HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis

Abstract

Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/- bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.

Keywords: HLA-profile; PD-1/PD-L1 blockade; cancer immunotherapy; immune-related pneumonitis; irAEs.

Figure 1

Computed tomography (CT) scan imaging. Panel (A–C): 80-year-old male with metastatic non-small-cell lung cancer (mNSCLC) showing a classical cryptogenic organized pneumonia pattern. (A) Axial chest CT image obtained after 10 months of treatment with nivolumab showing multiple consolidations involving both lungs. (B) Axial follow-up CT-image obtained 1 month later showing an improvement of pneumonitis and the presence of ground-glass opacities. (C) Axial follow-up CT image obtained 11 months later showing pneumonitis resolution and the presence of bilateral fibrotic alteration. Panel (D–E): 70-six-year-old male with mNSCLC presenting a not otherwise specified pattern of pneumonitis. (D) Axial chest CT image obtained 2 months after the beginning of the treatment with nivolumab showing multiple consolidations, interlobular septal thickening, subpleural reticulations. (E) Axial chest CT image obtained 8 months later showing a complete resolution of the signs.

Figure 2

Rate of immune checkpoint inhibitor-related pneumonitis (IRP) in metastatic non-small-cell lung cancer (mNSCLC) patients. (A) Histograms relative to the rate of IRP in patients stratified for gender (considering the whole population including also histology different from NSCLC), tyrosine kinase inhibitor (TKI) therapy, and metronomic chemotherapy with fractioned cisplatin and oral etoposide (mPE)/metronomic chemotherapy with fractioned cisplatin and oral etoposide + bevacizumab (mPEBev) regimen prior to PD-1/PD-L1 immune checkpoint inhibitors. (B) Histograms relative to the rate of IRP in all of the evaluated patients compared in terms of positive expression of the HLA-B*35 allele alone, DRB1*11 allele alone, and both alleles.

Figure 3

Kaplan–Meyer curves. (A) Median progression-free survival (PFS) and (B) Overall survival (OS) of metastatic non-small-cell lung cancer (mNSCLC) patients under treatment with PD-1/PD-L1 immune checkpoint inhibitors who showed (continuous line) or not (dashed line) radiological signs of IRP. Curves show a not statistically significant trend of longer PFS and OS in patients who present IRP compared to the others, respectively (PFS; 13.8 (95% CI: 11.2–16.3) vs. 6.7 (95% CI: 5.3–8.1) months, P = 0.16. OS; 19.7 (95% CI: 16.0–23.3) vs. 12.6 (95% CI: 7.8–17.4) months; P = 0.50).