Virtual Library
Start Your Search
Steven Dubinett
Author of
-
+
EP1.04 - Immuno-oncology (ID 194)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
-
+
EP1.04-20 - Phase I Trial of in Situ Vaccination with Autologous CCL21-Modified Dendritic Cells (CCL21-DC) Combined with Pembrolizumab for Advanced NSCLC (Now Available) (ID 1888)
08:00 - 18:00 | Author(s): Steven Dubinett
- Abstract
Background
Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) who progress on a programmed cell death-(ligand)1 [PD-(L)1] inhibitor and for those that are epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement positive after progression on tyrosine kinase inhibitor (TKI) therapy. One potential approach to improve immune checkpoint efficacy in these patient populations is to promote cytolytic T cell infiltration into tumors. This can be accomplished via in situ vaccination with functional antigen presenting cells (APCs) which can take advantage of the full repertoire of tumor antigens and convert the tumor into a lymph node-like environment promoting both local and systemic T cell activation. The chemokine CCL21 promotes co-localization of naive T cells and dendritic cells (DCs) to facilitate T cell activation. Our preclinical studies and phase I trial of intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) revealed augmentation of tumor antigen presentation in situ, resulting in effective T cell responses and systemic antitumor immunity. However, increased PD-L1 expression was observed in some patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust antitumor response. Similarly, improved PD-(L)1 inhibitor efficacy may be possible with enhanced T cell infiltration and augmented APC function following IT CCL21-DC. Therefore, we are conducting a phase I trial, combining IT CCL21-DC with pembrolizumab in patients with advanced NSCLC that are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy.
Method
This is a phase I, single institution, non-randomized, dose-escalating, multi-cohort trial followed by dose expansion. A maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC (5x106, 1x107, 3x107) when combined with pembrolizumab. Primary objective of dose expansion is objective response rate (ORR) of CCL21-DC at MTD combined with pembrolizumab. Secondary objectives include adverse event profiling and determination of drug target activity by immune monitoring studies. This trial, NCT03546361, is currently open for enrollment.
Result
Section not applicable
Conclusion
Section not applicable
-
+
MA15 - Usage of Computer and Molecular Analysis in Treatment Selection and Disease Prognostication (ID 141)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:John Le Quesne, Noriko Motoi
- Coordinates: 9/09/2019, 15:45 - 17:15, Tokyo (1982)
-
+
MA15.06 - Stage I Lung Adenocarcinoma Gene Expression Associated with Aggressive Histologic Features for Guiding Precision Surgery and Therapy (Now Available) (ID 1124)
15:45 - 17:15 | Author(s): Steven Dubinett
- Abstract
- Presentation
Background
Stage I lung adenocarcinomas (LUADs) show heterogeneity in histologic patterns which correlate with malignant behavior. Solid, micropapillary and cribriform patterns are associated with worse survival whereas lepidic (in situ) predominance has the best prognosis. In this study, we sought to characterize histologic pattern specific gene expression in resected clinical stage I LUADs. We also aimed to train and validate a genomic biomarker predictive of histologic aggressive patterns with the ultimate goal of being able to impact surgical and therapeutic decision making for post-biopsy management.
Method
A training cohort of 56 tumors from patients meeting NCCN high-risk screening criteria with stage I LUAD was included for pathologic annotation and whole exome RNA sequencing. Histologic pattern subtyping in 5% increments including all diagnostic slides was performed. A single representative FFPE block was chosen for RNA library-prep with Illumina TruSeq Access Kit and sequencing. Negative binomial models were used to identify gene expression differences associated with percent solid, cribriform, or micropapillary histology, and EnrichR was used for gene pathway enrichment analysis. Ss-GSEA was used to predict tumor infiltration of 20 immune cell types. A random-forest classifier for predicting aggressive histologic patterns was trained using 5-fold cross validation. A set of tumors from 16 independent patients with ≤2.0 cm clinical stage I LUAD was macro-dissected into 32 paired components (lepidic + non-lepidic regions) and subjected to RNAseq. Six tumors were defined as non-aggressive (lepidic + acinar/papillary) and ten tumors were defined as aggressive (lepidic + solid/micropapillary/cribriform). Four aggressive tumors were upstaged after surgical resection.
Result
In the training cohort, we identified 1322 genes associated with tumor histologic composition(FDR q <0.05 and fold-change > 2). Genes whose expression differs with solid histology% are enriched for involvement in DNA replication, cell cycle regulation and inflammation (FDR q<0.001). Genes whose expression is associated with micropapillary% are enriched for involvement in tRNA-aminoacylation and decrease of T-cell activity (FDR q<0.001). The functional enrichment of genes whose expression is associated with cribiform% was less informative. LUADs with micropapillary patterns exhibited gene expression consistent with decreased antigen presentation and low T-cell infiltration, and solid patterns exhibited gene expression consistent with increased infiltration of T-regulatory and Th2 cells (FDR q<0.05).
A gene expression classifier was trained to predict the presence of aggressive histologic patterns. We validated this classifier on a set of 16 tumor specimens from which we macro-dissected and analyzed tissue from the most aggressive histologic pattern (AUC = 1.00). We also found that this classifier could differentiate lepidic regions isolated from aggressive tumors from lepidic regions isolated from non-aggressive tumors (AUC = 0.74).
