抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

https://science.sciencemag.org/content/sci/early/2004/04/29/science.1099314.full.pdf

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

BackgroundNivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, disrupts PD-1–mediated signaling and may restore antitumor immunity. MethodsIn this randomized, open-label, international phase 3 study, we assigned patients with nonsquamous non–small-cell lung cancer (NSCLC) that had progressed during or after platinum-based doublet chemotherapy to receive nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks or docetaxel at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsOverall survival was longer with nivolumab than with docetaxel. The median overall survival was 12.2 months (95% confidence interval [CI], 9.7 to 15.0) among 292 patients in the nivolumab group and 9.4 months (95% CI, 8.1 to 10.7) among 290 patients in the docetaxel group (hazard ratio for death, 0.73; 96% CI, 0.59 to 0.89; P=0.002). At 1 year, the overall survival rate was 51% (95% CI, 45 to 56) with nivolumab ve...

/pdf/nivolumab-versus-docetaxel-in-advanced-nonsquamous-non-small-40wj90u7fi.pdf

Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer

BackgroundPatients with advanced squamous-cell non–small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, as compared with docetaxel in this patient population. MethodsWe randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival. ResultsThe median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 3...

/pdf/nivolumab-versus-docetaxel-in-advanced-squamous-cell-non-4zes54y5w7.pdf

Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer

Background We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non–small-cell lung cancer. Methods A total of 1207 patients with advanced non–small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. Results The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa011954

Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer.

<h3>Background</h3> Immune checkpoint inhibitors (ICI), either as monotherapy or in combination with platinum-based chemotherapy, is standard of care in aNSCLC. However, most patients do not respond to ICI therapy, even when PD-L1≥50% (PD-L1 high). At BC Cancer, only those patients with PD-L1 high are eligible for first line (1L) ICI monotherapy, offering an opportunity to study potential new biomarkers in a relatively unbiased cohort of patients treated by ICI without chemotherapy. DetermaIO (IO score) is a 27-gene RT-qPCR immuno-oncology assay that classifies the tumor immune microenvironment (TIME) as IO+ or IO- and has been previously shown to associate with clinical benefit to ICI therapy in multiple tumor types. <h3>Methods</h3> All available FFPE blocks were assembled for ECOG≤2 patients treated with at least one cycle of ICI monotherapy in the 1L (required to be PD-L1≥50%) or later line (2L+). DetermaIO was performed using a CAP/CLIA validated RT-qPCR assay for cases where sufficient tissue was available. IO score classification was analyzed for association with PFS and OS in patients treated in the 1L. <h3>Results</h3> Considering the entire cohort of 147 patients, DetermaIO was significantly associated with OS (HR=0.68, 95%CI 0.47–0.89, p=0.042) and PFS (HR=0.62, 95%CI 0.43–0.88, p=0.0069). When examining the cohort by line of therapy, 78 (53%) were treated in 1L with ICI monotherapy and were all PD-L1 high. DetermaIO in this subgroup was significantly associated with PFS (HR=0.55, 95%CI 0.32–0.94, p=0.028) and demonstrated meaningful clinical benefit when measuring OS (HR=0.60, 95%CI 0.34–1.06, p=0.078). The objective response rate in the 1L subgroup was 53% for IO+ (2CR, 28PR out of 56 patients) and 23% for IO- (5PR out of 22 patients). The net reclassification rate of IO- amongst the PD-L1 high 1L group was 54.5% (12/22, p&lt;0.01) for response. <h3>Conclusions</h3> Retrospective analysis of outcomes of aNSCLC patients treated 1L with ICI monotherapy found that DetermaIO was significantly associated with PFS and trended towards significance for OS. First-line PD-L1 high patients who were IO- had significantly worse outcomes for PFS than PD-L1 high IO+ patients potentially informing the selection of combination therapy in PD-L1 high patients. These data confirm and expand previous studies of DetermaIO in advanced NSCLC and suggest IO score classification may offer significant incremental information for helping to make complex treatment decisions in aNSCLC. <h3>Ethics Approval</h3> This study was approved by the Research Ethics Board (REB) of University of British Columbia (H20–02635). Individual consent for this retrospective analysis and the use of tumor samples for the IO score assay was required for live patients. Consent was waived by the REB for deceased patients. 

