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Gene Regulation and Targeted Therapy in Gastric Cancer Peritoneal Metastasis: Radiological Findings from Dual Energy CT and PET/CT
Published on: January 22, 2018
Intraperitoneal CF33-hNIS combined with PD-L1 blockade eradicates gastric cancer peritoneal metastases and prevents
Annie Yang1, Zhifang Zhang2, Anthony K Park3
1Depratment of Surgery, City of Hope National Medical Center, Duarte, California, USA.
Background:
Peritoneal metastasis (PM) from gastric cancer (GC) is associated with poor prognosis and limited treatment options. We investigated a novel peritoneal-targeted therapy using CF33-human sodium iodide symporter (hNIS), a chimeric orthopoxvirus, combined with anti-PD-L1 immune checkpoint blockade in an immunocompetent mouse model of GCPM.
Methods:
We evaluated replication and cytotoxicity of CF33-hNIS in human and murine GC cell lines. We assessed a syngeneic mouse model of PM using the transgenic mouse GC ACKPY3944 cells to test the efficacy of intraperitoneal (IP) CF33-hNIS alone and combined with intravenous or IP anti-PD-L1. Next, we performed flow cytometry and immunohistochemistry to analyze immune cell populations of CD3+ T cell subsets in the peritoneal cavity and tumor microenvironment. Mice that showed complete tumor regression (CTR) were rechallenged with ACKPY3944 cells to assess memory T cell responses.
Results:
CF33-hNIS efficiently infected and killed GC cells. In vivo, IP CF33-hNIS alone significantly prolonged survival and increased infiltration of CD3+ and CD8+ T cells within the peritoneal cavity and solid tumor. The most pronounced therapeutic effect was observed with a single high-dose of CF33-hNIS (108 plaque-forming units) combined with IP anti-PD-L1 (Combo 2) with 75% CTR. Notably, mice with CTR rejected tumor rechallenge, exhibiting significantly elevated effector and central memory T cell populations in the peritoneal cavity and spleen. IP CF33-hNIS demonstrates robust anti-tumor efficacy against GCPM, particularly when combined with IP anti-PD-L1 in the high-dose Combo 2 regimen.
Conclusions:
These findings support a simplified, high-dose IP treatment strategy to overcome immune resistance in GCPM and provide a strong rationale for future clinical evaluation.
Insights
A novel peritoneal-targeted therapy using CF33-human sodium iodide symporter (hNIS) virus and anti-PD-L1 immunotherapy shows significant promise for treating peritoneal metastasis from gastric cancer (GCPM). This combination therapy led to complete tumor regression in 75% of mice, suggesting a new treatment strategy for GCPM.
Area of Science:
- Oncolytic virotherapy
- Immunotherapy
- Gastric cancer research
Background:
- Peritoneal metastasis (PM) from gastric cancer (GC) presents a poor prognosis and limited therapeutic options.
- Investigating novel therapies is crucial for improving outcomes in advanced GC.
- CF33-human sodium iodide symporter (hNIS) is a chimeric orthopoxvirus with potential anti-cancer activity.
Purpose of the Study:
- To evaluate the efficacy of CF33-hNIS combined with anti-PD-L1 immunotherapy in a preclinical model of gastric cancer peritoneal metastasis (GCPM).
- To assess the impact of this combination therapy on immune cell infiltration and memory responses.
- To determine the optimal dosing and administration route for this novel therapeutic strategy.
Main Methods:
- In vitro assessment of CF33-hNIS replication and cytotoxicity in GC cell lines.
- Evaluation of intraperitoneal (IP) CF33-hNIS alone and with anti-PD-L1 in a syngeneic mouse model of GCPM.
- Flow cytometry and immunohistochemistry to analyze peritoneal immune cell populations (CD3+, CD8+ T cells).
- Tumor rechallenge experiments in mice achieving complete tumor regression (CTR) to assess immune memory.
Main Results:
- CF33-hNIS demonstrated efficient infection and killing of GC cells.
- IP CF33-hNIS monotherapy increased survival and T cell infiltration in the peritoneal cavity and tumor.
- A combination of high-dose IP CF33-hNIS and IP anti-PD-L1 achieved 75% complete tumor regression (CTR).
- Mice with CTR exhibited robust memory T cell responses and rejected tumor rechallenge.
Conclusions:
- High-dose IP CF33-hNIS combined with IP anti-PD-L1 is a highly effective strategy against GCPM in a preclinical model.
- This simplified treatment approach shows potential to overcome immune resistance in GCPM.
- The findings provide a strong rationale for advancing this combination therapy to clinical trials.
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