggest that elevated TSLP and early expansion of myeloid populations may represent an important mechanism of primary resistance to PD-1 inhibitors in mNSCLC.
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P14.24 - Evolution of TCR Clonality during Chemoradiation and Durvalumab as Predictors of Survival in Stage 3 NSCLC (ID 1955)
00:00 - 00:00 | Presenting Author(s): Sally Chui Mei Lau
- Abstract
Introduction
Novel blood-based biomarkers evaluating T-cell receptor (TCR) clonality and the frequency/activation of immune populations hold significant potential for predicting the immune response in stage 3 NSCLC treated with durvalumab. TCR repertoire analysis includes characterization using diversity indices and quantification of individual clones. We hypothesized that low TCR clonality on treatment signals the lack of expansion of functional tumor-specific clones and predicts for worse outcomes. In this study, we characterized the evolution of TCR clonality on CRT and durvalumab and its correlation with response and survival.
Methods
Stage 3 NSCLC patients undergoing chemoradiation (CRT) and maintenance durvalumab were recruited prospectively to undergo serial blood collections at baseline and pre- and post- durvalumab. TCR repertoire analysis (capTCRseq) was performed on cfDNA using hybrid-capture TCR sequencing and TCR diversity/clonality was estimated using the Shannon’s and Simpson’s entropy index. Correlations between TCR clonality, response and PFS were examined using logistic and cox regressions.
Results
Among 73 stage 3 NSCLC patients prospectively recruited to study, a pilot group of 22 patients who had completed induction CRT was analyzed for clonal TCR changes on treatment. In total, 17 received consolidation durvalumab, with best response of CR/PR in 7(41%) SD in 8(47%) and PD in 2 (12%). The median PFS from the start of durvalumab is 12.0 months (3.3-NR) and 53% of patients had progressed at the time of analysis. Baseline TCR clonality was not associated with response to CRT or durvalumab. However, lower TCR clonality measured pre-durvalumab trended with lower response (OR 0.82, p=0.09). Lower TCR clonality pre-durvalumab also trended with worse PFS (HR 1.16 P=0.10). Importantly, a decrease in TCR clonality compared to baseline, signaling the lack of clonal expansion on treatment, is significantly associated with a worse PFS (p=0.05). In patients whose TCR clonality decreased by 50% after CRT, the median PFS was 1.7 vs 12.0 months (HR 3.5, p=0.14) (Figure A). Clonal tracking, flow cytometry and measurement of minimal residual disease (CAPPseq) is in progress.
Conclusion
A decrease in TCR clonality on CRT is associated with poor PFS on consolidation durvalumab. TCR clonality may be a potential biomarker that can select for patients likely to benefit from durvalumab. Further characterization of TCR clonality, clonal tracking with treatment, percentage of shared tumor TCR clones is ongoing in the larger cohort.
