Comparison of the Prediction Accuracy of Lung Cancer Survival Using Our 64-Gene Signature and a Different 50-Gene Signature

<div><p>(A and B) Kaplan-Meier survival curves for dataset 6 under our 64-gene signature (A) and the 50-gene signature from Beer et al. [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030467#pmed-0030467-b005" target="_blank">5</a>] (B). Scores were estimated using two principle components.</p> <p>(C and D) Kaplan-Meier survival curves for dataset 7 using our 64-gene signature (C) and the 50-gene signature from Beer et al. [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0030467#pmed-0030467-b005" target="_blank">5</a>] (D). Scores were estimated using eight principle components.</p></div

Validation Analyses of Gene Expression Profiling

<div><p>(A) QRT-PCR validations of several candidate survival-related genes. Bars represent fold changes for the selected genes with differential expression between long- (>5 y) and short-term survival (<2 y) patients. Positive fold change represents up-regulated, and negative fold change represents down-regulated in short-term survival patients. * <i>p</i> ≤ 0.05; ** <i>p</i> ≤ 0.01; *** <i>p</i> ≤ 0.005.</p> <p>(B and C) Immunostaining analysis of CRABP1 and ABCC1 expression in long- and short- term survival lung cancer patients. Low magnification (B) and 40× (C). Positive CRABP1 immunoreactivity was observed in cytoplasm of an acinar ADC (lower left photomicrographs of B and C) from short-term survival patients, and no CRABP1 reactivity was seen in a lung ADC from a long-term survival patient (upper left). Strong ABCC1 membranous staining (lower right) in tumor cells from short-term survival patients was observed, and weak ABCC1 reactivity was seen in a lung ADC from a long-term survival patient (upper right).</p> <p>(D) Distribution of CRABP1 and ABCC1 protein levels in short- and long-term survival patients.</p></div

Survival Analyses of Stage I NSCLC

<div><p>(A) Kaplan-Meier survival curves for patients with stage IA and with IB NSCLC.</p> <p>(B) Kaplan-Meier survival curves for stage IA and IB patients defined by having positive (high-risk) or negative (low-risk) risk scores of overall survival. The risk scores were estimated with seven principle components based on the model built by 64 survival-related genes identified in five datasets.</p> <p>(C) Area under the ROC curve for survival models based on stage information or expression data, respectively.</p></div

Gene Expression Patterns of 64 Top Survival Genes for 197 NSCLC Patients from Datasets 1 to 5

<p>Patients were generally classified into two groups (short-term versus long-term survival) with distinct expression patterns. The first column on the left represents patient status: 0, alive; 1, dead; the second column on the left represents follow-up time (days).</p

Liquid biopsies for residual disease and recurrence

Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for “residual disease and recurrence” (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors

Table_1_Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein.docx

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.</p

Table_2_Translatability of findings from cynomolgus monkey to human suggests a mechanistic role for IL-21 in promoting immunogenicity to an anti-PD-1/IL-21 mutein fusion protein.docx

AMG 256 is a bi-specific, heteroimmunoglobulin molecule with an anti-PD-1 antibody domain and a single IL-21 mutein domain on the C-terminus. Nonclinical studies in cynomolgus monkeys revealed that AMG 256 administration led to the development of immunogenicity-mediated responses and indicated that the IL-21 mutein domain of AMG 256 could enhance the anti-drug antibody response directed toward the monoclonal antibody domain. Anti-AMG 256 IgE were also observed in cynomolgus monkeys. A first-in-human (FIH) study in patients with advanced solid tumors was designed with these risks in mind. AMG 256 elicited ADA in 28 of 33 subjects (84.8%). However, ADA responses were only robust and exposure-impacting at the 2 lowest doses. At mid to high doses, ADA responses remained low magnitude and all subjects maintained exposure, despite most subjects developing ADA. Limited drug-specific IgE were also observed during the FIH study. ADA responses were not associated with any type of adverse event. The AMG 256 program represents a unique case where nonclinical studies informed on the risk of immunogenicity in humans, due to the IL-21-driven nature of the response.</p

Additional file 1: of The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC)

Cancer Immunotherapy Guidelines- Lung Task Force Roster. (DOCX 13 kb

Additional file 2: of The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC)

Comments from Member Open Review. (DOCX 14 kb