1) Targeting the extracellular matrix in fibrotic tumors to maximize therapeutic delivery

 

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the development of a fibrotic barrier, mostly composed of the extracellular matrix (ECM) components hyaluronan and collagen, that prevents efficient delivery of standard chemotherapy and other anti-cancer agents. Using our tumor-colonizing Salmonella platform, we have successfully developed two unique recombinant strains capable of degrading tumor-derived hyaluronan and collagen. Studies to determine efficacy when used alone or in combination with standard chemotherapy are currently ongoing.

 

2) Modification of the tumor immune landscape to improve checkpoint inhibitor response rate and efficacy

 

The immune landscape present in lung tumors is dominated by suppressive immune subsets which include Tregs and pro-tumor (N1-polarized) neutrophils. We have developed several strains of attenuated Salmonella to target immunosuppressive proteins or to secrete cytokines, which have been shown to dramatically change the immune landscape in tumors to cause regression.  We are currently determining if sub-therapeutic doses of these strains could act synergistically with checkpoint blockade in pre-clinical models of lung cancer.

 

3) Characterization of anti-tumor immunity and the tumor-associated microbiome following epigenetic therapy

 

Immune evasion is an important hallmark of cancer. We recently demonstrated that, in pancreatic cancer, gene transcripts associated with antigen processing and presentation, immune recruitment and anti-viral responses were down-regulated during transition from non-malignancy to malignancy, which likely contributes to immune evasion. Reprogramming of pancreatic tumor cells using the epigenetic modifier 5-azacytidine resulted in enhanced expression of these gene transcripts and tumor growth control in vivo associated with significant increases in tumor-associated CD8+ and CD4+ T cells. Current studies include metagenomic analyses to determine changes in the pancreatic cancer microbiome during successful treatment with epigenetic therapy.