Elahe Minaei
University of Wollongong
Abstract
Despite promising results in the treatment of many cancers with immune checkpoints inhibitors (ICIs) like anti-PD1, pancreatic cancer (PC) remains insensitive to immunotherapy due to its immunosuppressive microenvironment. While evidence suggests that chemotherapy sensitises tumours to immunotherapy by causing immunogenic cell death and promoting T cell activation, it has not enhanced the efficacy of ICIs in PC. Combining chemotherapy with ICIs and other immune priming agents like anti-CD40 hasn't shown significant treatment enhancement due to suboptimal dosing to avoid immune-related adverse events. We investigated chemotherapy's effect on immune gene expression in PC and its stroma to assess its potential combination with immunotherapy in PC. Subsequently, we evaluated the safety and efficacy of a biodegradable polymeric implant in delivering anti-PD1 and anti-CD40 in a pancreatic mouse model compared to systemic administration, all in the presence of chemotherapy.
Materials & Method
- Gene expression profiling was conducted using the Immune Profiling Panel (NanoString Inc) on RNA isolated from human pancreatic stromal and tumour FFPE specimens from treatment-naïve (TN=3) or neoadjuvant chemotherapy-treated (NAC=3) patients.
- PCL capsules were fabricated via pultrusion, with inner alginate containing αCD40 and/or αPD1 fabricated using a 3D bio-printer and inserted into capsules to form the implant.
- Implants containing αCD40+αPD1 or empty implants were inserted into C57BL/6 mice with Luc-tagged KPC subcutaneous tumours for local treatment (LT) and control groups, respectively. Anti-tumour efficacy was assessed by comparing tumour growth via bioluminescence imaging with a group receiving fractionated systemic treatment (ST) with αCD40+αPD1. LT and ST groups received systemic chemotherapy (Gemcitabine + Nab-paclitaxel). Each cohort consisted of 10 mice.
- Immune system activation was analysed using flow cytometry on tumour-draining lymph nodes (TDLN) and spleens of sacrificed mice after the last treatment (early sacrifice). LEGENDplex cytokine assay was performed on collected plasma at early (day 11) and late (day 22) sacrifices.
- Pre- and post-study loading capacity of implants was assessed via SDS page to determine release profiles.
Results & Discussion
- In both tumour and stromal tissue, genes associated with antigen processing and T cell function (CD8, CD3, IL2R, HLA-DR) were upregulated in patients who underwent neoadjuvant chemotherapy (NAC) compared to those who were treatment-naïve (TN) (P < 0.05). There was a higher abundance of cytotoxic T lymphocytes (CTLs) in NAC compared to TN, indicating the immunostimulatory effect of chemotherapy in PC.
- The group receiving local treatment was the only one with no evidence of metastasis. Radiance intensity was significantly lower in LT compared to ST and the control group (P = 0.02 and 0.0002, respectively), demonstrating the efficacy of localised treatment in restraining tumour growth compared to systemic therapy.
- In the early sacrifice cytokine assay, inflammatory cytokines such as GM-CSF, IFNB, and IL-23 were elevated in the ST group compared to LT, leading to T cell activation in the tumour-draining lymph nodes (TDLN) marked by a significantly higher percentage of CD8+PD1+ cells compared to LT. Conversely, the proportion of LY6C- M1 anti-tumour macrophages was significantly higher in the lymph nodes and spleen of LT compared to ST, while the LY6C+ M1 pro-tumour macrophages were significantly higher in ST compared to LT. Late cytokine results indicated similar levels of inflammatory cytokines in both treatment groups, including a significant increase in IL-23 in both LT and ST compared to the control. There were higher levels of other activating cytokines such as the IL1 family and IFNB in LT compared to ST, suggesting a late and prolonged effect of LT due to a gradual release profile of the implantable device. This was confirmed by analysing the release profile of implants at the early and late stages of the study - showing that 17% and 8% of the antibodies were still present in the implant, respectively.
Awards
1st Place
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Runner Up Awards
Four remaining Finalists will each receive a limited edition Promega Lab Set with LEGO® Elements and a Duffel Bag
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