Abstract
ObjectivesWith 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.MethodsResponse to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed.ResultsWe 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.ConclusionThese novel preclinical data support initiation of a first‐in‐human clinical trial with this combination immunotherapy strategy in pancreatic cancer.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the third most lethal cancer worldwide with a 5-year survival of barely 8%.1,2 It is even projected to become the second leading cause of cancerrelated death by 2030.3 To date, it remains one of the most aggressive and challenging malignancies because of a complex tumor microenvironment including a strong desmoplastic reaction,[4] low immunogenicity[5,6] and a molecular signature in favor of the tumor, driven by loss of multiple tumor suppressor genes.[7]
We sought to investigate whether the combined treatment of IL-15 and a CD40 agonist antibody may lead to augmented anti-tumor responses in PDAC
IL-15 is a powerful stimulator of natural killer (NK) cells and CD8+ T cells and induces CD44hi memory T cells
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the third most lethal cancer worldwide with a 5-year survival of barely 8%.1,2 It is even projected to become the second leading cause of cancerrelated death by 2030.3 To date, it remains one of the most aggressive and challenging malignancies because of a complex tumor microenvironment including a strong desmoplastic reaction,[4] low immunogenicity[5,6] and a molecular signature in favor of the tumor, driven by loss of multiple tumor suppressor genes.[7]. Patients are treated with either FOLFIRINOX or gemcitabine/nab-paclitaxel depending on their physical fitness. These treatments are associated with major toxicity issues and have limited impact.[8,9] New promising approaches that are successful in other cancer types, such as anti-PD-1 and anti-CTLA-4, have shown little improvement over treatment with gemcitabine.[10,11] This highlights the need for other novel compounds to enter the battle arena of PDAC
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