Nationwide Survival Benefit after Implementation of First-Line Immunotherapy for Patients with Advanced NSCLC—Real World Efficacy

SIMPLE SUMMARY: The expected change in overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) after the clinical implementation of immune checkpoint inhibitor therapy (ICI) has not been substantially investigated in large real-world cohorts outside randomized controlled trials (RCTs). In this nationwide study, we compared OS before and after the implementation of ICI and found that 3-year OS tripled from 6% to 18%. Patients receiving ICI had a lower OS than demonstrated in RCTs, except for patients with performance status (PS) 0. More than a fifth of the patients progressed early within the first six ICI cycles. Adverse prognostic factors were PS ≥ 1 and metastases to the bone and liver. ABSTRACT: Background The selection of patients with non-small cell lung cancer (NSCLC) for immune checkpoint inhibitor (ICI) treatment remains challenging. This real-world study aimed to compare the overall survival (OS) before and after the implementation of ICIs, to identify OS prognostic factors, and to assess treatment data in first-line (1L) ICI-treated patients without epidermal growth factor receptor mutation or anaplastic lymphoma kinase translocation. Methods Data from the Danish NSCLC population initiated with 1L palliative antineoplastic treatment from 1 January 2013 to 1 October 2018, were extracted from the Danish Lung Cancer Registry (DLCR). Long-term survival and median OS pre- and post-approval of 1L ICI were compared. From electronic health records, additional clinical and treatment data were obtained for ICI-treated patients from 1 March 2017 to 1 October 2018. Results The OS was significantly improved in the DLCR post-approval cohort (n = 2055) compared to the pre-approval cohort (n = 1658). The 3-year OS rates were 18% (95% CI 15.6–20.0) and 6% (95% CI 5.1–7.4), respectively. On multivariable Cox regression, bone (HR = 1.63) and liver metastases (HR = 1.47), performance status (PS) 1 (HR = 1.86), and PS ≥ 2 (HR = 2.19) were significantly associated with poor OS in ICI-treated patients. Conclusion OS significantly improved in patients with advanced NSCLC after ICI implementation in Denmark. In ICI-treated patients, PS ≥ 1, and bone and liver metastases were associated with a worse prognosis

Epstein-Barr virus peptide presented by HLA-E is predominantly recognized by CD8(bright) cells in multiple sclerosis patients.

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection, but impaired immune suppression may be part of the disease pathogenesis. CD8(+) T cells that are restricted by HLA-E exert an important immunoregulatory mechanism. To explore how EBV might interfere with immune regulation, we examined the expression of HLA-E and the frequency of CD8(+) cells recognizing HLA-E, presenting either an EBV peptide from the BZLF1 protein or a signal sequence peptide from HLA-A2, in relapsing remitting (MS-RR), primary progressive (MS-PP) MS patients, and healthy controls (HC). Treatment with IFN-α or EBV increased HLA-E expression on CD4(+) cells. However, only MS-PP had increased expression of HLA-E on resting CD4(+) cells when compared with HC (p<0.005). CD8(+) cells were divided into CD8(bright) and CD8(dim) cells by flow cytometry analyses. MS-RR had significantly fewer CD8(dim) cells than HC (p<0.003). Flow cytometry analyses were performed with HLA-E tetramers folded in the presence of the EBV or HLA-A2 peptide to identify HLA-E-interacting cells. MS-RR had increased frequency of CD8(bright) cells recognizing HLA-E/A2 (p=0.006) and HLA-E/BZLF1 (p=0.016). Conversely, MS-RR had fewer CD8(dim) cells that recognized HLA-E/BZLF1 (p=0.001), but this could be attributed to the overall lower number of CD8(dim) cells in MS-RR. Whereas HLA-E/A2 was predominantly recognized by CD8(dim) cells, HLA-E/BZLF1 was predominantly recognized by CD8(bright) cells in MS-RR and MS-PP, but not in HC. As expected, HLA-E/A2 was also recognized by CD8-negative cells in a CD94-dependent manner, whereas HLA-E/BZLF1 was poorly recognized in all groups by CD8-negative cells. These data demonstrate that MS-RR patients have expanded their CD8(bright) cells recognizing HLA-E/BZLF1. Moreover, HLA-E/BZLF1 appears to be recognized by the immune system in a different manner than HLA-E/A2

Increased frequency of cells recognizing HLA-E/BZLF1 by CD8^bright cells in a CD94-independent manner in MS-RR and MS-PP patients.

<p>Tetramer HLA-E/A2 binding to CD8 total (A), CD8^bright (C), and CD8^dim (E) and tetramer HLA-E/BZLF1 binding to CD8 total (B), CD8^bright (D), and CD8^dim (F) are all expressed as percentage binding within lymphogate. Binding is analysed in the presence or absence of anti-CD94 blocking antibody. Comparisons between presence and absence of anti-CD94 are done using paired T-test. Other comparisons are done using Mann-Whitney U-test. The symbols indicating different p values are: * p≤0.0001, ** p≤0.001, *** p≤0.005, **** p≤0.003, ***** p≤0.007, # p≤0.01, ## p≤0.02, ### p≤0.03, #### p≤0.04.</p

Decreased binding of HLA-E/BZLF1 to CD8-negative cells in MS-RR patients.

<p>Tetramer binding of HLA-E/A2 (A) and HLA-E/BZLF1 (B) to CD8-negative cells is shown in percentage of lymphocytes (lymphogate). Binding is analysed in the presence or absence of anti-CD94 blocking antibody. Comparisons between presence and absence of anti-CD94 are done using paired T-test. Other comparisons are done using Mann-Whitney U-test. The symbols indicating different p values are: * p≤0.0001, ** p≤0.0008, *** p≤0.0017, **** p≤0.048.</p