HPB O05 Targeting the host in Pancreatic Cancer: A Novel Combination Therapeutic from Bench to Bedside

Abstract

Abstract Background We have designed a novel therapeutic approach to improve immunity whilst simultaneously reversing immune suppression in pancreatic cancer. Radiotherapy can cause the release of tumour specific antigens from lethally irradiated cells, as well as the generation of neopeptides resulting from novel mutations. In addition, Eganelisib, a small molecule inhibitor that blocks the pathway responsible for the phenotypic switch towards a suppressive phenotype in myeloid cells (PI3K-gamma) promotes antitumour immunity. We hypothesise that combined treatment will improve anti-tumour immunity in pancreatic cancer. Methods To generate primary pancreatic tumours, (KPC) pancreatic cancer cells were injected directly into the pancreas. Radiotherapy was delivered in 3 fractions of 4Gy via CT guidance. PI3K-gamma inhibition was carried out using TG100-115. For immune phenotyping, tumours were analysed by flow cytometry, multiplex immunohistochemistry and RNA sequencing. Combination treatmenthas been applied to primary human tissue slices (Avatars) in dynamic perfusion culture. Results In a preclinical model of pancreatic cancer, combined treatment with radiotherapy and Eganelisib resulted in significantly increased overall survival. Analysis of the tumour immune microenvironment in this group revealed decreased numbers of suppressive myeloid cells and increased numbers of cytotoxic CD8 T cells. RNA sequencing data demonstrated that pathways associated with innate inflammation and adaptive antitumor immunity were significantly elevated. Conclusions We have used our preclinical data to drive the translation of this novel therapeutic combination. Preclinical data has provided robust evidence that this combination approach results in effective antitumour immunity that may render tumours sensitive to immune checkpoint therapy. We are currently designing a Phase I clinical trial combining MR-LINAC guided radiotherapy with Eganelisib for patients with locally advanced pancreatic cancer.