Background
Pancreatic cancer continues to be a significant therapeutic challenge, with a 5-year overall survival rate of just 9% in the United States. This is largely due the lack of treatment modalities that provide high efficacy, a durable response, and a reputable safety profile. In addition, the use of immune checkpoint blockade as a monotherapy for pancreatic cancer has been historically unsuccessful, as pancreatic tumors are typically devoid of immune cell infiltration. Though alternative immunotherapeutic strategies with cancer vaccines and adoptive T-cell therapies have been identified, their efficacy has been extremely limited, leaving a continued need for novel treatment approaches. The dense dysplastic stroma of PDAC is a major obstacle to the delivery of chemotherapy drugs and plays an important role in the progression of PDAC
Methods
To overcome these challenges in the treatment of pancreatic cancer, we propose the development of novel microbial based vaccines as a novel immunotherapy for treatment of PDAC. We used physiologically relevant murine model of pancreatic cancer and treat tumor bearing mice with microbial based vaccines The vaccine was effective in human PDAC cell lines in vitro and in subcutaneous as well as orthotopic tumor models.
Results
The microbial derived anti-tumor immunological responses transformed the immune-suppressive ’cold’ tumor immune microenvironment (TIME) into an immunogenic ’hot’ TIME, which not only inhibits the growth of primary pancreatic cancer but also attacks the distant tumor. Our data shows significant tumor regression after treatment with vaccines. The microbial derived vaccine destroys PDAC associated stroma and kills tumor cells selectively and induces antitumor immune responses. We also evaluated the efficacy of microbial derived vaccine in combination with other Immune checkpoint inhibitors (ICIs) like anti-CTL4 and anti-PD1. The combinational treatment overcomes the resistant to ICIs quite studied phenomenon in the field of PDAC. We also discovered novel T-cell receptor sequences on the T cells with treatment with the novel microbial based vaccine.
Conclusions
The novel combination therapy may be useful to overcome the treatment resistance of stroma rich PDAC.