IL-15 and a Two-Step Maturation Process Improve Bone Marrow-Derived Dendritic Cell Cancer Vaccine.

Ananda Mookerjee,Lana E Kandalaft,Michele Graciotti

doi:10.3390/cancers11010040

Abstract

In the last 20 years, dendritic cells (DCs) have been largely used as a platform for therapeutic vaccination in cancer patients. However, despite its proven safety and ability to induce cancer specific immune responses, the clinical benefits of DC-based immunotherapy are currently very limited. Thus, novel approaches are still needed to boost its efficacy. Our group recently showed that squaric acid treatment of antigens is an important adjuvant that can increase vaccine-induced downstream immune responses and therapeutic outcomes. Here we further improved this dendritic cell vaccine formulation by developing a new method for differentiating and maturing DCs from their bone marrow precursors. Our data demonstrate that bone marrow-derived DCs differentiated with GM-CSF and IL-15 and matured with a maturation cocktail in two steps present a more mature and immunogenic phenotype, compared to standard DC preparations. Further suppression of the prostaglandin E2 pathway achieved even more immunogenic DC phenotypes. This vaccine was more potent at delaying tumor growth, improved animal survival and induced a more immunogenic and Th1-skewed T cell response in an ovarian cancer mouse model. These promising results support future efforts for the clinical translation of this approach.

Highlights

Ovarian cancer is one of the most severe gynecologic cancers and has a very high mortality rate.Over 230,000 women are diagnosed with ovarian cancer worldwide each year, and about 140,000 women die from the disease [1]
Our results demonstrate that dendritic cells (DCs) differentiated with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-15 and matured in the presence of anti-CD40, anti-prostaglandin E2 (PGE2), anti-PGE2 receptor (EP2), anti-interleukin 10 (IL-10) receptor antibodies and CpG oligonucleotides (CpG) exhibited higher levels of anti-tumor response compared to canonical DC formulations
Improving the Efficacy of GM15-2 Step DCs through Inhibiting the Prostaglandin Pathway differentiation [36], function [37,38] and IL-12 production [36], we focused on further improving our DC preparation protocol to achieve an even more immunogenic DC vaccine by introducing an antibody against PGE2 and one against its putative receptor EP2 throughout the DC culture

Summary

Introduction

Ovarian cancer is one of the most severe gynecologic cancers and has a very high mortality rate.Over 230,000 women are diagnosed with ovarian cancer worldwide each year, and about 140,000 women die from the disease [1]. T cells isolated from ovarian cancer patients are able to recognize tumor-associated antigens (TAAs) and exhibit tumor-specific cytotoxic activity in vitro [5]. Based on this collective evidence, subsequent clinical studies employed dendritic cell (DC) based cancer vaccines in an attempt to stimulate and sustain a tumor specific T cell response. These studies [6] (and others for other types of cancer) [7] importantly demonstrated the clinical safety and feasibility of DC based vaccines

Methods

Results

Discussion

Conclusion