Long-term activation of anti-tumor immunity in pancreatic cancer by a p53-expressing telomerase-specific oncolytic...

Area of Science:

• Immunotherapy
• Oncolytic Virotherapy
• Cancer Immunology

Background:

• Pancreatic cancer is an aggressive, immunologically
• cold
• tumor.
• Oncolytic virotherapy offers a promising strategy to enhance anti-tumor immunity.
• OBP-702 is a telomerase-specific oncolytic adenovirus engineered with the p53 gene.

Purpose of the Study:

• To investigate the long-term efficacy of OBP-702 in pancreatic cancer.
• To evaluate the role of OBP-702 in generating long-lived memory CD8+ T cells, including tissue-resident memory T cells (TRMs) and effector memory T cells (TEMs).
• To assess the combination therapy of OBP-702 with gemcitabine+nab-paclitaxel (GN).

Main Methods:

• In vitro assessment of OBP-702's effect on adenosine triphosphate (ATP) production.
• In vivo studies in murine pancreatic (PAN02) tumor models to evaluate OBP-702's impact on T cell populations (TEMps, TRMs, TEMs).
• Bilateral and neoadjuvant tumor models to assess long-term anti-tumor effects and immune memory.

Main Results:

• OBP-702 significantly induced ATP in vitro, crucial for memory T cell development.
• Local OBP-702 treatment in vivo increased effector memory precursor cells (TEMps) via ATP and IL-15Rα induction, leading to TRM and TEM generation.
• Combination therapy (GN + OBP-702) demonstrated significant anti-tumor effects, increased TRMs in uninjected tumors, and provided long-term immunity post-resection.

Conclusions:

• OBP-702 acts as a long-term immunostimulant for pancreatic cancer.
• Sustained anti-tumor effects are achieved through the induction of memory T cell responses.
• OBP-702 holds potential as a novel therapeutic agent for "cold" tumors like pancreatic cancer.