Attenuated Listeria monocytogenes: a powerful and versatile vector for the future of tumor immunotherapy

Abstract

For over a century, inactivated or attenuated bacteria have been employed in the clinic as immunotherapies to treat cancer, starting with the Coley's vaccines in the 19th century and leading to the currently approved bacillus Calmette-Guérin vaccine for bladder cancer. While effective, the inflammation induced by these therapies is transient and not designed to induce long-lasting tumor-specific cytolytic T lymphocyte (CTL) responses that have proven so adept at eradicating tumors. Therefore, in order to maintain the benefits of bacteria-induced acute inflammation but gain long-lasting anti-tumor immunity, many groups have constructed recombinant bacteria expressing tumor-associated antigens (TAAs) for the purpose of activating tumor-specific CTLs. One bacterium has proven particularly adept at inducing powerful anti-tumor immunity, Listeria monocytogenes (Lm). Lm is a gram-positive bacterium that selectively infects antigen-presenting cells wherein it is able to efficiently deliver tumor antigens to both the MHC Class I and II antigen presentation pathways for activation of tumor-targeting CTL-mediated immunity. Lm is a versatile bacterial vector as evidenced by its ability to induce therapeutic immunity against a wide-array of TAAs and specifically infect and kill tumor cells directly. It is for these reasons, among others, that Lm-based immunotherapies have delivered impressive therapeutic efficacy in preclinical models of cancer for two decades and are now showing promise clinically. In this review, we will provide an overview of the history leading up to the development of current Lm-based immunotherapies, the advantages and mechanisms of Lm as a therapeutic vaccine vector, the preclinical experience with Lm-based immunotherapies targeting a number of malignancies, and the recent findings from clinical trials along with concluding remarks on the future of Lm-based tumor immunotherapies.

Keywords: Listeria monocytogenes; cancer vaccines; tumor immunotherapy; tumor-associated antigens; vaccine vectors and adjuvants.

Figure 1

Pivotal events in the development of Lm-based vaccines for tumor immunotherapy. The last two decades have seen the emergence of Lm-based vaccines and their first clinical application for cancer. In this timeline (not to scale), we depict several pivotal events that have led to their current stage of development and point to a future with improved Lm-based vaccines and treatment strategies.

Figure 2

Mechanisms of Lm-based vectors in tumor immunotherapy. Several mechanisms governing the efficacy of Lm-based immunotherapies are depicted in the accompanying figure. (1) There are several very effective methods of attenuation available to construct a highly immunogenic Lm-based vector usually involving deletion of one or more virulence genes. (2) Once attenuated, Lm-based vectors are highly versatile producers of tumor-associated antigens and other therapeutic proteins. (3) After administration, Lm-based vaccines selectively infect antigen-presenting cells, escape the phagosome, and secrete tumor-associated antigens that are delivered to a high-efficiency processing and presentation pathway for activation of tumor-specific CTLs. (4) The detection of Lm-derived PAMPs facilitates tumor-specific CTL activation through the upregulation of costimulatory molecules and the secretion of proinflammatory cytokines. (5) The resultant effect of Lm-based vaccination is the ability to break central tolerance and produce therapeutic anti-tumor CTL responses against self TAAs. (6) This tumor-specific CTL response is further aided by reduced tumor-associated immunosuppression as evidenced by diminished functionality and lower numbers of Tregs and MDSCs in the tumor microenvironment after Lm-based vaccination. (7) In addition to activation of tumor-specific CTL responses, recent reports demonstrate the ability of Lm-based vaccines to target primary and metastatic tumors for infection and directly kill tumor cells. Each of these mechanisms of Lm-based vaccines highlight their powerful potential as vectors for tumor immunotherapy and their versatility in terms of construction and efficacy.

Figure 3

Lm-based vaccine clinical trials pipeline. Numerous Lm-based vaccines have progressed through the discovery and preclinical phase of development and are now being administered to oncology patients for a number of indications. In this figure, we summarize publicly available information for some of the Lm-based vaccines in clinical testing currently or planned for clinical testing in the near future.