Clinical development of Listeria monocytogenes-based immunotherapies

Abstract

Active immunotherapy targeting dendritic cells (DCs) has shown great promise in preclinical models and in human clinical trials for the treatment of malignant disease. Sipuleucel-T (Provenge, Dendreon, Seattle, WA), which consists of antigen-loaded dendritic cells (DCs), recently became the first targeted therapeutic cancer vaccine to be approved by the US Food and Drug Administration (FDA). However, ex vivo therapies such as Provenge have practical limitations and elicit an immune response with limited scope. By contrast, live-attenuated Listeria monocytogenes (Lm) naturally targets DCs in vivo and stimulates both innate and adaptive cellular immunity. Lm-based vaccines engineered to express cancer antigens have demonstrated striking efficacy in several animal models and have resulted in encouraging anecdotal survival benefit in early human clinical trials. Two different Lm-based vaccine platforms have advanced into phase II clinical trials in cervical and pancreatic cancer. Future Lm-based clinical vaccine candidates are expected to feature polyvalent antigen expression and to be used in combination with other immunotherapies or conventional therapies such as radiotherapy and chemotherapy to augment efficacy.

Copyright © 2012 Elsevier Inc. All rights reserved.

Figures

Figure 1

Listeria monocytogenes (Lm)-based vaccines induce robust innate and adaptive immunity. Two key attributes contribute to Lm's potency: the ability to target CD8α+ DCs in vivo, and the intracellular localization and triggering of cytosolic NLRs and STING host cell PAMP sensors. (A) Upon intravenous administration the majority of live Lm are found within CD8α+ DCs that have been shown to be critical for the induction of antigen-specific T-cell responses in vivo. (B) The quality and magnitude of the induced T-cell response depends on the subcellular localization of Lm upon infection of the host antigen-presenting cell (APC). Lm strains that are able to escape from the phagolysosome into the cytosol of the APC (cytosolic Lm) induce robust T-cell immunity of high quality. Lm strains that remain in the phagolysosome fail to induce protective T-cell immunity, partly due to the MyD88-dependent induction of IL-10.