Introduction
Pancreatic cancer (PC) remains insensitive to immune checkpoint inhibitors (ICIs) such as anti-PD1 and anti-CTLA4 due to its immunosuppressive microenvironment. While evidence suggests chemotherapy causes immunogenic cell death and promotes T cell activation, it has not enhanced the efficacy of ICIs) in PC. Even the combination of chemotherapy and ICIs with other immune priming agents such as anti-CD40 antibodies (αCD40) are yet to improve treatment outcomes as the effective dose does not reach the tumour site and often results in immune-related adverse events. For this reason, we developed a biodegradable polymeric implant and assessed its safety and efficacy in delivering αPD1+αCD40 in a pancreatic mouse model compared to systemic administration of those agents with chemotherapy.
Material and Methods
Implants containing αCD40+αPD1 or empty implants (control) were prepared as described by our group previously and inserted into C57BL/6 mice bearing Luc-tagged KPC subcutaneous tumours. Anti-tumour efficacy against systemic treatment was determined by measuring tumour growth using Bioluminescence imaging (N=10 mice per cohort). Mice also received gemcitabine+nab-paclitaxel chemotherapy. Immune system activation was analysed using flow cytometry and LEGENDplex assay on the tumour-draining lymph node and plasma, respectively.
Results and Discussions
The radiance intensity of tumours was significantly lower in mice treated with immunotherapy implants compared to other groups indicating local treatment's efficiency in restraining tumour growth. Further, mice treated with the immunotherapy implants showed no evidence of metastasis. Inflammatory cytokines including GM-CSF and IFNB and IL-23 were elevated in the systemic compared to the local treatment arm, leading to the activation of T cells marked by a higher percentage of CD8+PD1+ T cells compared to the local arm. On the contrary, the proportion of LY6C- M1-anti-tumour macrophages was significantly higher in the TDLN and spleen of the localised group, while the LY6C+ M1-pro-tumour macrophages were significantly higher in the systemic treatment arm.
At the later time point, there was an elevated amount of activating cytokines belonging to the IL1 family in the local compared to the systemic treatment arm, suggestive of a late and prolonged effect of the localised treatment due to a gradual and controlled release of the drugs from the implantable device. This finding was confirmed by analyzing the implant's release profile. We found 8% of the antibodies were still present at the end of the study.
Conclusion
Local administration of αCD40+αPD1 immunotherapy with chemotherapy was safe and more efficient in restraining tumour growth and metastasis than systemic treatment.