Background: Osteosarcoma, a highly aggressive pediatric cancer originating from aberrant bone cells, presents with symptoms like local pain and swelling, often leading to delayed diagnosis with imaging and biopsy. Chemotherapy and resection boosts prognosis, but metastatic cases, often lung-affected, have a poor 20% survival rate. Despite advancements, osteosarcoma remains prevalent, with 4.4 million cases annually and a 60% survival rate; early detection is paramount. CAR-T cell therapy is a cutting-edge personalized immunotherapy where genetically engineered patient T-cells, expanded ex vivo, recognize and target tumor cells. They show promise in treating malignancies by targeting the tumor microenvironment. However, their effectiveness against solid tumors is uncertain due to challenges in marker specificity and expression. High specificity against tumor-expressed markers is essential for solid tumor treatment to avoid off-target effects and maximize efficacy.

Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following keywords: "osteosarcoma", " CAR-T cell therapy", and " Chimeric Antigen Receptor T-cell”.

Results: Orthotopic implantation models demonstrated superior representation of osteosarcoma biology and metastasis compared to traditional models. Utilizing this model, targeting markers like ALP, B7-H3, CD166, and GD2, showed significant tumor suppression and improved survival rates.

Targeting ALP, two CAR-T constructs targeting OSCAR-1 and OSCAR-3 efficiently controlled peritoneal and lung metastases, significantly prolonging animal survival. Further, targeting the B7-H3 surface marker with CAR-T cells resulted in significantly smaller tumors, indicating its potential therapeutic benefit. Flow cytometric analysis revealed preferentially higher expression of B7-H3 in osteosarcoma cells, validating its suitability as a CAR-T target. CD166 CAR-T therapy efficiently targeted osteosarcoma cells, correlating with tumor CD166 expression. In mice, it effectively regressed tumors without acute toxicity. Additionally, a clinical trial evaluating GD2-CAR-T cell therapy highlighted the correlation between monocytes expressing CXCR3 and poor tumor eradication, suggesting the importance of immune cell dynamics in CAR-T therapy outcomes. In addressing CAR-T therapy drawbacks, an alternative approach employing IL12-modified mononuclear cells demonstrated efficacy against osteosarcoma with reduced toxicity and constrained tumor growth, serving as a promising alternate.

Conclusion: CAR-T cell therapy has shown limited success in treating blood cancers, but its effectiveness in solid tumors has been less promising, possibly due to lower surface expression levels of antigens on cancer cells. Skepticism exists about its superiority over alternative treatments like mononuclear cell therapy. However, CAR-T cell therapy has made strides in personalized treatment for osteosarcoma and holds potential as adjunct therapy for metastases, although its long-term efficacy remains uncertain.