Virtual Library
Start Your Search
Pierre-Olivier Gaudreau
Author of
-
+
P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
-
+
P1.04-11 - Depicting the Intra-Tumoral Viral and Microbial Landscape of Localized NSCLC Using Standard Next Generation Sequencing Data (ID 1126)
09:45 - 18:00 | Presenting Author(s): Pierre-Olivier Gaudreau
- Abstract
Background
Studies from our group and others have shown that bacteria and viruses present in the tumor may impact therapeutic responses. In the specific context of non-small cell lung cancer (NSCLC), intra-tumoral viral DNA and bacteria have been reported previously to be linked to therapeutic outcomes. However, the interplay between intra-tumoral microorganisms and the host immune response in NSCLC remains unknown. Moreover, the prognostic and predictive therapeutic value of localized NSCLC-specific microbial composition has yet to be defined.
Method
RNA-sequencing (RNA-seq) (n=82) and whole exome sequencing (WES) (n=80) was performed on surgically resected (pTNM I-III) tumors from lung cancer patients enrolled in the ImmunogenomiC prOfiling of NSCLC (ICON) project. Intra-tumoral bacteria, viruses and fungi were queried with MetaPhlAn2, a bioinformatical analysis pipeline which employs unique clade-specific marker genes, using reads from RNA-seq and WES that did not map to the human genome/transcriptome. Generated data were correlated to patients’ clinicopathologic parameters as well as immune profiling using previously validated multiplex IHC panels based on Vectra 3.0™ multispectral microscopy IHC panels and image analysis (InForm™ 2.2.1 software).
Result
Our analyses revealed that 18.29% (n=15/82) of tumors contained bacterial signatures. The most frequent bacterial signature was related to Escherichia (n=9/15). Moreover, 6.49% (n= 5/77) of tumors had evidence of human viral signatures, including the Epstein-Barr virus (n=1/5). No tumors contained fungal signatures. Preliminary clinicopathologic analyses suggested that patients whose tumors harbor bacterial signatures had a trend towards decreased overall survival (p=0.12). Tumors from former smokers were also more likely to contain bacterial signatures (p=0.11). Preliminary multiplex immune cell IHC analyses did not highlight statistically significant associations with the presence of intra-tumoral bacteria.
Conclusion
Our results suggest that a significant proportion of localized NSCLC tumors may harbor components of the human microbiome. Further studies using larger cohorts and dedicated intra-tumoral microbiome and virome methodologies will be needed to better define these findings and to delineate associations with the local immune infiltrate.
-
+
P1.04-26 - EMT-Associated Response and Resistance to MEK Inhibitor and Immune Checkpoint Blockade Combinations in KRAS-Mutant NSCLC (ID 1129)
09:45 - 18:00 | Presenting Author(s): Pierre-Olivier Gaudreau
- Abstract
Background
Current work by our group using mutant KRAS and TP53 (KP) mouse models of NSCLC have shown that rationally designed therapies combining PD-L1 immune checkpoint blockade (ICB) with MEK inhibitors (MEKi) significantly decreases tumor growth and metastases compared to either monotherapies in syngeneic KP mice tumors. Despite these encouraging results, therapeutic resistance still occurs. Analyses from these tumors showed an increase in Tregs and CTLA-4 immune checkpoint expression. As anti-CTLA-4 ICB is particularly effective in increasing the CD8 / Treg ratio, we hypothesized that the addition of this agent may improve the outcome.
Method
Using in vivo KP syngeneic mouse models, we compared tumor size, tumor weight and lung metastatic nodules between two treatment regimens: the triple combination of selumetinib (MEKi) and anti-PD-L1 with either: 1) anti-CTLA-4 or; 2) IgG2b isotype control. FACS-based immunoprofiling was conducted at the time of response (5 weeks following treatment initiation) and resistance (maximal tumor volume). Whole tumors at the time of response and resistance, as well as ex vivo resistant cell lines, were also characterized by qPCR and Western Blotting (WB). Moreover, whole tumors from multiple treatment combinations and KP models were processed for custom codeset Nanostring mRNA analyses.
