PD-1 Immune Checkpoint Inhibitors and Immune-Related Adverse Events

Davar, Diwakar; Kirkwood, John M.

doi:10.1001/jamaoncol.2019.0413

Cited by 32 publications

(17 citation statements)

References 16 publications

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“…The immune checkpoints CTLA-4 and the PD-1/PD-L1 axis have an important physiologic role in normal adaptive immunity to render lymphocytes unresponsive after activation. In melanoma and other cancers, these checkpoints may be inappropriately suppressed, and blocking these checkpoints allows an immune response directed against cancer cells . In a subset of individuals, blocking negative immune regulation also leads to an immune response targeting normal self-tissues and thus development of an irAE .…”

Section: Discussionsupporting

confidence: 85%

“…Immune checkpoint inhibitors (ICIs) have significantly transformed the treatment of advanced-stage melanoma and other cancers; however, a wide range of immune-related adverse events (irAEs) can result from treatment, especially those targeting self-tissues. 1,2 Notable irAEs after ICI therapy include colitis, hypothyroidism, hepatitis, pneumonitis, vitiligo, type 1 diabetes (the immunemediated form of diabetes), and hypophysitis (pituitary gland inflammation). 3 Previous studies have shown associations between the specific immune checkpoint receptor being targeted and the irAEs that develop.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

et al. 2022

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ImportanceTreatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)–DR alleles in conferring irAE risk has not been well studied.ObjectiveTo evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma.Design, Setting, and ParticipantsThis case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis.ExposuresImmune checkpoint inhibitors (anti–cytotoxic T-lymphocyte antigen 4, anti–programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma.Main Outcomes and MeasuresThe association between irAEs and response to therapy, survival, and HLA-DR alleles.ResultsAmong the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4.Conclusions and RelevanceThese findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

et al. 2022

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“…Immune checkpoint molecules have been demonstrated play important roles in anti-tumor T-cell activity (61)(62)(63). Immunotherapy can stimulate cell-mediated immunity to recognize and destroy cancer cells by modulating T-cell function and targeting relevant mechanisms of immune resistance, such as immune inhibitory molecules in the tumor microenvironment (64). Both inhibitory of checkpoints (CTLA-4 and PDCD1) commonly seen on activated T-cells have been found to be the most reliable targets for the treatment of cancer (65)(66)(67).…”

Section: Discussionmentioning

confidence: 99%

Development of an Oncogenic Driver Alteration Associated Immune-Related Prognostic Model for Stage I-II Lung Adenocarcinoma

Chen

Xie

et al. 2021

Front. Oncol.

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Lung adenocarcinoma (LUAD) needs to be stratified for its heterogeneity. Oncogenic driver alterations such as EGFR mutation, ALK translocation, ROS1 translocation, and BRAF mutation predict response to treatment for LUAD. Since oncogenic driver alterations may modulate immune response in tumor microenvironment that may influence prognosis in LUAD, the effects of EGFR, ALK, ROS1, and BRAF alterations on tumor microenvironment remain unclear. Immune-related prognostic model associated with oncogenic driver alterations is needed. In this study, we performed the Cox-proportional Hazards Analysis based on the L1-penalized (LASSO) Analysis to establish an immune-related prognostic model (IPM) in stage I-II LUAD patients, which was based on 3 immune-related genes (PDE4B, RIPK2, and IFITM1) significantly enriched in patients without EGFR, ALK, ROS1, and BRAF alterations in The Cancer Genome Atlas (TCGA) database. Then, patients were categorized into high-risk and low-risk groups individually according to the IPM defined risk score. The predicting ability of the IPM was validated in GSE31210 and GSE26939 downloaded from the Gene Expression Omnibus (GEO) database. High-risk was significantly associated with lower overall survival (OS) rates in 3 independent stage I-II LUAD cohorts (all P < 0.05). Moreover, the IPM defined risk independently predicted OS for patients in TCGA stage I-II LUAD cohort (P = 0.011). High-risk group had significantly higher proportions of macrophages M1 and activated mast cells but lower proportions of memory B cells, resting CD4 memory T cells and resting mast cells than low-risk group (all P < 0.05). In addition, the high-risk group had a significantly lower expression of CTLA-4, PDCD1, HAVCR2, and TIGIT than the low-risk group (all P < 0.05). In summary, we established a novel IPM that could provide new biomarkers for risk stratification of stage I-II LUAD patients.

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“…The recent development of treatments that disrupt the PD-1 and PD-L1 pathway, commonly referred to as immune checkpoint inhibitors, have fundamentally changed how patients with metastatic NSCLC are treated. These treatments are thought to stimulate cell-mediated immunity to recognize and destroy cancer cells and act by modulating T-cell function and targeting relevant mechanisms of immune resistance, such as immune inhibitory molecules in the tumor microenvironment . One such inhibitory ligand is PD-L1 and it is frequently expressed in NSCLC …”

Section: Immunotherapy In Nsclcmentioning

confidence: 99%

Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

Arbour

Riely

2019

JAMA

868

697

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IMPORTANCE Non-small cell lung cancer remains the leading cause of cancer death in the United States. Until the last decade, the 5-year overall survival rate for patients with metastatic non-small cell lung cancer was less than 5%. Improved understanding of the biology of lung cancer has resulted in the development of new biomarker-targeted therapies and led to improvements in overall survival for patients with advanced or metastatic disease.OBSERVATIONS Systemic therapy for metastatic non-small cell lung cancer is selected according to the presence of specific biomarkers. Therefore, all patients with metastatic non-small cell lung cancer should undergo molecular testing for relevant mutations and expression of the protein PD-L1 (programmed death ligand 1). Molecular alterations that predict response to treatment (eg, EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations) are present in approximately 30% of patients with non-small cell lung cancer. Targeted therapy for these alterations improves progression-free survival compared with cytotoxic chemotherapy. For example, somatic activating mutations in the EGFR gene are present in approximately 20% of patients with advanced non-small cell lung cancer. Tyrosine kinase inhibitors such as gefitinib, erlotinib, and afatinib improve progression-free survival in patients with susceptible EGFR mutations. In patients with overexpression of ALK protein, the response rate was significantly better with crizotinib (a tyrosine kinase inhibitor) than with the combination of pemetrexed and either cisplatin or carboplatin (platinum-based chemotherapy) (74% vs 45%, respectively; P < .001) and progression-free survival (median, 10.9 months vs 7.0 months; P < .001). Subsequent generations of tyrosine kinase inhibitors have improved these agents. For patients without biomarkers indicating susceptibility to specific targeted treatments, immune checkpoint inhibitor-containing regimens either as monotherapy or in combination with chemotherapy are superior vs chemotherapy alone. These advances in biomarker-directed therapy have led to improvements in overall survival. For example, the 5-year overall survival rate currently exceeds 25% among patients whose tumors have high PD-L1 expression (tumor proportion score of Ն50%) and 40% among patients with ALK-positive tumors.CONCLUSIONS AND RELEVANCE Improved understanding of the biology and molecular subtypes of non-small cell lung cancer have led to more biomarker-directed therapies for patients with metastatic disease. These biomarker-directed therapies and newer empirical treatment regimens have improved overall survival for patients with metastatic non-small cell lung cancer.

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PD-1 Immune Checkpoint Inhibitors and Immune-Related Adverse Events

Cited by 32 publications

References 16 publications

Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

Development of an Oncogenic Driver Alteration Associated Immune-Related Prognostic Model for Stage I-II Lung Adenocarcinoma

Systemic Therapy for Locally Advanced and Metastatic Non–Small Cell Lung Cancer

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