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Ignacio Gil-Bazo
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MA06 - PDL1, TMB and DNA Repair (ID 903)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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MA06.03 - PD-1 and Id-1 Combined Blockade Impacts Tumor Growth and Survival Through PD-L1 Expression and Tumor Infiltration by Immune-Related Cells (ID 14033)
13:40 - 13:45 | Presenting Author(s): Ignacio Gil-Bazo
- Abstract
- Presentation
Background
PD-1/PDL-1 inhibitors are approved in advanced non-small cell lung cancer (NSCLC). Long-term survival rates associated to PD-1/PDL-1 blockade have changed treatment paradigm. However, many patients do not benefit from PD-1/PDL-1 blockade. New therapeutic combinations are under investigation. Id1 is involved in proliferation, angiogenesis and immunosuppression. We described Id1 as an independent prognostic factor in NSCLC (Ponz-Sarvise, Clin Cancer Res 2011) and more recently showed Id1’s role in lung cancer metastasis (Castanon, Cancer Letters 2017). Here we test a combined therapeutic strategy targeting PD-1 and Id1 in a murine lung cancer model.
a9ded1e5ce5d75814730bb4caaf49419 Method
Three in vivo studies evaluated the impact of Id1 inhibition in tumor cells, tumor microenvironment and in both, on tumor volumes and mice survival. A syngeneic tumor model using C57BL/6 and Id1-/- Id3+/- mice was created by subcutaneous injection of Lewis Lung Carcinoma (3LL) cells and Id1 silenced 3LL (Id1Sh) cells. After injection, mice were treated with an anti-PD-1 (RMP-1-14) monoclonal antibody or PBS. Tumor volumes according to mice strain, Id1 status in tumor cells and treatment were quantified. Mice's survival was calculated in those groups. Tumor CD8+ and CD3+ TILs and CD68+ cells were quantified by specific immunostainings.
4c3880bb027f159e801041b1021e88e8 Result
Id1 inhibition in the tumor environment and the injected tumor cells, combined with anti-PD-1 treatment, induced a significant tumor growth impairment (p < 0.0001) and increased survival (p = 0.0051). CD3+ and CD8+ TILs and tumor CD68 + cells were significantly higher in tumors from mice with the combined Id1-PD-1 blockade treated with the anti-PD-1 inhibitor compared to control animals suggesting that tumor increased immune-related cells infiltration exerts the effector phase of the antitumor immune response. Additionally, PD-L1 expression seemed to be higher when Id1 expression was absent in the immune microenvironment (p = 0.04). Additional data based on multiplexed immunohistochemistry results will be presented at the meeting.
8eea62084ca7e541d918e823422bd82e Conclusion
Id1 and PD-1 combined blockade in our syngeneic murine lung cancer model significantly impaired tumor growth and increased survival. Increased tumor PD-L1 expression and CD3+ and CD8+ TILs and CD68+ cells may explain these findings.
6f8b794f3246b0c1e1780bb4d4d5dc53Only 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.
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MA11 - Biomarkers of IO Response (ID 912)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 203 BD
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MA11.12 - Discussant - MA 11.09, MA 11.10, MA 11.11 (ID 14621)
11:45 - 12:00 | Presenting Author(s): Ignacio Gil-Bazo
- Abstract
- Presentation
Abstract not provided
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.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-51 - Study of CD26/DPP4 Expression in a Large Series of Non-Small Cell Lung Cancer Patients (ID 13794)
16:45 - 18:00 | Author(s): Ignacio Gil-Bazo
- Abstract
Background
Lung cancer is a leading cause of cancer-related death worldwide and the prognosis remains poor CD26/dipeptidyl peptidase 4 (DPP4) is a transmembrane exopeptidase expressed on various hematopoietic but also somatic cells including malignancies of breast, colon, and mesothelioma. We previously found that the activity of CD26/DPP4 in human lung adenocarcinoma is four times higher than in normal lung tissue and the inhibition of CD26/DPP4 decreased the growth of lung tumors in experimental models. These data prompted us to analyze the expression of CD26/DPP4 in samples from lung cancer patients to unravel the role of CD26/DPP4 as a potential therapeutic target to reduce lung cancer burden.
a9ded1e5ce5d75814730bb4caaf49419 Method
To identify CD26/DPP4, we performed immunohistochemistry (IHC) on multi-organ tissue micro array (TMA) using four different antibodies. We finally selected the antibody produced by Cell Signaling Technology. For the analysis of CD26/DPP4 by IHC, TMAs constructed from the samples of non-small cell lung cancer patients were used. The cohort consisted of 1110 patients (Adenocarcinoma (AC): 567; Squamous carcinoma (SC): 443). Three pathologists independently scored the staining intensity from zero to three in a blinded manner. Lung AC cell lines from tissue (H2347, H522, A549, and Hop62) and pleural malignant effusion (H1437, H460, Mai9, and Gon8) were employed to assess the expression of CD26/DPP4. ELISA was used to quantify CD26/DPP4 from cell lines.