Result
The addition of anti-CTLA-4 to anti-PD-L1 and MEKi improved survival in the epithelial 393P KP mouse model (HR=3.517; p=0.03). Because FACS immunoprofiling of cytotoxic CD8+ T cells subtypes, NK cells and Tregs did not reveal statistically significant changes (p>0.05), we investigated potential tumor-intrinsic mechanisms. All resistant 393P cell lines displayed a mesenchymal morphology. Furthermore, whole tumors from the anti-CTLA-4 group demonstrated significantly less expression of Zeb1 (WB; p=0.05) at the time of response. Nanostring analyses comparing anti-PD-1 + anti-CTLA-4 vs anti-PD-L1 monotherapy in 344SQ KP mesenchymal tumors also showed statistically significant downregulation of epithelial-to-mesenchymal (EMT) markers (p=0.001). Finally, in vivo experiments using resistant 393P (MEKi + ICB) and mesenchymal 344SQ cells, demonstrated abrogation of the survival benefit initially observed with sensitive epithelial 393P cells upon treatment with combination therapies.
Conclusion
The combination of a MEKi, anti-PD-L1 and anti-CTLA-4 improves survival in epithelial syngeneic KP pre-clinical models of NSCLC, and this benefit is associated with downregulation of EMT markers. Therefore, further in-depth studies are required to understand the effect of ICB on EMT. In an upcoming single center, Phase I / II clinical trial, two combination schedules of selumetinib, tremelimumab and durvalumab will be compared with historical controls in patients with previously treated, metastatic NSCLC.
-
+
P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 2
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
-
+
P2.04-19 - Neoadjuvant Chemotherapy Is Associated with Immunogenic Cell Death and Increased T Cell Infiltration in Early-Stage NSCLC (ID 1122)
10:15 - 18:15 | Presenting Author(s): Pierre-Olivier Gaudreau
- Abstract
Background
Recent success using immune checkpoint blockade (ICB) in the metastatic setting has raised the need to understand the immune microenvironment (IME) in early-stage disease. Moreover, pre-clinical evidence suggests that cytotoxic agents can modulate this IME. A recent study conducted by our group showed that non-small cell lung cancer (NSCLC) patients who received neoadjuvant chemotherapy followed by surgery (NCT), as compared to patients who received upfront surgery (US), had higher densities of CD3+ lymphocytes and CD68+ tumor-associated macrophages (TAMs). CD3+CD4+ lymphocytes and TAMs also correlated with better clinical outcomes. In this study, we explored the relationships between NCT and the IME by harvesting tumor samples of multiple surgical NSCLC cohorts.
Method
The PROSPECT microarray database was queried in NCT (n=45) and US (n=200) patients to investigate differentially expressed genes related to immunogenic cell death (ICD), susceptibility to CD8+ T cell and NK cell cytotoxicity, priming of antigen presenting cells, immunosuppressive enzymes and intra-tumoral cytokines. Available data from the ImmunogenomiC prOfiling of NSCLC (ICON) and other surgical NSCLC cohorts was evaluated to determine: 1) differential immune profiling using FACS (NCT=17; US=39) and multiplex IHC imaging (NCT=10; US=72); 2) plasma circulating cytokines (NCT=18; US=73); 3) tumor mutational burden (TMB) (NCT=40; US=61). Participants who received NCT or US were excluded according to these criteria: 1) concurrent treatment in addition to NCT; 2) sarcomatoid and small cell histologies; 3) clinical or pathological TNM Stage 4 disease; 4) synchronous malignancies other than lung.
