Background
Immunotherapy with immune checkpoint inhibitors (ICI) has revolutionized cancer treatment for many cancers. However, it is associated with low response rates because many cancers have little immune cell infiltration into tumors and the immunosuppressive tumor microenvironment. In addition, after intravenous administration, most ICI is delivered to noncancerous tissues which can activate immune responses and cause immune-mediated toxicities in some patients. Parental formulation is expensive during transportation and storage and inconvenient for patients. The goal of this project is to develop oral cancer-specific bacteria-based immunotherapy to address the unmet needs of parental immunotherapy.
Materials and Methods
Bacteria are bio-engineered to specifically target cancers after oral administration. Bacteria are further bio-engineered to deliver an ICI, cytokine and other diagnostic and therapeutic agents. Mice carrying syngeneic bladder cancers and patient-derived bladder cancer xenografts as well as transgenic mice with spontaneous bladder cancer were used to determine the anti-cancer efficacy and perform molecular correlative studies.
Results
After oral administration, bioengineered bladder cancer-specific bacteria (BCSB) are delivered to bladder cancer tumors. On average, BCSB in subcutaneous tumors was 4,469 times (median: 777, ranging from 35 to 46,360 times) higher than the colonies in vital organs, including the heart, lung, liver, spleen, and kidney at 48 and 72 hours after oral administration. In SV40T/Ras double transgenic mice with spontaneous bladder cancer, cancer-specific delivery to the bladder cancer is between 33,793 to 205,172 times that of the normal bladder. BCSB can induce macrophage M1 differentiation in tumors, deliver chemokine CXCL11 and induce CD8 T cell infiltration to tumors. Using a chimeric anti-PD1-green fluorescent protein, the expression of anti-PD1 protein is confirmed within tumors starting at 24 hours after oral administration and peaked at 72 and 96 hours. Oral BCSB carrying an anti-PD1 protein is at least as effective as anti-PD1 antibody through intraperitoneal injection.
Conclusions
We have developed an oral cancer-specific platform for cancer immunotherapy. After oral administration, BCSB confers cancer-specific delivery, alters tumor microenvironment and can potentially be developed for cancer immunotherapy in humans.
C. Pan: E. Ownership Interest (stock, stock options, patent or other intellectual property); Modest; LP Therapeutics. V. Reddy Chittepu: None. Z. Zhu: None. C. Yang: None. L. Sun: None. A. Ma: None. S. Wang: None. R. Curtiss: None.