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453 Novel combination immunotherapy for boosting and priming immune responses in pancreatic cancer: strong anti-tumour effects with interleukin-15 and CD40 agonist treatment
  1. Jonas Van Audenaerde1,
  2. Elly Marcq1,
  3. Bianca von Scheidt2,
  4. Ashleigh Davey2,
  5. Amanda Oliver2,
  6. Jorrit De Waele1,
  7. Delphine Quatannens1,
  8. Jinthe Van Loenhout1,
  9. Patrick Pauwels3,
  10. Geert Roeyen3,
  11. Filip Lardon1,
  12. Clare Slaney2,
  13. Marc Peeters3,
  14. Michael Kershaw2,
  15. Phillip Darcy2 and
  16. Evelien Smits1
  1. 1University of Antwerp, Wilrijk, Belgium
  2. 2Peter MacCallum Cancer Centre, Melbourne, Australia
  3. 3Antwerp University Hospital, Edegem, Belgium


Background With the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. In this era of combination immunotherapies, we sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer.

Methods Two different mouse models of pancreatic cancer were used to assess the potential of this combination regimen. Therefore, effects on tumour growth kinetics and survival were charted. Differential effects on immune signatures was investigated using RNA sequencing. Functional immune subset involvement was tested using different immune depletion experiments and multicolour flow cytometry in different relevant immune sites. Immune memory was checked using re-challenge experiments.

Results We demonstrated profound reduction in tumour growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented dose reduction of CD40 agonist without losing any efficacy (fig 1). RNA sequencing analysis showed involvement of natural killer cell and T cell mediated anti-tumour responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumours by both cytotoxic T cells and natural killer cells, as well as a striking increase in the ratio of CD8+ T cells over T regulatory cells. We also observed a significant increase in numbers of dendritic cells in tumour draining lymph nodes, particularly CD103+ dendritic cells with cross-presentation potential. A critical role for CD8+ T cells and involvement of natural killer cells in the anti-tumour effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8+ T cells only when both interleukin-15 and the CD40 agonist were combined.

Abstract 453 Figure 1

Tumour kinetics and survival in Panc02 (left) and KPC (right) pancreatic cancer mouse models

Conclusions We demonstrated profound synergistic anti-tumour effects upon combination of CD40 agonist and interleukin-15 treatment in mouse models of pancreatic cancer. This preclinical data supports initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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