Result
PROSPECT NCT patients expressed increased damage-associated molecular pattern (DAMP) genes (HSPA2, HSPA4, HSPE1, and S100A2; p<0.05) and T cell-related chemotaxis and antigen presentation genes (CXCR7, CD1A; p<0.05). Concordantly, the ICON cohort FACS results showed that NCT patients display increases in: 1) infiltration of CD8+ T cells (p=0.004); 2) proliferating Ki67+CD8+ T cells (p=0.02); 3) tissue resident memory CD8+CD103+ (p=0.02) and CD4+CD103+ non-Treg cells (p=0.01). Trends from the ICON multiplex IHC also highlighted increases in CD8+ T cells (p=0.09), CD20+ cells (p=0.08), as well as PD-L1+ malignant cells (p=0.08) and PD-L1+ TAMs (p=0.08) in NCT patients, the latter finding being supported by increased circulating MCP-1 (p=0.03). TMB was similar between NCT and US groups (p=0.912).
Conclusion
Our data provides the first evidence of ICD (i.e., increased DAMP gene expression) following NCT in human early-stage NSCLC. Furthermore, our data highlights the association of NCT with a favorable IME (i.e., increased T cell infiltration), supporting the rationale of NCT and ICB combinations in localized NSCLC.
-
+
P2.04-37 - Phase I/II Trial of Durvalumab and Tremelimumab with Continuous or Intermittent MEK Inhibitor Selumetinib in Advanced NSCLC (ID 1130)
10:15 - 18:15 | Presenting Author(s): Pierre-Olivier Gaudreau
- Abstract
Background
Despite therapeutic progress in other molecular subsets of non-small cell lung cancer (NSCLC), little progress has been made for KRAS-mutant NSCLC. Because RAS remains an elusive pharmacological target, agents targeting downstream elements of the MAPK signaling pathway have been developed, including MEK inhibitors. However, substantial benefits have not been achieved due to the development of drug resistance. Current strategies to improve outcomes in this population include MEK inhibitors and PD-1 / PD-L1 immune checkpoint blockade (ICB) combinations (e.g., NCT03225664). On the other hand, combined anti-CTLA-4 and PD-1 / PD-L1 axis ICB improves response rates in melanoma, but similar benefits remain to be seen in NSCLC: MYSTIC trial updates failed to show a progression-free survival (PFS) advantage over standard of care, and CheckMate 227 reported significantly longer PFS with first-line double ICB in the high tumor mutational burden subgroup only. Thus, the objectives of this study are: 1) to determine the safety and efficacy of combined MEK inhibition, anti-PD-L1 and anti-CTLA-4 and; 2) to unveil mechanistic insights for response and resistance.
Method
This is a single center, Phase I/II study comparing two combination schedules of selumetinib (AZD6244, ARRY-142886), tremelimumab and durvalumab with historical controls in patients with previously treated, unresectable NSCLC. Forty patients will be accrued at the University of Texas MD Anderson Cancer Center. In the first arm, participants receive selumetinib PO BID on days 1-7 and 15-21 and durvalumab IV on day 1. Participants also receive tremelimumab IV on day 1 for courses 1-4 (courses repeat every 28 days in the absence of disease progression or unacceptable toxicity). The second arm differs by the continuous selumetinib schedule: PO BID on days 1-28. Primary objectives include the maximum tolerated dose (MTD; dose-escalation phase) and PFS (dose expansion phase). Standard 3+3 design will be applied to determine the MTD among the three pre-defined dose levels. Estimated PFS will be provided with 95% confidence interval. Secondary objectives include: 1) response rate by RECIST 1.1; 2) disease control rate (complete response + partial response + stable disease); 3) overall survival; 4) safety and; 5) duration of response. Exploratory objectives will assess biomarkers of response and resistance in pre- and on-treatment biopsies as well as peripheral blood using immune profiling, transcriptome and protein readouts.
Result
Section not applicable (Clinical Trial in Progress)
Conclusion
The estimated start date for this trial (NCT03581487) is April 15th, 2019, and the estimated study completion is scheduled for April 2021.
