Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma
Abstract
:Simple Summary
Abstract
1. Background
2. Material and Methods
2.1. Patients and Treatment
2.2. Disease Characteristics and Response Assessment
2.3. Sample Collection and Processing
2.4. Plasma Cytokine Analysis
2.5. Statistical Analysis
3. Results
3.1. Patient Characteristics
3.2. Baseline Cytokine Profile Does Not Predict Response to Checkpoint Inhibitors
3.3. Checkpoint Inhibitor Treatment Induces an Inflammatory Cytokine Profile Distinct from Baseline and Healthy Donors
3.4. On-Treatment Cytokine Profile Predicts Response to Checkpoint Inhibitors
3.5. High PD-1 Increment Predicts Response to Nivolumab plus Ipilimumab
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
OS | Overall survival |
PFS | Progression-free survival |
HR | Hazard ratio |
CI | Confidence interval |
Pembro | Pembrolizumab |
Nivo/ipi | Nivolumab plus ipilimumab |
MM | Malignant melanoma |
ECOG | Eastern Cooperative Oncology Group |
U/L | Units/liter |
LHD | Lactate dehydrogenase |
CRP | C-reactive protein |
PD-L1 | Programmed death ligand 1 |
EDTA | Ethylenediaminetetraacetic acid |
IFN | Interferon |
IL | Interleukin |
CXCL10 | C-X-C motif chemokine ligand 10 |
CCL20 | Chemokine (C-C-motif) ligand 20 |
TNF | Tumor Necrosis factor |
MCP | Monocyte Chemoattractant Protein 1 |
PD-1 | Programmed cell death protein 1 |
CTLA-4 | Cytotoxic T-lymphocyte-associated protein 4 |
UMAP | Uniform Manifold Approximation and Projection |
CD8 | Cluster of differentiation 8 |
TGF-β | Transforming growth factor β |
PET/CT | Position emission tomography/computed tomography |
MRI | Magnetic resonance imaging |
NSCLC | Non-small cell lung cancer |
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Parameter | Pembrolizumab (anti-PD1) | Nivolumab/Ipilimumab (anti-PD1/CTLA-4) | p |
---|---|---|---|
Total | 29 | 48 | |
Age, year mean (range) | 68 (31–89) | 60 (30–85) | |
Sex, n (%) - Male - Female | 18 (62) 11 (38) | 29 (60.4) 19 (39.6) | 0.89 |
AJCC stage, n (%) - Stage III - Stage IV | 3 (10.3) 26 (89.7) | 5 (10.4) 43 (89.6) | 0.99 |
BRAF status, n (%) - Wild type - Mutated | 16 (55.2) 13 (44.8) | 26 (54.2) 22 (45.8) | 0.93 |
Tumor PD-L1 expression, n (%) - < 1% - ≥ 1% - N/A | 4 (13.8) 22 (75.9) 3 (10.3) | 43 (89.6) 2 (4.2) 3 (6.2) | <0.0001 |
Serum LDH, n (%) - Normal - Elevated - N/A | 21 (72.4) 6 (20.7) 2 (6.9) | 32 (66.7) 14 (29.2) 2 (4.1) | 0.65 |
Progression, n (%) - No - Yes | 9 (31) 20 (69) | 18 (37.5) 30 (62.5) | 0.56 |
Alive, n (%) - No - Yes | 13 (44.8) 16 (55.2) | 24 (50) 24 (50) | 0.81 |
Parameters | PFS | |
---|---|---|
Hazard Ratio (95% Confidence Interval) | p | |
Univariate Cox regression analysis | ||
Age | 1 (0.97–1.03) | 0.92 |
Gender (Female vs male) | 1.13 (0.54–2.48) | 0.75 |
LDH (normal vs elevated) | 0.56 (0.24–1.32) | 0.18 |
Performance status (ECOG) (0 vs 1 or 2) | 2.19 (1.06–4.53) | 0.034 |
PD-1 fold change (above vs below median) | 0.35 (0.16–0.77) | 0.0086 |
