Investigating the oncolytic bacteria product SGN1 and its impact on PD-L1 expression, CD8+ T cell infiltration, and synergy with anti-PD-L1 combo in preclinical models of pancreatic adenocarcinoma, hepatocellular cancer, and melanoma.

e15188 Background: Despite success of immunotherapy in a wide range of solid tumors, immune checkpoint inhibitors (ICIs, such as α-PD-1 or α-PD-L1) remain to be ineffective in the treatment of pancreatic adenocarcinoma (PDAC) owing to the very low objective response rate (ORR). Although ICIs have already been approved for the treatment of hepatocellular carcinoma (HCC), the low ORR remains a clinical challenge for the treatment of these two types of highly aggressive malignancies. The oncolytic bacteria product, SGN1, is a genetically engineered attenuated Salmonella strain that overexpresses an L-methioninase, which can specifically target and reduce methionine supply within tumor tissues (Zhou et al, Cell Reports Medicine , 2023, 4, 101070;). In all preclinical models as well as in clinical trials, SGN1 has shown strong activities in inducing oncolysis and suppressing metastasis. Currently, SGN1 is undergoing Phase I/IIa trials in the US, Mainland China, & Taiwan (NCT05103345; NMPA: CTR20233735). Lately, we revealed that SGN1 treatment could elicit a strong elevation of PD-L1 expression and CD8+ T cell infiltration in melanoma model (Zhou et al, JITC, 2024, 12:e008238). We aimed to examine if SGN1 can induce PD-L1 expression, stimulate the infiltration of cytotoxic T cell infiltrations, and the combination application can generate in pancreatic cancer and liver cancer. Methods: Methionine restriction was applied to examine the expression of PD-L1 in cultured PDAC or HCC cells. SGN1 was co-incubated with human PBMC and PD-L1 to examine the combo effects on cultured PDAC or HCC cells. Lastly, tumor suppression effects of combination of SGN1 and α-PD-L1 were evaluated in the growth of pancreatic and liver cancer models. Results: SGN1 can induce strong and significant elevation of PD-L1 expression and CD8+ T cell infiltration in PDAC or HCC tumors. These effects of SGN1 are stronger than that of the bacterial vector alone, indicative of methionine restriction plays a prominent role. In the PDAC and HCC models, sequential use of SGN1 and anti-PD-L1 generated synergistic effect that strongly suppressed the tumor growth of PDAC and HCC, very similar to those effects observed in melanoma model. Conclusions: The genetically engineered oncolytic bacteria agent, SGN1, can induce robust changes in the immune environment and, when used in combination with α-PD-L1, can have strong synergistic effects on restricting the growth of PDAC or HCC tumors. Further clinical trials of such combination applications in these malignancies are warranted.