About the Project
BACKGROUND
Immunotherapeutic strategies are showing efficacy in several cancer types including melanoma and lung, but progress in Pancreatic Ductal Adenocarcinoma (PDAC) has been slow with poor efficacy of single agent regimens. However, our work, and the work of others is revealing that understanding active immune avoidance mechanisms specific to PDAC, and targeting these using combination therapies can lead to meaningful responses. Our preclinical team demonstrated that CXCR2 inhibition enhances T-cell infiltration through inhibiting myeloid-derived suppression of T-cell recruitment in murine models, and is effective in increasing survival in combination with checkpoint inhibition. Based on these data, we commenced a clinical trial of this combination, under the auspices of Precision-Panc, a dynamic therapeutic development platform for the investigation and treatment of PDAC.
As part of our studies through the International Cancer Genome Consortium (ICGC), we identified 4 transcriptomic subtypes of primary untreated PDAC. This classifier is associated with varying prognostic outcomes and may predict response to therapy. We aim to extend these data to define the effects of current standard of care treatment on the molecular pathology of PDAC, specifically the immune mechanisms that are dysregulated in this context; and to use these insights to define vulnerabilities that can be exploited for treatment. This is important, as therapeutic development of immune agents is mostly focused in 2nd-line, after initial chemotherapy in many cancer types, particularly pancreatic cancer. Emerging data suggests that chemotherapy significantly alters the immune system and the tissue microenvironment (TME), with response to immune therapy potentially determined by the type of prior treatment. Whilst these data suggest that pre-treatment may profoundly impact immunotherapeutic approaches, we have minimal understanding of the molecular pathology of post-chemotherapy tumours, in any cancer, let alone PDAC. This is of central importance as most immune therapies are being developed after patients have received chemotherapy.
METHODS AND AIMS
This project will employ a number of techniques including flow cytometry, transcriptomics, multiplex IHC, digital pathology spatial immune profiling and integrative bioinformatics utilising murine model samples as well as human biopsy and surgically resected material obtained before and after chemotherapy. Overall this project aims:
1) To better understand the immune processes after 1st-line chemotherapy in murine models and patients with pancreatic cancer.
2) To establish if molecular subtypes can be integrated with immune profile features to enable a more stratified approach for the treatment of PDAC in particular immunotherapies.
Keywords: Pancreatic cancer; subtypes, immune profile; mouse models; predictive biomarkers; biopsy
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