Cancer vaccinesSection II: Diverse vaccine platformsClinical Development of Listeria monocytogenes–Based Immunotherapies
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.