Virtual Library
Start Your Search
F.J. Giles
Author of
-
+
MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
-
+
MA 05.11 - Endothelial Adhesion Molecule Overexpression Correlates to Decreased CD8 T Cells and Increased B/Treg Cells in Lung Cancer (ID 8609)
16:55 - 17:00 | Author(s): F.J. Giles
- Abstract
- Presentation
Background:
Immunotherapy has become a promising recourse for lung cancer therapy. The endothelium separates circulating immune cells and the tumor microenvironment, and it is necessary for immune cells to penetrate this barrier to accost the tumor. This requires cell-matrix interactions via endothelial adhesion molecules(EAM) such as selectin and integrin. While it is expected that higher expression of EAM is linked to greater immune cell infiltration in general, little is known as to its actual effect on various types of immune cells in human lung cancer.
Method:
Based on the TCGA database, mRNA-seq values of genes related to the leukocyte recruitment cascade were analyzed in 504 patient samples with lung squamous cell carcinoma(SCC) and 522 patient samples with lung adenocarcinoma. The genes were divided into 3 sets: rolling, firm adhesion, and transmigration. Immune cell infiltration of each set was analyzed using Gene Set Enrichment Analysis(GSEA), and p values were derived from Fisher’s exact and Chi-squared tests.
Result:
In lung SCC, overexpression(z score>2.0) of the above genes was statistically significantly correlated with decreased infiltration of activated CD4/CD8 T cells, but increased infiltration of activated B/Treg cells (Figure1). Similar trend was also observed in lung adenocarcinoma. Macrophage, dendritic cells, and natural killer cells showed increased infiltration in the EAM overexpression groups of both SCC and adenocarcinoma. Overall survival showed no significant difference in all three EAM gene overexpression groups in both types of lung cancer.Figure 1
Conclusion:
We demonstrate for the first time that overexpression of EAM genes is linked to differential infiltration of various immune cells (including decreased CD4/CD8 T cells and increased activated B/Treg cells) in human lung cancer tissue. Recruitment of B/Treg cells by EAM may have an impact on inactivation of infiltrated T cells in the tumor microenvironment. This suggests that EAM status may serve as a predictive biomarker for T cell-mediated immunotherapy.
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.
-
+
OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
-
+
OA 07.03 - Circulating Tumor DNA Mutant Allele Frequency and Tumor Burden as Biomarkers for Response to Immune Checkpoint Blockade (ID 9606)
16:05 - 16:15 | Author(s): F.J. Giles
- Abstract
- Presentation
Background:
Identifying biomarkers to select patients who respond to immune checkpoint blockade in non-small cell lung cancer (NSCLC) remains a challenge. Cell-free circulating tumor DNA (ctDNA) has emerged as a non-invasive, quantitative method of monitoring genomic alterations in the peripheral blood. We evaluated the clinical utility of ctDNA mutant allele frequency (MAF) and tumor burden based on imaging as biomarkers for response to immune checkpoint blockade in NSCLC.
Method:
From a cohort of 136 patients with ctDNA samples, 20 patients were retrospectively identified with ctDNA testing before initiation of anti-PD-1/PD-L1 treatment or within 90 days of therapy initiation. ctDNA testing was performed by Guardant360 (Guardant Health, Redwood City, CA). MAF of the dominant clone was identified quantitatively for each patient. In addition, baseline tumor burden was estimated using RECIST version 1.1. MAF and tumor burden were correlated with progression free survival (PFS) and overall survival (OS). Logistic regression of response rate (RR) and clinical benefit rate (CBR) was also performed.
Result:
Higher median ctDNA MAF was correlated with significantly shorter PFS and OS (hazard ratio (HR) 3.4, p=0.03 and HR 10.4, p=0.03, respectively) (Figure 1). There was no significant association between tumor burden estimation and PFS and OS. However, tumor burden was significantly correlated with MAF (r=0.58, p=0.007). MAF and tumor burden estimation did not correlate with RR or CBR in this small sample. Figure 1
Conclusion:
ctDNA MAF appears to be a promising, non-invasive, prognostic biomarker for response to immune checkpoint blockade in NSCLC with higher MAF associated with shorter PFS and OS. ctDNA MAF may also serve as a surrogate for tumor burden. Prospective studies with serial ctDNA sampling are necessary to further validate these findings.
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.