/pdf/59-determaio-io-score-is-associated-with-efficacy-of-ici-353towpo.pdf

59 DetermaIO (IO score) is associated with efficacy of ICI monotherapy in advanced NSCLC patients: a retrospective BC Cancer study

Platinum-based chemotherapy is the cornerstone of care for patients with metastatic non–small-cell lung cancer (NSCLC). It provides symptom relief, improved quality of life, and prolongation of life, compared with supportive care alone. However, all patients with stage IV disease inevitably develop resistance to chemotherapy and progressive disease. Many of these patients continue to have acceptable performance status and would therefore be eligible for second-line or even third-line treatments. Unfortunately, despite an increasing number of chemotherapeutic agents (which are effective in chemo-naive NSCLC), very few have been shown to have reproducible activity in the second-line setting. Nevertheless, recent randomized clinical trials have demonstrated that single-agent docetaxel improves survival and quality of life when delivered as second-line therapy, resulting in FDA-approval for this indication. Phase II studies evaluating other new agents, delivered singly or in combination, also have reported that gemcitabine, weekly paclitaxel, and the epidermal growth factor receptor (EGFR) inhibitors are active in a subset of patients who progress after first-line platinum-based therapy. Clinical trials are imperative in identifying additional new agents and approaches that may improve outcomes in this disease. In view of the recently established role of docetaxel, ongoing randomized studies are using a common design of single-agent docetaxel versus docetaxel plus a novel investigational agent.

Non-small-cell Lung Cancer Progression after First-line

<h3>Background</h3> Predictive biomarkers for ICI regimens in NSCLC, namely PD-L1 and tumor mutational burden (TMB), remain suboptimal, leaving oncologists with limited decision-making tools. We sought to develop a more comprehensive solution, integrating genomic alterations detected by comprehensive genomic profiling (CGP), to enrich for association with progression-free survival (PFS) and overall survival (OS). <h3>Methods</h3> Lung Master Protocol (Lung-MAP) is an NCI-sponsored public-private partnership evaluating new therapies for previously-treated advanced stage NSCLC. In this analysis, 320 SCC patients from sub-studies S1400A (n=68; durvalumab) and S1400I (n=252; nivolumab ± ipilimumab) had tissue CGP data by Foundation Medicine. 204 patients from S1400A (n=43; SP263) and S1400I (n=161; 28–8 pharmDX) had PD-L1 IHC. We evaluated TMB (0–9, 10–20, &gt;20 mut/Mb), PD-L1 IHC, HLA loss of heterozygosity (LOH) of ≥ 1 gene (evaluable for n=206), mutations in KEAP1/NFE2L2, DNA damage response genes,ARID1A, and loss of CDKN2A as potential ICI biomarkers. Wilcoxon and Fisher’s exact tests assessed association between continuous TMB/PDL1 IHC (&lt;1%, 1–49%, ≥50%) and each binary biomarker, and between pairs of binary markers. Cox proportional hazards model evaluated the association between each biomarker and OS/PFS, adjusting for age, sex, smoking status, and stage. Based on significance (at the nominal 0.1 level without correction for multiplicity) from univariate analysis, multiple combination signatures were analyzed using a predetermined scoring system. Biomarkers in the most significant combination signature was further examined by adjusting for TMB and PD-L1, to demonstrate if they provided additional value. <h3>Results</h3> Despite associations between TMB and ARID1A mutations (P = 0.009), PD-L1and KEAP1/NFE2L2 mutations (P = 0.007) and ARID1A mutations and KEAP1/NFE2L2 mutations (OR = 2.89; 95% CI, 1.43 – 5.91, P = 0.0016), the magnitude of correlation was modest, thus representing complementary predictors. Higher TMB (&gt;20 vs. 10–20 vs. 0–9) was the most significant positive predictor of OS (HR=0.79; 95% CI, 0.65–0.95, p=0.01). A composite combinatorial signature (ICIsig) inclusive of TMB, PD-L1, HLA LOH, ARID1A, and KEAP1/NFE2L2 mutations was associated with better OS (HR=0.76; 95% CI, 0.63–0.92, p=0.005) and PFS (HR=0.84; 95% CI, 0.70–0.99, p=0.048). Landmark 3-year OS rates were 29% vs. 6% in ICIsig high vs. low. ICIsig high represented 39% of the evaluable population. <h3>Conclusions</h3> We show that a composite ICIsig extending beyond TMB and PD-L1 captures NSCLC patients benefiting from ICI therapy more effectively than single biomarkers. ICIsig could inform treatment selection in today’s rapidly expanding therapeutic landscape. Validation from a large randomized Phase III trial is ongoing. <h3>Acknowledgements</h3> We would like to acknowledge funding from: NIH/NCI grants U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180868; and by AstraZeneca and Bristol-Myers Squibb Company, through the Foundation for the National Institutes of Health, in partnership with Friends of Cancer Research. 

https://jitc.bmj.com/content/jitc/10/Suppl_2/A31.full.pdf

David R. Gandara

Papers

59 DetermaIO (IO score) is associated with efficacy of ICI monotherapy in advanced NSCLC patients: a retrospective BC Cancer study

Non-small-cell Lung Cancer Progression after First-line

29 Lung-MAP composite signature for immune checkpoint inhibitor (ICI) efficacy in advanced squamous cell lung cancer (SCC)

North American Cooperative Group Research Efforts in Lung Cancer

Therapeutic Ratio of Targeted Therapies in Non–Small-Cell Lung Cancer