Use of patient-derived organotypic tumor spheroids for testing of viral vector gene therapy in combination with checkpoint blockade

Author(s):Show less -

Domingues, Ana Carolina M. ; de Oliveira, Soraia B. ; Tessarollo, Nayara G. ; Lepique, Ana Paula ; Rodrigues, Otavio ; Sharova, Tatyana ; Lawless, Aleigha ; Li, David ; Basnet, Madak ; Boland, Genevieve M. ; Cohen, Sonia ; Jenkins, Russell W. ; Strauss, Bryan E.

• Document type: Journal article
• Source: MOLECULAR THERAPY ONCOLOGY; v. 33, n. 1, p. 12-pg., 2025-02-13.

Abstract

Checkpoint inhibitors have revolutionized cancer treatment, but a significant proportion of patients do not respond to these therapies, underscoring the need for alternative strategies. Although gene therapy has made substantial strides, its application in solid tumors remains underexplored, with limited treatments approved. Here, we further investigated a gene therapy approach with non-replicating adenoviral vectors encoding the alternate reading frame (ARF) and interferon beta (IFNb) and tested it in a clinically relevant setting. We previously showed that this combined gene therapy induces immunogenic cell death in melanoma models, and now, we utilize patientderived organotypic tumor spheroids (PDOTS), a model that closely recapitulates the immune environment of tumors, to test its effects using patient tumors. Our results demonstrate, for the first time, the effectiveness of using PDOTS to evaluate viral-vector-based gene therapies. While the addition of antiPD-1 did not enhance therapeutic outcomes, the gene therapy alone suppressed tumor growth and triggered antitumor immune responses across different cancer models, notably those with low immunogenicity and specific genome profiles. These findings suggest that this gene therapy could serve as a valuable alternative for patients not responsive to checkpoint inhibitors and who have solid tumors with limited treatment and impaired p53-ARF-MDM2 pathways, such as liposarcomas. (AU)

• FAPESP's process: 17/25290-2 - A study of the role of neoantigens in the modulation of the anti-tumor response promoted by the treatment of B16 cells with p19Arf and IFN-beta.
• Grantee: Nayara Gusmão Tessarollo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/25555-9 - Rational combination between checkpoint blockade and gene therapy with p19Arf and IFN-beta in a mouse model of melanoma
• Grantee: Ana Carolina Martins Domingues
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/25284-2 - Construction and characterization of adenoviral vectors encoding the canine cDNAs for p14Arf and IFN-beta
• Grantee: Otavio Augusto Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 22/15913-0 - Evaluation of the practice and safety of gene therapy in spontaneous cases of oral Melanoma in dogs
• Grantee: Bryan Eric Strauss
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/26580-9 - Cancer gene therapy: strategic positioning for translational studies
• Grantee: Bryan Eric Strauss
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 22/04368-1 - Rational combination of checkpoint blockade and gene therapy with p14Arf and IFN-b in patient-derived organotypic tumor spheroids
• Grantee: Ana Carolina Martins Domingues
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)