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Don Lynn Gibbons
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MA 02 - Emerging Targets (ID 656)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Ravi Salgia, Shun Lu
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 511 + 512
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MA 02.09 - A Ph I/II Study of BGB324, a Selective AXL Inhibitor as Monotherapy and in Combination with Erlotinib in Advanced NSCLC (ID 10388)
11:00 - 12:30 | Presenting Author(s): Don Lynn Gibbons
- Abstract
- Presentation
Background:
BGB324 is an orally available selective inhibitor of the receptor tyrosine kinase AXL (Biochemical IC50 0.4nM). In animal models of NSCLC exposure, BGB324 restricts cellular plasticity and prevents the development of resistance to Epithelial Growth Factor Receptor (EGFR) inhibitors through mesenchymal transformation.
Method:
BGB324 was administered at an oral loading dose (600 mg) on days one and two followed by a daily maintenance dose (200 mg) to eight patients with previously treated NSCLC (EGFR mutant or wildtype). The tolerability of two different loading doses BGB324 (600 mg on days one and two or 400 mg on days one two and three) were then explored in combination with erlotinib at a dose of 150 mg daily in patients with EGFR mutated NSCLC.
Result:
Two of eight patients treated with BGB324 monotherapy achieved at least six months of stable disease. Both dose levels of BGB324 were tolerated in combination with erlotinib although most patients experienced a transient worsening in gastrointestinal toxicity during the loading dose prior to returning to baseline. A three day loading dose was preferred. Treatment with BGB324 was accompanied by increases in patient serum levels of soluble AXL receptorconsistent with receptor inhibition. One patient who previously experienced progression during treatment with another EGFR inhibitor remains on treatment with erlotinib plus BGB324 for more than eighteen months with a best response of stable disease. The most common treatment related adverse events were increased serum creatinine, diarrhea, nausea and dysguesia.
Conclusion:
Conclusion BGB324 can be safely administered to patients with advanced NSCLC for prolonged periods at doses that abrogate AXL signalling either as monotherapy or in combination with erlotinib. A proportion of patients achieve durable disease stabilisation following treatment with BGB324 alone further exploration of the efficacy of the combination is ongoing.
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OA 13 - Immuno-Biology (ID 677)
- Event: WCLC 2017
- Type: Oral
- Track: Immunology and Immunotherapy
- Presentations: 2
- Moderators:Hiroyuki Suzuki, Scott N. Gettinger
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 301 + 302
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OA 13.01 - CD38-Mediated Immunometabolic Suppression as a Mechanism of Resistance to PD-1/PD-L1 Axis Blockade (ID 10157)
11:00 - 12:30 | Presenting Author(s): Don Lynn Gibbons
- Abstract
- Presentation
Background:
Although immune checkpoint inhibitors of the PD-1/PD-L1 axis provide significant clinical benefit for patients with lung cancer, effective use of these agents is encumbered by a high rate of primary or acquired resistance. Strategies for optimal therapeutic application of immunotherapy require a thorough understanding of resistance mechanisms. To date, there have been only a few studies reporting potential mechanisms of resistance to PD-1/PD-L1 blockade.
Method:
In multiple immunocompetent syngeneic and spontaneous animal models of K-ras/p53 mutant lung cancer, we explored the resistance mechanisms to PD-1/PD-L1 blockade using both pharmacologic and genetic approaches (therapeutic antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. Additionally, to determine the applicability to patients with lung cancer, we analyzed 259 tumor specimens with IHC staining and mRNA expression, and further confirmed the analyses in publically-available TCGA datasets.
Result:
In multiple models of antibody blockade and genetic knockout of PD-L1, we identified the up-regulation of CD38 on tumor cells as a marker of treatment resistance. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines we demonstrated in vitro and in vivo that CD38 expression inhibits CD8[+] T cell proliferation, anti-tumor cytokine secretion, and tumor cell killing capability. The T cell suppressive effect is dependent upon the ectoenzyme activity of CD38 that regulates the extracellular levels of adenosine. To test whether CD38 blockade might be therapeutically efficacious to prevent anti-PD-L1/PD-1 resistance, we applied combination therapy with anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in a set of 259 resected lung cancer specimens, ~15% exhibited positive staining for CD38 on tumor cells, and the expression correlated with cytolytic T cell score and an immune/inflammatory signature across multiple large datasets.
Conclusion:
CD38 was found to be a novel mechanism for tumor escape from immune checkpoint PD-1/PD-L1 inhibitor therapy. Targeting this resistance pathway may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.
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OA 13.05 - Immune, Molecular and T Cell Repertoire Landscape of 235 Resected Non-Small Cell Lung Cancers and Paired Normal Lung Tissues (ID 8766)
11:00 - 12:30 | Author(s): Don Lynn Gibbons
- Abstract
- Presentation
Background:
Non-small cell lung cancer (NSCLC) is characterized by a high mutational load. Accordingly, it is also among the tumor types responding to immune checkpoint blockade, likely through harnessing of the anti-tumor T cell response. However, the lung is continuously exposed to the outside environment, which may result in a continuous state of inflammation against outside pathogens unrelated to the tumor microenvironment. Therefore, further investigation into the T cell repertoire and T cell phenotypes across normal lung and tumor is warranted.
