Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

Area of Science:

• Oncology
• Immunotherapy
• Gene Therapy

Background:

• The tumor suppressor p53 is crucial for cellular stress response.
• Emerging evidence indicates p53's role in regulating immune responses.
• Immune checkpoint inhibitors like anti-PD1 antibodies show promise but face resistance.

Purpose of the Study:

• To investigate the efficacy of combining p53 gene therapy (SGT-53) with anti-PD1 antibody therapy.
• To determine if SGT-53 can sensitize tumors refractory to anti-PD1 therapy.
• To explore the mechanisms by which p53 influences anti-tumor immunity and adverse events.

Main Methods:

• Utilized three syngeneic mouse tumor models (breast cancer, NSCLC, glioblastoma).
• Administered SGT-53 (nanomedicine carrying p53 plasmid) in combination with anti-PD1 antibody.
• Assessed tumor response, immunogenicity, innate and adaptive immune responses, and hypersensitivity reactions.

Main Results:

• SGT-53 sensitized tumors resistant to anti-PD1 antibody across all models.
• SGT-53 increased tumor immunogenicity and enhanced innate and adaptive immunity in a 4T1 breast cancer model.
• SGT-53 reduced tumor-induced immunosuppression and alleviated anti-PD1-associated hypersensitivity.

Conclusions:

• Restoring p53 function via SGT-53 augments anti-PD1 immunotherapy.
• This combination strategy can overcome resistance to anti-PD1 therapy.
• SGT-53 shows potential to improve anti-tumor immunity and mitigate immune-related adverse events.