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

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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.

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR THERAPY ONCOLOGY; v. 33, n. 1, p. 12-pg., 2025-02-13.

Resumo

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)

• Processo FAPESP: 17/25290-2 - O estudo do papel dos neoantígenos na modulação da resposta anti-tumoral promovido pelo tratamento com p19Arf e IFN-beta em células B16
• Beneficiário: Nayara Gusmão Tessarollo
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 18/25555-9 - Combinação racional entre checkpoint blockade e terapia gênica com p19Arf e IFN-b em modelo murino de melanoma
• Beneficiário: Ana Carolina Martins Domingues
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 17/25284-2 - Construção e caracterização de vetores adenovirais portadores dos cDNAs caninos de p14Arf e IFN-beta
• Beneficiário: Otavio Augusto Rodrigues
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 22/15913-0 - Avaliação da prática e segurança de terapia gênica em casos espontâneos de Melanoma oral em cães
• Beneficiário: Bryan Eric Strauss
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/26580-9 - Terapia gênica do câncer: alinhamento estratégico para estudos translacionais
• Beneficiário: Bryan Eric Strauss
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 22/04368-1 - Combinação racional de checkpoint blockade e terapia gênica com p14Arf and IFN-b em modelo de esferoides organotípicos de tumores derivados de pacientes
• Beneficiário: Ana Carolina Martins Domingues
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto