Elsevier

Seminars in Oncology

Volume 39, Issue 3, June 2012, Pages 311-322
Seminars in Oncology

Cancer vaccines
Section II: Diverse vaccine platforms
Clinical Development of Listeria monocytogenes–Based Immunotherapies

https://doi.org/10.1053/j.seminoncol.2012.02.008Get rights and content

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.

Section snippets

Bacterial-Based Vaccine Vectors

The immunostimulatory properties of live bacteria or bacterial components have been recognized as potential cancer therapies since the early 20th century. Work pioneered by Dr William Coley demonstrated that live organisms or bacterial extracts from the bacteria Streptococcus pyogenes and Serratia marscencens had potent anti-tumor activities in cancer patients. To date, several FDA-approved products are based on live-attenuated or killed bacteria, including Salmonella typhi Ty21a for typhoid

Lm-Based Immunotherapies

The striking potency of Lm-based immunotherapies has been demonstrated in multiple animal models of cancer and infectious disease.30, 31, 34, 37, 39, 40, 41, 42, 43 In addition to its potency, Lm offers a number of features favorable for tumor immunotherapy: (1) the ease of strain engineering that allows for the expression of multiple tumor antigens44; (2) Lm is not neutralized by an antibody response and is immunogenic upon repeat administration45, 46, 47; (3) antibiotic sensitivity, an

Lm-Based Immunotherapies Undergoing Clinical Evaluation

Once Lm strains that had been modified to decrease virulence while maintaining immunogenicity became available, the introduction into human hosts both healthy and cancer bearing became possible. The Lm platforms based on deletion of virulence genes and aberrant expression of PrfA have been evaluated in human clinical trials. The early clinical trials were intended to demonstrate safety and assess for signals of immune activation, but two trials also provided anecdotal evidence of efficacy.

Next Steps

With completion of multiple phase I trials showing acceptable safety profiles and a variable degree of immune activation and clinical activity, several phase II studies are underway to confirm safety and assess for signs of clinical activity. An additional phase I study is also examining the transcutaneous route of administration in healthy subjects. Many questions remain unanswered with regard to antigen selection, dose selection, dose interval, number of doses, requirement for inpatient

Future Combinations

For most cancer types, such as NSCLC and pancreatic cancer, any single agent vaccine, especially in the advanced disease setting, is unlikely to be of major therapeutic benefit. This is borne out in preclinical models more representative of tolerant tumors. Optimal combinations will likely have to induce a diverse repertoire of high avidity T cells. In addition to combinations with standard therapies such as radiation and chemotherapy, investigators have evaluated both heterologous prime-boost

Acknowledgment

The authors would like to thank Steven Bodovitz, Elizabeth Jaffee, Marcella Fassò, Aimee Luck Murphy and Justin Skoble for their critical review of the manuscript.

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    Financial disclosure: Dirk Brockstedt and Thomas Dubensky are shareholders in Aduro BioTech, Inc, a company developing immunotherapies that are based on Listeria monocytogenes.

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