4c3880bb027f159e801041b1021e88e8 Result
Overall survival of the patients showed no difference between AC and SC groups. IHC scores revealed AC expressing significantly higher CD26/DPP4 levels vs. normal lung or SC (p=0.035, p<0.0001, respectively). In consistency with our previous findings, early stage cancer (IA) expresses significantly higher levels of CD26 than other stages IIB (p=0.0012), IIIA (p=0.0019), and IV (p=0.02) among AC samples. From our in vitro studies, we found that early stage derived cell line (H2347: stage I) expresses significantly more CD26/DPP4 compared to others (H522: stage II, A549 and HOP62 stage IV). In contrast, metastatic AC cell lines secrete significantly more CD26/DPP4 in culture medium compared to tissue derived cell lines, while the cellular level of CD26/DPP4 was higher in tissue derived cell lines.
8eea62084ca7e541d918e823422bd82e Conclusion
AC expresses significantly more CD26/DPP4 than SC. Furthermore, the expression of CD26/DPP4 was higher at early stages of AC compared to advanced stages. Human cell line data suggest that metastatic AC secretes CD26/DPP4 more actively than primary cancer. We therefore deem CD26/DPP4 to be a target for inhibition of human AC.
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.15 - Treatment in the Real World - Support, Survivorship, Systems Research (Not CME Accredited Session) (ID 964)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.15-25 - NIVEX TRIAL (GECP 1605): Nivolumab in the Real World: Spanish Expanded Access Program Experience in Pretreated Advanced NSCLC Patients (ID 13030)
16:45 - 18:00 | Author(s): Ignacio Gil-Bazo
- Abstract
Background
Nivolumab is a standard treatment for pretreated patients with advanced non-small cell lung cancer (NSCLC). Real world data about toxicity and efficacy of nivolumab is needed.
a9ded1e5ce5d75814730bb4caaf49419 Method
We have analyzed patients from the Expanded Access Program in Spain that included patients with advanced pretreated NSCLC. We have retrospectively analyzed 665 patients that had received at least 1 dose of nivolumab 3mg/kg q2w from 01/2015 for squamous ﴾Sq﴿ and 06/2015 for non‐Sq NSCLC, to 11/2017.
4c3880bb027f159e801041b1021e88e8 Result
Median age was 61 (32-85) years, 73% were men, 85% had ECOG 0-1, 88% were current or former smokers and 15% presented brain metastases. 128 (19,2%) patients presented Sq NSCLC and 537 (80,8%) patients Non‐Sq NSCLC. 7% of patients presented EGFR mutation. PD-L1 was ≥ 1% in 32,9% of analyzed patients.
Best response was complete response 1,7%, partial response 22,4%, stable disease 24,1%, and progressive disease 37,1%, and was not assessed in 14,7% of patients. No differences in response rate were observed according to histology.
After a median follow‐up of 8,2 months, the median OS was 8,97 (95%CI 7,69-10,24) months, and the median PFS was 3,23 (95%CI 2,77-3,70) months. Estimated 1-year OS was 42,4% (95%CI 38,5-42,8%) and estimated 1-year PFS was 22,2% (95%CI 19,1-25,3%). No differences in OS or PFS according to histologies were observed.
296 (44,5%) patients presented toxicity related to Nivolumab, that was grade ≥3 in 69 (10,4%) patients. Grade ≥3 diarrhea was reported in 1,2% of patients and pneumonitis occurred in 1,2% of patients (1 patient presented a grade 5 pneumonitis). According to the presence of grade ≥3 toxicity, the median OS was 14,57 (CI95% 8,45-20,68) months for patients with grade ≥3 toxicity and 8,73 (CI95% 7,50-9,96) months for patients without grade ≥3 toxicity (p= 0,074).
Additional efficacy data including treatment lines, presence of immune-related adverse events, PS2, brain metastasis, response to first line, or post-nivolumab treatment will be presented.
8eea62084ca7e541d918e823422bd82e Conclusion
Efficacy and safety of nivolumab was in line with previously shown data. There was a trend to a better OS for those patients experiencing grade ≥3 toxicity.
6f8b794f3246b0c1e1780bb4d4d5dc53