CXCL10 fold change (above vs below median) | 1.15 (0.55–2.41) | 0.71 |
TNFα fold change (above vs below median) | 1.09 (0.52–2.29) | 0.82 |
PD-L1 fold change (above vs below median) | 1.27 (0.60–2.66) | 0.53 |
IFNγ fold change (above vs below median) | 0.98 (0.47–2.07) | 0.97 |
IL10 fold change (above vs below median) | 0.94 (0.45–1.98) | 0.87 |
Multivariable Cox regression analysis | ||
Age | 0.98 (0.95–1.026) | 0.49 |
Gender (Female vs male) | 1.042 (0.43–2.5) | 0.93 |
LDH (normal vs elevated) | 0.16 (0.041–0.64) | 0.0096 |
Performance status (ECOG) (0 vs 1 or 2) | 2.41 (0.81–7.19) | 0.12 |
PD-1 fold change (above vs below median) | 0.13 (0.0034–0.49) | 0.0026 |
CXCL10 fold change (above vs below median) | 2.43 (0.68–8.71) | 0.17 |
TNFα fold change (above vs below median) | 0.81 (0.18–3.69) | 0.79 |
PD-L1 fold change (above vs below median) | 0.46 (0.14–1.5) | 0.20 |
IFNγ fold change (above vs below median) | 1.42 (0.53–3.82) | 0.48 |
IL10 fold change (above vs below median) | 2.095 (0.51–8.53) | 0.30 |
Parameters | PFS | |
---|---|---|
Hazard Ratio (95% Confidence Interval) | p | |
Univariate Cox regression analysis | ||
Age | 1 (0.97–1.28) | 0.89 |
Gender (Female vs male) | 1.84 (0.71–4.80) | 0.21 |
LDH (normal vs elevated) | 2.17 (0.77–6.079) | 0.14 |
Performance status (ECOG) (0 vs 1 or 2) | 1.72 (0.69–4.31) | 0.24 |
IFNγ fold change (above vs below median) | 1.74 (0.69–4.34) | 0.24 |
CXCL5 fold change (above vs below median) | 0.64 (0.26–1.6) | 0.34 |
IL6 fold change (above vs below median) | 0.64 (0.26–1.6) | 0.34 |
Multivariable Cox regression analysis | ||
Age | 0.99 (0.95–1.024) | 0.47 |
Gender (Female vs male) | 2.21 (0.67–7.24) | 0.19 |
LDH (normal vs elevated) | 1.74 (0.50–6.052) | 0.38 |
Performance status (ECOG) (0 vs 1 or 2) | 0.91 (0.3–2.81) | 0.87 |
IFNγ fold change (above vs below median) | 1.91 (0.45–8.032) | 0.38 |
CXCL5 fold change (above vs below median) | 0.8 (0.23–2.75) | 0.72 |
IL6 fold change (above vs below median) | 0.66 (0.21–2.067) | 0.48 |
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Pedersen, J.G.; Sokac, M.; Sørensen, B.S.; Luczak, A.A.; Aggerholm-Pedersen, N.; Birkbak, N.J.; Øllegaard, T.H.; Jakobsen, M.R. Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma. Cancers 2022, 14, 3342. https://doi.org/10.3390/cancers14143342
Pedersen JG, Sokac M, Sørensen BS, Luczak AA, Aggerholm-Pedersen N, Birkbak NJ, Øllegaard TH, Jakobsen MR. Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma. Cancers. 2022; 14(14):3342. https://doi.org/10.3390/cancers14143342
Chicago/Turabian StylePedersen, Jesper Geert, Mateo Sokac, Boe Sandahl Sørensen, Adam Andrzej Luczak, Ninna Aggerholm-Pedersen, Nicolai Juul Birkbak, Trine Heide Øllegaard, and Martin Roelsgaard Jakobsen. 2022. "Increased Soluble PD-1 Predicts Response to Nivolumab plus Ipilimumab in Melanoma" Cancers 14, no. 14: 3342. https://doi.org/10.3390/cancers14143342