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Peter Szlosarek
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MA 19 - Mesothelioma: Bench to Bedside (ID 680)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:Dean A Fennell, Hedy Lee Kindler
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 315
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MA 19.05 - Pegylated Arginine Deiminase Potentiates PD-1/PD-L1 Immune Checkpoint Blockade in Malignant Mesothelioma (ID 9207)
11:30 - 11:35 | Presenting Author(s): Peter Szlosarek
- Abstract
Background:
Malignant pleural mesothelioma is a difficult to treat asbestos-driven cancer that is on the increase globally. The urea cycle and tumor suppressor enzyme argininosuccinate synthetase 1 (ASS1), involved in arginine synthesis, is downregulated in half of mesotheliomas which are then sensitive to arginine deprivation therapy. Trials of the arginine depletor pegylated arginine deiminase, ADI-PEG20, have confirmed single-agent and combination safety and efficacy in patients with mesothelioma. Here, we explored the immunometabolic consequences of ASS1 loss in mesothelioma uncovering a role for combining ADI-PEG20 with PD1/PD-L1 checkpoint blockade.
Method:
Three ASS1-negative and one ASS1-positive MPM cell lines were assessed for PD-L1 expression by real-time quantitative PCR, western blot and FACS analysis. Cell lines were manipulated for ASS1 overexpression (endogenous and genetic) and siRNA followed by gene expression analysis. Cell lines were cultured with and without ADI-PEG20 and assessed for PD-L1 expression and cytokine production by ELISA. An immunocompetent murine tumor model of ASS1 loss mimicking aggressive mesothelioma was treated with PBS control, ADI-PEG20, anti-PD-1 antibody, and ADI-PEG20 plus anti-PD-1 antibody. Tumors were harvested and analysed for immune cell subsets by FACS. Finally, human mesothelioma biopsies from trials of ADI-PEG20 were analyzed for ASS1 and PD-L1 and immune cell subsets.
Result:
PDL1 protein was absent in the three ASS1 negative MPM cell lines but was present in the ASS1 positive cell line. Transfection of ASS1 in the ASS1 negative MPM cell lines led to an increase in PD-L1 expression, which was reversible following ASS1 knockdown. Induction of PD-L1 expression by forced ASS1 overexpression was accompanied by an increase in interferon type I signaling. Similar results were obtained in a mesothelioma cell line developing resistance to ADI-PEG20 under long-term culture. Next, ADI-PEG20 treatment triggered release of interferon-alpha/beta which induced PD-L1 expression by 24hrs in the ASS1-negative MPM cell lines before declining by 48hrs. Analysis of MPM biopsies of patients progressing on ADI-PEG20 revealed upregulation of ASS1 and a concomitant increase in tumoral PD-L1 and CD3 positive T cells. ADI-PEG20 synergized with PD-1 blockade in the immunocompetent murine tumor model that was refractory to PD-1 inhibition.
Conclusion:
ASS1 and ADI-PEG20 modulate PDL1 expression via type I interferon signaling in malignant mesothelioma cell lines. Arginine deprivation with ADI-PEG20 combined with PD-1 blockade is synergistic and warrants further exploration in the clinic. A phase 1 trial of ADI-PEG20 combined with PD1 blockade is planned in patients with ASS1-negative cancers, including malignant mesothelioma.
Information from this presentation has been removed upon request of the author.
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P3.04 - Clinical Design, Statistics and Clinical Trials (ID 720)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.04-013a - CONFIRM: A Phase III Randomized Trial to Evaluate the Efficacy of Nivolumab versus Placebo in Relapsed Mesothelioma (ID 8542)
09:30 - 09:30 | Author(s): Peter Szlosarek
- Abstract
Background:
Mesothelioma is an incurable, apoptosis-resistant cancer caused in most cases by previous exposure to asbestos and is increasing in incidence. It represents a growing health burden but remains under-researched, with limited treatment options. Despite a significant number of clinical studies in the second line setting, no randomized study has been positive. Early promising signals of activity relating to both PD-L1 and PD-1 targeted treatment in mesothelioma implicate a dependency of mesothelioma on this immune checkpoint, and support the development of a randomized phase III trial to evaluate the efficacy of nivolumab. CONFIRM is the first ever placebo controlled, randomized phase III trial of a PD-1/PD-L1 immune checkpoint inhibitor in mesothelioma.
Method:
The primary objective is to determine whether nivolumab increases overall survival (OS) in relapsed mesothelioma. Secondary objectives are to determine whether nivolumab a) increases progression-free survival, b) increases response rate, c) has good safety/tolerability, and d) results in acceptable patient quality of life and cost per quality adjusted life year. A translational study will be undertaken to determine the correlation between OS and i) PD-L1 expression, ii) mutational burden (estimated by genome-wide analysis of copy number alterations), iii) immunotranscriptomic profile. Developed by researchers at the Universities of Leicester and Southampton on behalf of the UK NCRI Lung Clinical Studies Group the trial is co-ordinated by the Cancer Research UK Southampton Clinical Trials Unit in the UK, within the Centre of Cancer Immunotherapy. The trial will recruit 336 patients with pleural or peritoneal mesothelioma who have received at least two prior lines of therapy, from UK sites between March 2017 and 2021. We are also investigating opening recruitment to international sites. Patients will be randomized 2:1 (treatment: control), stratified according to epithelioid vs. non-epithelioid and center, to receive 240mg nivolumab (anti PD-1 antibody) monotherapy or saline placebo as a 30-minute intravenous infusion. Allocation will be double-blind. Treatment will be on day one of each 14-day cycle, until disease progression for a maximum of 12 months. Trial follow up will continue for 6 months after the last participant has progressed, or completed or discontinued treatment. The trial is powered (80%, with 2-sided 4% significance level) to detect a hazard ratio of 0.7 using an adjusted Cox regression model (time-to-event) and will be analyzed using intention-to-treat. This trial is funded by Cancer Research UK (C16728/A21400) and Bristol Myers Squibb (CA 209-841). Trial registrations: NCT03063450 and ISRCTN79814141.
Result:
Section not applicable
Conclusion:
Section not applicable
