A combined bioengineered IL-12 and immune checkpoint inhibitor therapy shows differential in vivo responses in immune-cold pancreatic ductal adenocarcinoma (PDAC)


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Chanthirika Ragulan1, Patrick Varun Lawrence1, Ps Hari1, Krisha Desai1, Jun Ishihara2, Sadanandam Anguraj1
1Institute of Cancer Research (ICR), 2Imperial College London

Abstract

Background

PDAC remains a lethal disease. Immune checkpoint inhibitor (ICI) is approved only for those PDAC patients (2-3%) with microsatellite instable/mismatch repair-deficient tumours. ICI's inefficiency in PDAC is attributed to a highly immunosuppressive (immune cold) and desmoplastic tumour microenvironment (TME). To turn immune cold to hot tumours, we applied a bioengineered collagen-binding-domain-linked IL-12 (CBD-IL-12; T-cell stimulant with optimal delivery into collagen-rich TME) and studied the differential responses to anti-PD1 (ICI) in selected immune-cold PDAC mouse models.

Method

Using our in silico method, 12 mice from three different genetically engineered mouse (GEM) PDAC models were categorised into immune-hot (T-cell and its machineries enriched) or -cold (T-cell low/devoid). Collagen profiles using gene expression were assessed. Cell lines derived from these models were used to develop syngeneic orthotopic mouse models that were treated with vehicle control or two treatment arms - CBD-IL-12 (25mg/mouse) or CBD-IL-12 + anti-PD1 (100mg/mouse). Tumour growth was monitored by in vivo bioluminescent imaging (IVIS) and characterised by transcriptome profiling and multiplex immunohistochemistry (IHC).

Results

We identified two GEM/syngeneic models (7947 and 7784; among 12 models) as immune-cold (7947-collagen-high, 7784-collagen-low). 7947-collagen high mice showed significantly (p=0.1) improved body weights in two treatment arms – CBD-IL12 or combination with anti-PD1 than control. There was a significant (p<0.02) reduction in tumour burden (IVIS/wet tumour weight) and distant metastasis to liver peritoneum and spleen in mice from the two treatment arms than control. Intriguingly, there was no liver metastases in treatment arms, which was found in vehicle control. Furthermore, an increase in apoptosis was observed in both mono (p=0.004) and combination (p=0.06) therapies. Differential transcriptome analysis revealed a greater than 2-fold increase in T-cell-specific-genes in the treatment than control. This was further confirmed by IHC analysis. In contrast to 7947 model, 7784 model with low collagen showed no significant differences in any of the above phenotypes. 

Conclusion

Our results demonstrate a novel strategy of potentiating response to anti-PD1 therapy in immune-cold/collagen-high tumours using CBD-IL-12 and highlight the importance of a potential personalised ICI combined therapeutic approach in the clinic. 

Impact statement

Significant reduction in metastatic burden upon CBD-IL-12 treatment may indicate a potential therapeutic option for metastatic-PDAC patients in the future.