Faculty Bibliography

The current standard of Response Evaluation Criteria in Solid Tumors (RECIST)-based tumor response evaluation is limited in its ability to accurately monitor treatment response. Radiomics, an approach involving computerized extraction of several quantitative imaging features, has shown promise in predicting as well as monitoring response to therapy. In this article, we provide a brief overview of radiomic approaches and the various analytical methods and techniques, specifically in the context of predicting and monitoring treatment response for non-small cell lung cancer (NSCLC). We briefly summarize some of the various types of radiomic features, including tumor shape and textural patterns, both within the tumor and within the adjacent tumor microenvironment. Additionally, we also discuss work in delta-radiomics or change in radiomic features (e.g., texture within the nodule) across longitudinally interspersed images in time for monitoring changes in therapy. We discuss the utility of these approaches for NSCLC, specifically the role of radiomics as a prognostic marker for treatment effectiveness and early therapy response, including chemoradiation, immunotherapy, and trimodality therapy.

Self-replication is the engine that drives all biologic evolution, including neoplastic evolution. A key oncotherapy challenge is to target this, the heart of malignancy, while sparing the normal self-replication mandatory for health and life. Self-replication can be demystified: it is activation of replication, the most ancient of cell programs, uncoupled from activation of lineage-differentiation, metazoan programs more recent in origin. The uncoupling can be physiologic, as in normal tissue stem cells, or pathologic, as in cancer. Neoplastic evolution selects to disengage replication from forward-differentiation where intrinsic replication rates are the highest, in committed progenitors that have division times measured in hours versus weeks for tissue stem cells, via partial loss of function in master transcription factors that activate terminal-differentiation programs (e.g., GATA4) or in the coactivators they use for this purpose (e.g., ARID1A). These loss-of-function mutations bias master transcription factor circuits, which normally regulate corepressor versus coactivator recruitment, toward corepressors (e.g., DNMT1) that repress rather than activate terminal-differentiation genes. Pharmacologic inhibition of the corepressors rebalances to coactivator function, activating lineage-differentiation genes that dominantly antagonize MYC (the master transcription factor coordinator of replication) to terminate malignant self-replication. Physiologic self-replication continues, because the master transcription factors in tissue stem cells activate stem cell, not terminal-differentiation, programs. Druggable corepressor proteins are thus the barriers between self-replicating cancer cells and the terminal-differentiation fates intended by their master transcription factor content. This final common pathway to oncogenic self-replication, being separate and distinct from the normal, offers the favorable therapeutic indices needed for clinical progress.

BACKGROUND:Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS:In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS/RESULTS:Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION/CONCLUSIONS:ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING/BACKGROUND:Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center.

INTRODUCTION/BACKGROUND:Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors show significant clinical activity in non-small-cell lung carcinoma (NSCLC). However, there is a relative lack of data on comparative efficacy of these drugs in the first-line setting versus chemotherapy-treated patients. We compared the efficacy and toxicity of these drugs in these 2 distinct groups of patients. MATERIALS AND METHODS/METHODS:statistic was used to assess heterogeneity. RESULTS:Seventeen distinct trials (8 with treatment-naive patients [n = 937]; 14 with chemotherapy-treated patients [n = 3620]; 5 with separate treatment-naive and previously treated arms) were included. Treatment-naive patients had a statistically significant higher ORR (30.2%; 95% confidence interval [CI], 22.70-38.2) than patients previously treated with chemotherapy (ORR, 20.1%; 95% CI, 17.5-22.9; P = .02). No significant differences in PFS were observed between the 2 groups. Treatment-naive patients had statistically significant higher rates of all grade pneumonitis compared with previously treated patients (4.9%; 95% CI, 3.4-6.7 vs. 3.0%; 95% CI, 2.0-4.1; P = .04); however, no significant differences in any other immune-related adverse events were observed. CONCLUSION/CONCLUSIONS:PD-1/PD-L1 inhibitor therapy for advanced NSCLC has a significantly higher ORR and a higher rate of immune-mediated pneumonitis when used in the first-line setting compared with chemotherapy treated patients.

Purpose: Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human non-small cell lung cancer (NSCLC).Experimental Design: Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1, and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin⁺ tumor epithelial cells, CD3⁺ T cells, CD4⁺ T-helper cells, CD8⁺ cytotoxic T cells, CD20⁺ B lymphocytes and CD68⁺ tumor-associated macrophages. We determined the association between the targets, clinicopathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA were also performed.Results: VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8⁺ T cells and CD68⁺ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival.Conclusions: VISTA is frequently expressed in human NSCLC and shows association with increased tumor-infiltrating lymphocytes, PD-1 axis markers, specific genomic alterations and outcome. These results support the immunomodulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target. Clin Cancer Res; 24(7); 1562-73. ©2017 AACR.

Differentiation between benign and malignant nodules is a problem encountered by radiologists when visualizing computed tomography (CT) scans. Adenocarcinomas and granulomas have a characteristic spiculated appearance and may be fluorodeoxyglucose avid, making them difficult to distinguish for human readers. In this retrospective study, we aimed to evaluate whether a combination of radiomic texture and shape features from noncontrast CT scans can enable discrimination between granulomas and adenocarcinomas. Our study is composed of CT scans of 195 patients from two institutions, one cohort for training ([Formula: see text]) and the other ([Formula: see text]) for independent validation. A set of 645 three-dimensional texture and 24 shape features were extracted from CT scans in the training cohort. Feature selection was employed to identify the most informative features using this set. The top ranked features were also assessed in terms of their stability and reproducibility across the training and testing cohorts and between scans of different slice thickness. Three different classifiers were constructed using the top ranked features identified from the training set. These classifiers were then validated on the test set and the best classifier (support vector machine) yielded an area under the receiver operating characteristic curve of 77.8%.

INTRODUCTION/BACKGROUND:Immune checkpoint pathways are key immune regulatory pathways that play a physiologic role in maintaining immune-homeostasis and are often co-opted by cancer cells to evade the host immune system. Recent developments in cancer immunotherapy, mainly drugs blocking the immune checkpoint pathways, have revolutionized the treatment paradigm for many solid tumors. A wide spectrum of immune-related adverse events (irAEs) have been described with the use of these agents which necessitate treatment with immunosuppression, lead to disruption of therapy and can on occasion be life-threatening. There are currently no clinically validated biomarkers to predict the risk of irAEs. Areas covered: In this review, the authors describe the current progress in identifying biomarkers for irAEs and potential future directions. Literature search was conducted using PubMed-MEDLINE, Embase and Scopus. In addition, abstracts from major conference proceedings were reviewed for relevant content. Expert commentary: The discovery of biomarkers for irAEs is currently in its infancy, however there are a lot of promising candidate biomarkers that are currently being investigated. Biomarkers that can identify patients at a higher risk of developing irAEs or lead to early detection of autoimmune toxicities are crucial to optimize patient selection for immune-oncology agents and to minimize toxicity with their use.