Novel combination immunotherapy for pancreatic cancer: potent anti‐tumor effects with CD40 agonist and interleukin‐15 treatment

Clinical & Translational Immunology

Bianca vonScheidt¹  Michael H Kershaw¹  Clare Y Slaney¹  Phillip K Darcy¹  Amanda J Oliver¹  Ashleigh S Davey¹  Filip Lardon²  Jorrit De Waele²  Evelien LJM Smits²  Jinthe Van Loenhout²  Jonas RM Van Audenaerde²  Delphine Quatannens²  Patrick Pauwels²  Elly Marcq²  Marc Peeters²  Geert Roeyen³ 

[1] Cancer Immunotherapy and Immune Innovation Laboratory Peter MacCallum Cancer Centre Melbourne VIC Australia;Center for Oncological Research (CORE) Integrated Personalized & Precision Oncology Network (IPPON) University of Antwerp Wilrijk Belgium;Department of Hepatobiliary, Endocrine and Transplantation Surgery Antwerp University Hospital Edegem Belgium;

关键词: CD40 agonist;    combination immunotherapy;    interleukin‐15;    natural killer cells;    pancreatic cancer;    T cells;   

DOI  :  10.1002/cti2.1165

来源: DOAJ

【 摘 要 】

Abstract Objectives With the poorest 5‐year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. 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 Response to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed. Results We demonstrated profound reduction in tumor growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented 8‐fold dose reduction of CD40 agonist without losing any efficacy. RNAseq analysis showed involvement of natural killer (NK) cell‐ and T‐cell‐mediated anti‐tumor responses and the importance of antigen‐presenting cell pathways. This combination resulted in enhanced infiltration of tumors by both T cells and NK cells, as well as a striking increase in the ratio of CD8+ T cells over Tregs. We also observed a significant increase in numbers of dendritic cells (DCs) in tumor‐draining lymph nodes, particularly CD103+ DCs with cross‐presentation potential. A critical role for CD8+ T cells and involvement of NK cells in the anti‐tumor 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. Conclusion These novel preclinical data support initiation of a first‐in‐human clinical trial with this combination immunotherapy strategy in pancreatic cancer.

【 授权许可】

Unknown