Aduro BioTech won a $867,846 grant through the DoD’s Congressionally Directed Medical Research Programs initiative to complete preclinical development of a live-attenuated Listeria monocytogenes–based therapeutic vaccine for prostate cancer. The grant will be used to generate Listeria strains that express a combination of tumor-associated prostate cancer antigens, which the firm says should help increase the likelihood that vaccination will trigger broader, more effective immune responses. The funds will in addition support evaluation of candidate vaccine strains in animal models, and toxicology and manufacturing of the lead strain in preparation for IND application.
Aduro has developed both a live attenuated Listeria vaccine platform and a killed but metabolically Active (KBMA) Listeria platform. The live-attenuated vaccines are based on a Listeria that lacks two wild-type genes required for pathogenicity, but not for immunogenicity. Deletion of actA blocks the ability of Listeria to spread from cell to cell, while deletion of lnlB blocks the direct uptake of Listeria by hepatocytes, minimizing the potential for liver-related toxicity.
The KBMA vaccines are designed to combine the safety of a killed vaccine with the potency of a live vaccine. This is achieved by building infrequent cross-links into the DNA of a Listeria strain that can’t repair the effective damage. Aduro says this inability to remove the cross-links means very few are needed to prevent the bacterium from replicating (by virtue of it not being able to separate its DNA into daughter strands), but still ensure most of the bacterial genes can be expressed, triggering innate immunity and allowing antigen presentation to T cells.
Aduro’s L. monocytogenes platform has already been evaluated in three Phase I clinical trials. Lead vaccine candidate, CRS-207, is designed to expresses the tumor-associated antigen mesothelin, and is currently undergoing a Phase II trial in patients with metastatic pancreatic cancer. CRS-207 is separately poised to start in Phase I trials against mesothelioma and nonsmall cell lung cancer. The firm’s preclinical pipeline includes L. Monocytogenes-based vaccines against glioblastoma, melanoma, malaria, tularemia, and HBV.