Gene-based immunotherapy in osteosarcoma: from oncolytic vectors to engineered immune cells.
This review synthesizes osteosarcoma-specific and extrapolated evidence for oncolytic vectors, engineered immune cells, antigen-directed strategies, and non-viral gene delivery, while outlining combination approaches, knowledge gaps, and the clinical-trial landscape.
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This review synthesizes osteosarcoma-specific and extrapolated evidence for oncolytic vectors, engineered immune cells, antigen-directed strategies, and non-viral gene delivery, while outlining combination approaches, knowledge gaps, and the clinical-trial landscape.
Research significance
The supplied evidence shows limited checkpoint-inhibitor activity in unselected osteosarcoma and describes several barriers to antitumor immunity; the inferred therapeutic hypothesis is that gene-based platforms could overcome these barriers by inducing antigen release, delivering local immune signals, or engineering tumor recognition, although efficacy and safety in pediatric osteosarcoma remain unestablished.
Source abstract
Osteosarcoma remains difficult to cure once it metastasizes, recurs, or becomes resistant to chemotherapy. Surgery combined with multi-drug chemotherapy improves outcomes in localized disease, but outcomes for high-risk patients have plateaued, prompting renewed interest in immunotherapy. However, immune checkpoint blockade has limited efficacy in unselected osteosarcoma patients: in SARC028, one objective response was observed among 22 patients with osteosarcoma treated with pembrolizumab. This limited response is consistent with antigen heterogeneity, enrichment of immunosuppressive myeloid populations, insufficient cytotoxic lymphocyte infiltration, matrix-associated immune exclusion, and metastatic immune adaptation. Gene-based immunotherapy offers a complementary strategy. When endogenous immune priming is inadequate, these platforms may initiate, reshape, or amplify antitumor immunity by promoting oncolytic antigen release, local cytokine or chemokine expression, engineered immune-cell recognition, or non-viral delivery of immunomodulatory payloads. This article discusses oncolytic vectors, cytokine-armed vectors, CAR-T and CAR-NK cells, TCR- or neoantigen-directed strategies, and non-viral gene delivery systems as potential approaches for reshaping osteosarcoma immunity. It also examines combination strategies and translational challenges in pediatric and adolescent patients. Beyond summarizing platform-level evidence, we distinguish findings generated directly in osteosarcoma from evidence extrapolated from other tumor types, identify the principal unresolved knowledge gaps for each platform, and summarize the current osteosarcoma-specific clinical trial landscape to clarify the translational maturity of these strategies.