Conclusion
We identified solid-, micropapillary- and cribriform-specific gene expression and associated immune response among clinical stage I LUADs, and developed a classifier predictive of aggressive histologic features using either lepidic (in situ) or non-lepidic components. As such, this biomarker has the potential to predict histologic aggressiveness even from pre-surgical tumor biopsies where all histologic patterns may not be represented. Such a biomarker may be useful in guiding clinical decision making including extent of surgical resection.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
-
+
P1.11 - Screening and Early Detection (ID 177)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
-
+
P1.11-14 - SGLT2 Is a Diagnostic and Therapeutic Target for Early-Stage Lung Adenocarcinoma (ID 2854)
09:45 - 18:00 | Author(s): Steven Dubinett
- Abstract
Background
Early diagnosis of lung adenocarcinoma (LUAD) is crucial. The National Lung Screening Trial showed a 20% reduction in lung cancer mortality in high risk individuals using low-dose helical computed tomography (CT). CT is highly sensitive for detecting lung nodules, but is limited by low specificity, especially for LUAD. On CT, LUAD may appear as solid or subsolid nodules. Most subsolid nodules are not cancer, and many will remain stable or resolve; however, subsolid lesions can represent premalignancy or adenocarcinoma in situ. These lesions in the early spectrum of LUAD may persist for months to years before transforming into invasive disease. As a result, current standard of care is to follow these patients with CT imaging to monitor these indeterminate lesions for radiologic signs of malignant progression. The identification of novel biomarkers to predict the malignant potential of these nodules at their initial identification is of paramount importance.
Method
We have recently discovered that premalignant ad early invasive lesions of the LUAD spectrum rely on sodium-glucose transporter 2 (SGLT2) for glucose uptake, whereas advanced carcinomas up-regulate transporters of the GLUT family. This is consistent with the observation that positron emission tomography (PET) with 2-[18F] fluorodeoxyglucose (FDG), which detects GLUT but not SGLT activity, is a standard tool for staging advanced disease, but has low sensitivity for early-stage LUAD. We measured SGLT2 activity in vivo with the PET tracer methyl-4-[18F] fluorodeoxyglucose (Me4FDG).
Result
Me4FDG detects early-stage, FDG-negative LUAD in mouse models and in patients. Importantly, Me4FDG uptake correlates with tumor growth rate in patient-derived LUAD xenografts (fig. 1). Targeting SGLT2 with FDA-approved inhibitors significantly reduces tumor growth and prolongs survival in genetic and patient-derived murine models, confirming an important role of SGLT2 in early-stage LUAD.
Fig. 1. Me4FDG PET detects early lung adenocarcinoma and predicts growth rate. A) Time course of Me4FDG and FDG imaging in genetically engineered mice with LUAD. The early time point was taken when tumor nodules reached an average diameter of 7 mm (left panels), and the advanced time point was performed on the same mice 1 month later (right panels). B) Representative image of Me4FDG PET/CT imaging in mice carrying patient-derived LUAD xenografts. C) Correlation between Me4FDG uptake in the patient-derived xenografts and the fold increase in volume in a 1-month period following the PET/CT scan.
Conclusion
SGLT2 is a promising biomarker not only to diagnose early-stage tumors by PET imaging, but also to predict response to SGLT2 inhibitors.
-
+
P2.11 - Screening and Early Detection (ID 178)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.11-39 - Multimodal Monitoring of Patient-Derived Early-Stage Lung Adenocarcinoma with the Chicken Chorioallantoic Membrane System (ID 2827)
10:15 - 18:15 | Author(s): Steven Dubinett
- Abstract
Background
Positron-emission-tomography (PET), imaging uptake of [18F] fluorodeoxyglucose (FDG), is a powerful tool for lung cancer staging, but lacks sensitivity in early lesions. We have recently discovered that early-stage lung adenocarcinoma (LUAD) depends on another system for glucose uptake, the sodium- glucose transporter 2 (SGLT2), not detected by FDG PET. The tracer methyl 4-[18F] fluorodeoxyglucose (Me4FDG) is specific for SGLTs.
Because the establishment of patient-derived xenografts (PDXs) from early-stageLUAD is characterized by low efficiency and long experimental times, we have developed an alternative model to study tumor metabolism in LUAD, based on the implantation of tumor tissue on the chorioallantoic membrane (CAM) of chicken eggs (in ovo system).
Method
PDXs of LUAD were established in ovo by implanting tumor fragments or dissociated cells in matrigel onto the CAM of fertilized chicken eggs. Xenografts were grown for up to 10 days. After day 7, the eggs were imaged with FDG and Me4FDG PET to characterize glucose uptake, then rescanned with both tracers after treatment with SGLT2 inhibitor dapagliflozin to prove SGLT2 specificity of Met4FDG. Multiparametric magnetic resonance imaging (MRI) was performed to assess tumor growth, morphology (T1w, T2w, diffusion-weighted imaging) and vasculature (angiography; GadospinP). At day 10, the xenografts were harvested for histology and immunohistochemistry or reimplanted onto a new CAM for continuous passaging.
Result
FDG- and Me4FDG-PET adenocarcinomas confirmed the presence of both glucose transporters, GLUT1 and SGLT2. MRI angiography revealed that both tumor plaques and tumor fragments were connected to the embryonic vasculature. Following dapagliflozin treatment, Met4FDG uptake was successfully blocked in the PD tumor fragments.
Conclusion
The CAM xenograft model is useful for studying the heterogeneity of glucose uptake in ovo by imaging the activity of different transporters with FDG and Me4FDG. The novel PET tracer Met4FDG allows to validate SGLT2 expression as well as its blockage by SGLT2 inhibitors gliflozins.
