Live-attenuated bacteria as a cancer vaccine vector

Abstract

In the emerging field of active and specific cancer immunotherapy, strategies using live-attenuated bacterial vectors have matured in terms of academic and industrial development. Different bacterial species can be genetically engineered to deliver antigen to APCs with strong adjuvant effects due to their microbial origin. Proteic or DNA-encoding antigen delivery routes and natural bacterial tropisms might differ among species, permitting different applications. After many academic efforts to resolve safety and efficacy issues, some firms have recently engaged clinical trials with live Listeria or Salmonella spp. We describe here the main technological advances that allowed bacteria to become one of the most promising vectors in cancer immunotherapy.

Keywords::

• attenuation
• cancer vaccine
• danger signal
• listeriolysin
• Listeria monocytogenes
• live bacteria
• Pseudomonas aeruginosa
• Salmonella typhimurium
• type 3 secretion system

Financial & competing interests disclosure

A Le Gouëllec, B Toussaint, B Polack are all co-funders of APCure. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Live-attenuated bacterial strains have long been used for prophylactic vaccines, and firms have expertise in preparing and formulating these vaccines. Moreover, easy manufacturing makes these organisms attractive vaccine vectors.

• • Several pathogen-based active immunotherapies for the treatment of cancer are currently in preclinical and clinical development, such as the use of Salmonella spp., Pseudomonas aeruginosa and Listeria monocytogenes, each of which has different modes of action.

• • To stimulate an immune response, a tumor-associated antigen has to be delivered into an APC in the vaccinated host. Several techniques have been investigated in relation to bacterial pathophysiology, such as intracellular delivery via Listeria and S. typhimurium and protein-injection via the T3SSs of Pseudomonas and Salmonella spp.

• • Concomitant delivery of the antigen with the pathogen danger signal leads to the overall stimulation of the immune system and better long-term protection due to correlation of the microbial threat with the inflammatory response.

• • The toxicity of these vectors was problematic until the molecular determinants of toxicity were discovered based on improved knowledge of microbial genetics. However, synthetic biology studies are also needed.

• • Bacterial vectors allow the delivery of complex antigens that can be optimized to stimulate both CD8 and CD4 T cells to obtain a long-term effector response while diminishing suppressor responses.

• • Numerous clinical trials are currently underway, mainly by three firms: Advaxis Inc., Aduro BioTech Inc. and VAXIMM.

• • Live-attenuated bacterial-based vaccines can be used in combination with current chemo-and radio-therapies or immune modulators (e.g., anti-cytotoxic T-lymphocyte antigen-4).