Cell-selective telomere damage by thiopurine-based oligonucleotide for diffuse large B cell lymphoma immunotherapy

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Telomerase (TERT) is crucial for telomere maintenance in diffuse large B cell lymphoma (DLBCL).
• Previous TERT-targeting strategies faced challenges like delayed responses and off-tumor toxicities.
• Developing targeted therapies for TERT-positive DLBCL remains a significant clinical need.

Purpose of the Study:

• To develop and evaluate a novel oligonucleotide-based therapeutic strategy targeting TERT in DLBCL.
• To assess the efficacy and safety of 6-thio-2'-deoxy-guanosine oligonucleotides (6tdGO) in preclinical DLBCL models.
• To investigate the immunomodulatory effects and underlying mechanisms of 6tdGO treatment.

Main Methods:

• In vitro cytotoxicity assays of 6tdGO against TERT-positive DLBCL cells and control cells.
• In vivo efficacy studies using xenotransplanted human DLBCL and syngeneic mouse lymphoma models.
• Analysis of immune responses, including CD8 T cell activation and STING-mediated signaling pathways.
• Safety and tolerability assessments in humanized mouse models.

Main Results:

• 6tdGO demonstrated selective cytotoxicity towards TERT-positive DLBCL cells in vitro.
• Intravenous 6tdGO administration showed significant antitumor effects in both xenograft and syngeneic DLBCL models.
• 6tdGO treatment induced lymphoma-specific CD8 T cell-mediated antitumor immunity via STING-dependent pathways.
• Repeated 6tdGO administration was well-tolerated in humanized mice with minimal impact on other hematopoietic cell populations.

Conclusions:

• 6tdGO represents a promising, safe, and effective therapeutic agent for aggressive TERT-positive DLBCL.
• The mechanism involves direct telomere damage, apoptosis induction, and activation of T cell-mediated antitumor immunity.
• This approach offers a potential strategy to overcome limitations of previous TERT-targeting therapies.