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J. Kern
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MINI 12 - Biomarkers and Lung Nodule Management (ID 109)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:J.M. Siegfried, H.I. Pass
- Coordinates: 9/07/2015, 16:45 - 18:15, 401-404
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MINI12.11 - Screening for Lung Cancer with the Early CDT-Lung and Computed Tomography (ID 204)
17:45 - 17:50 | Author(s): J. Kern
- Abstract
- Presentation
Background:
Early CDT-Lung, a serum based biomarker consisting of a panel of seven autoantibodies that develop in response to tumor associated antigens, has been shown to detect lung cancer in all stages of disease. We hypothesized that this biomarker when used in combination with a low-dose CT (LDCT) in screening of a high-risk population would increase the detection of early stage lung cancer.
Methods:
A prospective study of 1,600 subjects at high risk for lung cancer was designed. Eligibility criteria included persons 50-75 years of age, current or former smokers of ≥ 20 pack years and < 10 years since quit smoking. Those with a history of lung cancer in first degree relative(s) and any history of smoking were included. Exclusion criteria ware any history of cancer within 10 years (except skin cancer), any use of oxygen, and life expectancy of < 5 years. A direct mail campaign was conducted with study announcements sent to the homes of potentially high-risk individuals, who then contacted us for consideration of participating in this screening study. Those fitting inclusion criteria received the Early CDT-Lung blood test and a LDCT. A nodule of ≥ 3mm was considered as a positive scan. The Early CDT-Lung test was considered positive if any one of the seven autoantibodies was positive. All participants are to have yearly telephone follow-up for two years.
Results:
From May 2012 through November 2014, 815 individuals were enrolled and 814 completed the initial blood and LDCT screening tests. The cohort median age was 59 years with 55% female and 45% male gender distribution. The mean smoking history was 44 pack-years. Fifty-four per cent were current smokers while 46% were former smokers. Forty-six per cent of the LDCTs were negative for any lung nodule while 38% were positive. Incidental non-lung cancer findings were identified in 15% of the study group. The Early CDT-Lung biomarker was positive in 60 (7%) of participants, 23 males and 37 females. In those with a positive LDCT (n=313), the biomarker was positive in 25 (8%). As of January 30, 2015, there have been six confirmed lung cancers: two limited stage small cell, two Stage IB adenocarcinoma (ACA), and two Stage IA (one ACA and one squamous cell). The Early CDT-Lung blood test was positive in two of the four Stage IA/B lung cancers and negative in the two small cell cancers.There are 35 Early CDT-Lung biomarker positive individuals whose LDCT had no nodule. These individuals are being followed with yearly LDCT for two years. The study is continuing to accrue with a goal of 1,600. (NCT01700257)
Conclusion:
The Early CDT-Lung biomarker was positive in 7% of our high-risk population. The biomarker was positive in two of six lung cancers, specifically in two of four Stage I lung cancers. Accrual to the study and follow-up of 35 biomarker positive but LDCT negative participants continues.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-046 - Kinome RNAi Screens Identify Essential Genes and Therapeutics In 'Driver Negative' Non-Small Cell Lung Cancer (ID 2970)
09:30 - 09:30 | Author(s): J. Kern
- Abstract
Background:
Lung adenocarcinoma is a leading cause of cancer-related death worldwide. The discovery of “driver” mutations in genes such as the epidermal growth factor receptor (EGFR) which are required for malignant transformation have revolutionized lung cancer care as chemotherapy directed against these proteins has resulted in dramatic improvements in survival. Approximately 75% of the non-small cell lung cancer (NSCLC) patients harbor a driver gene (KRAS, EGFR, ALK, ROS etc) from the recent molecular characterization of lung adenocarcinomas by The Cancer Genome Atlas. Unfortunately, ~25% of the patients are “driver negative”. Therefore, identifying genes essential for malignant pathogenesis in these “driver negative” NSCLC may serve as new therapeutic targets for these patients.