-
+
P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P1.04-004 - Phase I/Ib Study of Nivolumab and Veliparib in Advanced Solid Tumors and Lymphoma with and without Alterations in Selected DNA Repair Genes (ID 8357)
09:30 - 09:30 | Author(s): F.J. Giles
- Abstract
Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been a successful treatment strategy in a minority of patients with many different tumor histologies (non-small cell lung cancer, squamous cell head and neck cancer, melanoma, Hodgkin lymphoma, renal cell carcinoma, urothelial carcinoma). An increase in the proportion of patients that benefit from this emerging mechanism is needed. Veliparib is an inhibitor of poly (ADP-ribose) polymerase (PARP), and it has been shown in preclinical models and in patients with BRCA mutant ovarian cancer to exert anti-tumor effects through lethal exacerbation of DNA repair defects. Extensive genomic sequencing of tumors of varying histologies has revealed that approximately 5% of all tumors harbor defects in DNA repair genes such as BRCA1/2, RAD51, CHEK1, ATM, ATR, CHEK2, FANCD2, FANCA. We propose combining PD-1 inhibition with nivolumab with PARP inhibition with veliparib in patients with DNA repair gene defects in order to maximize the proportion of patients with clinical responses to these novel treatment strategies.
Method:
We are currently enrolling patients on this phase I/Ib clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. The study schema is shown below. Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
-
+
P1.04-005 - Phase 2 Study of Nivolumab and Metformin in Advanced Non-Small Cell Lung Cancer with and without Prior Treatment with PD-1/PD-L1 Inhibitors (ID 8505)
09:30 - 09:30 | Author(s): F.J. Giles
- Abstract
Background:
Inhibition of the PD-1/PD-L1 axis with nivolumab has been proven to be a successful treatment strategy in a minority of patients with non-small cell lung cancer. An increase in the proportion of patients that benefit from this emerging mechanism is needed, and many novel combination therapies are being tested. Furthermore, many patients with non-small cell lung cancer are excluded from further clinical trials if they have received prior checkpoint inhibitor therapy, so this trial provides for this additional unmet need. Epidemiologic studies have consistently demonstrated an association between decreased cancer incidence and mortality in patient treated with metformin. Preclinical models have demonstrated that this anti-cancer effect is potentially mediated by inhibition of insulin like growth factor-1 (IGF-1) and mTOR, as well as activation of AMPK and tuberous sclerosis complex (TSC1, TSC2). Also, metformin has recently been found to exert immunomodulatory functions, inhibiting the exhaustion of CD8+ tumor infiltrating lymphocyte (TIL) function, thereby upregulating tumor-specific immune function. It accomplishes this by preventing apoptosis of CD8+ TILs and converting CD8+ TILs from quiescient central memory T cells to effector memory T cells with active anti-tumor effects. In vivo, the addition of metformin to vaccination enhances the generation of effector memory T cells, congruent with the overall hypothesis. We propose a proof-of-concept parallel phase 2 trial using the combination regimen of nivolumab and metformin. We hypothesize that the combination of nivolumab and metformin will be synergistic and can overcome resistance to single agent PD-1/PD-L1 inhibitors.
Method:
We are currently enrolling patients in this phase II clinical trial at the Northwestern Medicine Developmental Therapeutics Institute. Figure 1
Result:
Section not applicable
Conclusion:
Section not applicable
-
+
P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
-
+
P1.07-043 - Barrier Molecule Overexpression is Associated with Increased CD8 T Cells and Decreased B/Treg Cells in Human Lung Cancer (ID 8617)
09:30 - 09:30 | Author(s): F.J. Giles
- Abstract
Background:
Immunotherapy is an encouraging therapeutic option for lung cancer therapy. For immune cells to interact with tumors, they must first traverse the cell junctions between neighboring cells. While it is expected that higher expression of barrier molecules is linked to lesser immune cell infiltration in general, little progress has been made in our understanding of how these barrier molecules mechanistically interact with immune cells in lung cancer.
Method:
Barrier molecule genes were divided into 3 types: tight junction, adherens junction, and desmosome. mRNA-seq values of each type were analyzed in 504 patient samples with lung squamous cell carcinoma(SCC) and 522 patient samples with lung adenocarcinoma from the TCGA database. Immune cell infiltration of each set was evaluated using Gene Set Enrichment Analysis(GSEA), and p values were analyzed from Chi-squared and Fisher’s exact tests.
Result:
In lung adenocarcinoma, overexpression(z-score>2.0) of desmosome genes significantly correlated with increased infiltration of activated CD4/CD8 T cells, and Th17 cells, but decreased infiltration of activated B cells, mast cells, macrophages, and regulatory T cells(Figure1). There was no significant difference in the immune cell landscape of groups overexpressing desmosome genes in lung SCC. In addition, there was no significant difference in groups overexpressing tight or adherens junction genes in both types of cancer. Overall survival also showed no significant difference in all 3 barrier molecular gene overexpression groups in both types of lung cancer.Figure 1
Conclusion:
Our study demonstrates that elevated barrier molecule(desmosome) gene expression is associated with increased infiltration of cytotoxic CD8 T cells and decreased infiltration of activated B/Treg cells in human lung adenocarcinoma. The inverse association between cytotoxic CD8 T cells and activated B/Treg cells aligns with previous reports of tumor-infiltrating B cells inhibiting T cells. Further investigation is required to understand the roles of barrier molecules and its immune modulatory effect in various types of cancers.
