Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients
2.2. Assessments
2.3. PD-L1 Staining
2.4. Isolation of PBMCs
2.5. In Vitro Assay
2.6. Flow Cytometric Analyses
2.7. Immunofluorescence Staining
3. Results
3.1. Disorder of Coagulation-Fibrinolysis System Triggered by Immune Checkpoint Blockade in Advanced Lung Cancer
3.2. Association of Coagulation-Fibrinolysis System Disorders with the Efficacy of Anti-PD-1/PD-L1 Monoclonal Antibody Therapies in NSCLC
3.3. T Cell Activation Induce Tissue Factor Expression on PD-L1-Positive Monocytes
4. Discussion
4.1. Link between PD-L1 Expression on Tumor Cells and Efficacy of ICIs and Disorders of Coagulation-Fibrinolysis System Triggered by ICIs
4.2. Underlying Mechanisms of Disorders of the Coagulation-Fibrinolysis System as an irAE
4.3. Targeting PD-1/PD-L1 Signaling: A Double-Edged Sword in Cancer
4.4. Limitation
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Patient | Age/Gender | Coagulation-fibrinolysis System AE | Hemorrhagic Complication | CTCAE Grade | Therapeutic Antibody/Treatment Line | Onset (Cycle) | Histopathology/Clinical Stage | PD-L1 Expression | Tumor Response | Reference |
---|---|---|---|---|---|---|---|---|---|---|
1 | 60/F | ACS | 3 | Nivolumab/2 | 2 | Adeno/IVB | NE | PR | Ferreira et al. [22] | |
2 | 61/M | ACS, Cerebral lacunar infarction | 3, 1 | Nivolumab/3 | 11 | Adeno/IVB | ≥75% | CR | Tomita et al. [14] | |
3 | 63/M | Multiple cerebral infarcts, Intracranial hemorrhage | + | 3, 5 | Pembrolizumab/1 | 1 | Adeno/IVB | ≥75% | SD | Horio et al., [13] |
4 | 72/M | Multiple cerebral infarcts | 1 | Atezolizumab/3 | 1 | Sq/IIIA recurrence | ≥50% | NE | ||
5 | 71/M | Gastrointestinal bleeding, Multiple cerebral infarcts | + | 2, 1 | Pembrolizumab/1 | 1, 6 | Adeno/IVB | ≥75% | CR | |
6 | 67/M | Cerebral microbleed and lacunar infarction | + | 1 | Pembrolizumab/1 | 12 | Sq/IVB | 80% | PR | |
7 | 48/F | DVT, PTE | 2, 3 | Pembrolizumab/1 | 1 | Adeno/IVB | ≥90% | PR | Kunimasa et al. [29] | |
8 | 76/M | Purpura, DVT | + | 2, 2 | Nivolumab/4 | 1, 2 | Adeno (EGFRm)/IVB | 20–30% | PD | |
9 | 68/F | DVT, Bronchial hemorrhage | + | 2, 2 | Nivolumab/3 | 1, 4 | Adeno/IVB | 1–24% | PR | |
10 | 81/M | Bronchial hemorrhage | + | 2 | Nivolumab/3 | 16 | Sq/IVB | ≥75% | PR | |
11 | 74/M | Purpura | + | 2 | Pembrolizumab/1 | 4 | Adeno/IVB | 80% | PR | |
12 | 79/M | Gastrointestinal bleeding | + | 2 | Pembrolizumab/1 | 1 | Sq/IIIB recurrence | 50–75% | SD |
Patient | Age/Gender | Coagulation-Fibrinolysis System AE during ICI Therapy | Hemorrhagic Complication | Use of Anticoagulants or Antiplatelet Agents | Past Medical History of Diseases Associated with Disorders of Coagulation-Fibrinolysis System | Reference |
---|---|---|---|---|---|---|
1 | 60/F | ACS | none | none | Ferreira et al. [22] | |
2 | 61/M | ACS, Cerebral lacunar infarction | none | none | Tomita et al. [14] | |
3 | 63/M | Multiple cerebral infarcts, Intracranial hemorrhage | + | none | none | Horio et al. [13] |
4 | 72/M | Multiple cerebral infarcts | none | none | ||
5 | 71/M | Gastrointestinal bleeding, Multiple cerebral infarcts | + | Aspirin, Clopidogrel | Coronary stenosis | |
6 | 67/M | Cerebral microbleed and lacunar infarction | + | none | Cerebral bleed | |
7 | 48/F | DVT, PTE | none | none | Kunimasa et al. [29] | |
8 | 76/M | Purpura, DVT | + | none | none | |
9 | 68/F | DVT, Bronchial hemorrhage | + | none | none | |
10 | 81/M | Bronchial hemorrhage | + | Aspirin, Dipyridamole | Myocardial infarction | |
11 | 74/M | Purpura | + | none | none | |
12 | 79/M | Gastrointestinal bleeding | + | Cilostazol, Clopidogrel | Cerebral infarction |
Study [Reference] | No. of Patients Who Received ICI | Phase | Histology | Treatment | AEs Associated with Disorders of Coagulation-Fibrinolysis System | No. of Patients (%) |
---|---|---|---|---|---|---|
CheckMate017 [40] | 135 | III | Sq | Nivolumab | Not reported * | |
CheckMate057 [44] | 292 | III | NonSq NSCLC | Nivolumab | Hemoptysis | 16 (6%) |
Pulmonary embolism | 1 (<1%) | |||||
Cerebrovascular accident | 1 (<1%) | |||||
KEYNOTE010 [41] | 690 | II/III | NSCLC | Pembrolizumab | Not reported * | |
KEYNOTE024 [33] | 154 | III | NSCLC | Pembrolizumab | Not reported | |
OAK [43] | 425 | III | NSCLC | Atezolizumab | Not reported * | |
POPLAR [42] | 144 | II | NSCLC | Atezolizumab | Not reported * |
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Sato, R.; Imamura, K.; Sakata, S.; Ikeda, T.; Horio, Y.; Iyama, S.; Akaike, K.; Hamada, S.; Jodai, T.; Nakashima, K.; et al. Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies. J. Clin. Med. 2019, 8, 762. https://doi.org/10.3390/jcm8060762
Sato R, Imamura K, Sakata S, Ikeda T, Horio Y, Iyama S, Akaike K, Hamada S, Jodai T, Nakashima K, et al. Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies. Journal of Clinical Medicine. 2019; 8(6):762. https://doi.org/10.3390/jcm8060762
Chicago/Turabian StyleSato, Ryo, Kosuke Imamura, Shinya Sakata, Tokunori Ikeda, Yuko Horio, Shinji Iyama, Kimitaka Akaike, Shohei Hamada, Takayuki Jodai, Kei Nakashima, and et al. 2019. "Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies" Journal of Clinical Medicine 8, no. 6: 762. https://doi.org/10.3390/jcm8060762