Methods:
Four “driver negative” NSCLC cell lines – H292, H1703, H228, and H322C – were used in the kinome RNAi essential screen. Cells were transduced with a short-hairpin loop lentiviral kinome library (~3700 shRNAs targeting ~600 kinases) developed by The RNAi Consortium (TRC 1.0/1.5). Cells were cultured and harvested after 2, 7, and 14 days of transduction. ShRNAs from surviving cells were extracted, reverse transcribed and barcoded for individual replicates. These samples were sequenced on the Illumina HiSEQ 2000. BiNGS! software was used for analyzing and interpreting the essential screen. Kinases were considered essential if were present at day 2 but they were lost (i.e. knocked out causing cell death) at both day 7 and day 14. We then queried these essential kinases to K-Map, a bioinformatics platform that systematically connects a kinase profile with a reference kinase inhibitor database and predicts the most effective inhibitor for a queried kinase profile.
Results:
All samples from four cell lines had on average 85% of mapping rates (70% - 92%) with 5 to 24 million mapped reads per sample. In total, twenty kinases were identified as essential kinases for these “driver negative” cell lines. For example, MAPK4 for H292; ERBB3 for H322C; ATR for H228; and KDR for H1703. We queried the K-Map using the twenty essential and potentially transformative kinases to connect them to drugs. One of the top kinase inhibitors connected by K-Map was sunitinib. From published papers, we found that H1703 has been validated to be sensitive to sunitinib, supporting the K-Map prediction of inhibitors on the essential kinases. Further validation will be performed and presented in the conference.
Conclusion:
Functional genetic screens have the potential to identify genes essential for cancer cell survival and proliferation, providing a “functional” map in “driver negative” NSCLC. Using a series of novel bioinformatics analyses, specifically connecting the essential kinases with small molecules based on inhibition activities, we have identified that candidate drugs effectively inhibits the essential kinases in “driver negative” NSCLC cell lines resulting in cell death. Further investigation of these candidate drugs and the functional role of these essential kinases could provide personalized treatment for the “driver negative” lung cancer patients.
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P2.04-079 - Targeting Antigen Presentation by Tumor Infiltrating B Cells to CD4 T Cells in Non-Small Cell Lung Cancer Patient Tumors (ID 3241)
09:30 - 09:30 | Author(s): J. Kern
- Abstract
Background:
B cells in tumors (TIL-Bs) are detected in non-small cell lung cancer (NSCLC) and their frequency correlates with improved survival, however, the functional mechanism of TIL-Bs in solid tumors is not well understood. We hypothesize that TIL-Bs help generate potent, long-term immune responses against cancer by presenting tumor antigens to CD4 tumor infiltrating lymphocytes (TILs) in primary human lung tumors.
Methods:
not applicable
Results:
Using un-manipulated, primary human B cells from fresh tumor, tumor-adjacent, and normal (cancer-free) lung tissue we observed that the total number of B cells at the site of the tumor versus the tumor-adjacent tissue was increased compared to other immune subsets. Further, in analyzing B cell markers of activation and exhaustion, we observed a spectrum of activation of TIL-Bs. Finally, we showed that TIL-Bs present autologous tumor antigens to CD4 TILs in a subset of NSCLC patients, and that depending on the activation or exhaustion profile of the TIL-Bs, differentiate CD4 TILs to T regulatory cells (Treg). These data suggest that some patients with TIL-Bs have differential function that is influenced by their activation or exhaustion phenotype.
Conclusion:
In conclusion, the anti-tumor functon of TIL-Bs can be stimulated in some NSCLC patients, and TIL-Bs that cannot be stimulated have increased immune exhaustion and promote Treg differentiation. Ultimately, results from this study will help predict which TIL-B functions to target in future TIL-B-specific immunotherapies or in combination with current immunotherapies for NSCLC patients like blockade of the inhibitory receptor, PD-1.
