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H. Inoue
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OA13 - Immunotherapy in Malignant Pleural Mesothelioma: Current Status of Trials and New Approaches (ID 392)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
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OA13.05 - Somatic Genetic Alterations and Immune Microenvironment in Malignant Pleural Mesothelioma (ID 5087)
15:05 - 15:15 | Author(s): H. Inoue
- Abstract
- Presentation
Background:
The genomic landscape of malignant pleural mesothelioma (MPM) is not well understood. Advanced high-throughput sequencing technologies allow comprehensive characterization of genetic alterations. Knowledge of the somatic mutations and the immune microenvironment in patients with MPM will help to develop effective targeted therapies.
Methods:
We examined biopsy specimens from 12 MPM patients (8 epithelioid and 4 biphasic) that were removed during maximal cyto-reductive surgery. Specimens from 3 different sites (anterior, posterior and diaphragm, a total of 36 tissue samples) were studied through whole exome sequencing, T cell receptor (TCR) repertoire analysis of tumor-infiltrating T cells (TILs), and expression levels of immune-related genes. We also performed in silico prediction of potent neoantigens derived from non-synonymous somatic mutations in each specimen. For the comparison of tumor tissues from 3 different sites, we performed hierarchical clustering to assess the tumor heterogeneity and differences in immune environment.
Results:
High mutation/neoantigen load was significantly correlated with higher clonal expansion of TILs (R=0.46) and high expression levels of immune-associated cytolytic factors, granzyme A (R=0.25) and perforin 1 (R=0.48), in tumor tissues. In the clustering analysis, heterogeneous MPM cases revealed unique neoantigens and clonotypes of TILs that were restricted to each of tumor site, suggesting infiltration of the neoantigen-specific T cells. Further sub-analysis according to histologic types showed that biphasic tumors had higher mutation/neoantigen load and stronger oligo-clonal T cell expansion (p=0.01) than epithelioid tumors.
Conclusion:
Our analysis demonstrated a significant correlation between somatic mutation/neoantigen load, clonality of TILs, and the immune-related tumor microenvironment in MPM. Our findings suggest that high mutation/neoantigen load in tumor cells might promote effective expansion and infiltration of functional (tumorocidal) T cells into the tumor bed. These findings provide a rationale for selecting MPM patients who can benefit from treatment with immune checkpoint blockades. This may accelerate development of the neoantigen targeting TCR-engineered T cell therapy for MPM.
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-058 - In-Depth Molecular Characterization of T Cell Clonal Expansion Induced by Anti-PD1 Therapy in NSCLC (ID 5183)
14:30 - 14:30 | Author(s): H. Inoue
- Abstract
Background:
Inhibitors of PD1/PD-L1 checkpoint have been shown to be active among a broad range of cancers including NSCLC. They induce proliferation of T cells within the tumor microenvironment (as revealed by IHC) leading to tumor eradication. There is however lack of detailed molecular characterization of these proliferating T cells including the dynamics of their clonalilty during treatment and its correlation with response, their antigen specificity and the molecular changes induced in the expanded clones at single cell level. Such understanding will serve as a biomarker to detect early response after one dose of therapy, ascertain efficacy (especially when radiological assessments are equivocal) and guide determination of optimal duration of therapy. Furthermore, insight into molecular changes in the proliferating T cell clones induced by these agents at single-cell level will identify the baseline unique characteristics of T cells clones that undergo rapid expansion upon exposure to anti-PD1 therapy, define the molecular mediators of tumor eradication in responders and serve as a foundation for the development of novel treatment strategies for non-responders.
Methods:
We performed next-generation T cell receptor alpha/beta chain sequencing on serially obtained tumor and PBMC samples from 54 NSCLC patients undergoing anti-PD1 therapy. We compared the dynamics of the T cell repertoire in responders versus non-responders within unsorted PBMC and in CD8 positive/negative T cells. We also assessed the expression of key mediators of cytotoxicity and T cell activation/dysfunction in these expanded CD8 T cell clones at single cell level among responders and non-responders.
Results:
We identified concordant early clonal T cell expansion after 1-4 doses of anti-PD1 therapy within the tumor and PBMC of responders. We confirmed these expanded T cell clones to be CD8 positive subgroup of CD3+ T cells in responders and CD8 negative subgroup of CD3+ T cells in non-responders. Furthermore, among responders we found that persistence of the expanded T cell clones for several months while on treatment is associated with durable response. Additional results on antigen specificity and gene expression of the expanded T cell clones in responders versus non-responders will be presented.
Conclusion:
Our results showed that early concordant clonal expansion of a defined population of CD8+ T cells detected both within the tumor and PBMC correlate with response to therapy. We also confirmed that the persistence of these unique T cell clones several months after their initial expansion correlates with durable response.