Method:
We performed T cell receptor (TCR) sequencing on peripheral blood mononuclear cells (PBMC), normal lung, and tumor from 225 NSCLC patients, among which, 96 patients were also subjected to whole exome sequencing (WES) of PBMC, tumor and normal lung tissues. We further performed Cytometry by Time-of-Flight (CyTOF) on 10 NSCLC tumors and paired normal lung tissues to phenotype immune and T cell subsets.
Result:
Comparison of the T cell repertoire showed 9% (from 4% to 15%) of T cell clones were shared between normal lung and paired tumor. Furthermore, among the top 100 clones identified in the tumor, on average 57 (from 0 to 95) were shared with paired normal lung tissue. Interestingly, T cell clonality was higher in the normal lung in 89% of patients suggesting potential differences in the immune response and immunogenicity. A substantial number of somatic mutations were also identified not only in NSCLC tumors (average 566; from 147 to 2819), but also in morphologically normal lung tissues (average 156; from 50 to 2481). CyTOF demonstrated striking differences in the immune infiltrate between normal lung and tumor, namely a lower frequency of PD-1+CD28+ T cells (both CD4+ and CD8+) in the normal lung (2.7% versus 3.0% in tumor). In addition, a unique GITR+ T cell subset (0.96%) was entirely restricted to the normal lung. Conversely, increases in regulatory T cell frequency (CD4+FoxP3+) were observed in the tumor (10.4% vs 1.7% in normal lung), further highlighting the differences in T cell phenotype and response across normal lung and tumor.
Conclusion:
These results suggest that a substantial proportion of infiltrating T cells in NSCLC tumors may be residential T cells associated with response to environmental factors. However, normal lung and NSCLC tumors carry T cells of distinct phenotypes including increases in immunosuppressive T cells within the tumor which may further highlight the differences in the anti-tumor immune response.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-041 - Update on Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer (ICON Project) (ID 10156)
09:30 - 16:00 | Author(s): Don Lynn Gibbons
- Abstract
Background:
Given the rapidly changing therapeutic landscape for non-small cell lung cancer (NSCLC), a thorough understanding of the tumor immune environment is critical to the appropriate selection of patients and testing of immuno-oncology agents. We established a project aimed at defining the comprehensive and integrated immunogenomic landscape in NSCLC, including immune, genomic and clinical data from 100 surgically resected lung cancers.
Method:
Tissue samples were collected at the time of surgery, and blood samples before and after surgery up to 1-year. Tissue samples were subjected to tumor infiltrating lymphocyte (TIL) isolation and expansion; generation of PDX models,WES and in-silico neoantigen prediction, RNA sequencing, RPPA, CyTOF, T cell receptor sequencing, and multiplex immunofluorescence evaluation of immune cells and markers. Blood samples were processed for cfDNA, microRNA, and cytokine profiling.
Result:
93 out of 131 enrolled patients with median age 67 years contributed samples to ICON; 44% males, 80% former smokers, 12% never smokers. Majority had adenocarcinoma (60%) and 26% SCC. 37 (40%) had stage I, 29 (31%) stage II, and 20 (22%) stage III disease; 14 patients received neoadjuvant chemotherapy. Median tumor size was 4.0cm and 79 (85%) underwent R0 and 9 (10%) R1 resection. TIL expansion was 68% successful. Phenotypic and functional analysis of TIL is ongoing. Preliminary analysis show suppression of intratumoral CD8[+] cells with low perforin levels and high CD8[+]PD1 levels as compared to normal tissue; however tumor CD8[+]CD28 co-stimulatory molecule expression was high. PDX success rate is 35%. IHC analyses show higher CD8[+]PD1, CD3, CD8[+]BTLA expression in SCC than in adenocarcinoma or normal tissue. WES and RNA sequencing show that median mutation burden is 9.3/MB in adenocarcinomas and 11.2/MB in SCC. Other immunogenomic analyses are in process.
Conclusion:
The ICON is an ambitious multi-team project designed to integrate multiple levels of tumor related data. Preliminary analysis demonstrates the project to be feasible, with a high rate of prospective sample acquisition. Tumor profiles from ICON will serve as a reference for upcoming neoadjuvant single and dual checkpoint immunotherapy trials. ICON Team: A. Weissferdt, A. Vaporciyan, A. Futreal, T. Karpinets, C. Yee, C. Haymaker, L. Federico, M.-A. Forget, G. Lizee, A. Talukder, J. Roszik, H. Tran, M. Vasquez, E. Prado, C. Behrens, E. Parra, J. Rodriguez-Canales, J. Fujimoto, L. Vence, J. Roth, I. Meraz, E. Roarty, L. Lacerda, L. Byers, S. Swisher, W. William Jr., P. Sharma, J. Allison, B. Fang, H. Wagner, E. Bogatenkova, I. Wistuba, J. Heymach and C. Bernatchez
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-062b - DNA Damage Repair Targeting Upregulates PD-L1 Level and Potentiates the Effect of PD-L1 Blockade in Small Cell Lung Cancer (ID 9733)
09:30 - 16:00 | Author(s): Don Lynn Gibbons
- Abstract
Abstract not provided
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P2.15 - SCLC/Neuroendocrine Tumors (ID 716)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.15-016a - Exploiting G2-M Cell Cycle Checkpoint Dependency in Small Cell Lung Cancer (SCLC) by Targeting Checkpoint Kinase 1 (CHK1) (ID 9680)
09:30 - 16:00 | Author(s): Don Lynn Gibbons
- Abstract
Abstract not provided
