Sriranjani Darbha

Introduction: Osteosarcoma, a highly aggressive pediatric cancer originating from abnormal bone cells¹, presents with symptoms like local pain and swelling⁵, often leading to delayed diagnosis^1,2. Standard treatment involves chemotherapy and resection^1,5, improving prognosis, but metastatic cases have a poor 20% survival rate⁴, commonly affecting the lungs⁴. Despite advancements, osteosarcoma remains prevalent, with 4.4 million cases annually and a 60% survival rate². Diagnosis relies on imaging and biopsy, emphasizing the need for better awareness and early detection^4,5. CAR-T cell therapy, a cutting-edge personalized immunotherapy, shows promise in treating malignancies by targeting the tumor microenvironment^2,3; its success in solid tumors is uncertain^1,2,3,4,5,6. CAR-T cells are genetically engineered via modifying patient T-cells with chimeric receptors to recognize surface proteins on tumor cells^1,6; they combine extracellular fragments for antigen recognition with intracellular signaling domains and are expanded ex-vivo before reintroduction into the patient. Four generations of CAR-T cells have been developed thus far, enhancing therapeutic effects by incorporating co-stimulatory domains¹⁰. 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.

Objective: This study aims to evaluate the efficacy of CAR-T cell therapy targeting specific surface markers in osteosarcoma, utilizing innovative in-vitro, in-vivo, and clinical trial experimentation and alternative therapeutic approaches.

Search 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 and were utilized to study the following markers¹¹: Targeting ALP, two CAR-T constructs targeting OSCAR-1 and OSCAR-3, efficiently controlled tumor spread in peritoneal and lung metastasis models, prolonging animal survival⁶. Targeting B7-H3 surface marker with CAR-T cells resulted in significantly smaller tumors, indicating its potential therapeutic benefit⁴. Flow cytometric analysis revealed preferentially higher expression of B7-H3 in osteosarcoma cells, validating its suitability as a CAR-T target⁴. The CD166 CAR-T cell therapy proved very efficient against osteosarcoma cells⁷; particularly, the proportion of tumor cell ablation corresponded to the tumor CD166 expression⁷. In vivo, this treatment yielded successful to regress tumors in mice without any acute toxicity⁷. Additionally, a clinical trial evaluating GD2-CAR-T cell therapy highlighted the correlation between monocytes expressing CXCR3 and poor tumor eradication⁸, suggesting the importance of immune cell dynamics in CAR-T therapy outcomes⁸. 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 alternate⁹.

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 therapy⁹. However, CAR-T cell therapy has made strides in personalized osteosarcoma treatment and holds potential as adjunct therapy for metastases, although its long-term efficacy remains uncertain.

Works Cited:

1. Eaton BR, Schwarz R, Vatner R, et al. Osteosarcoma. Pediatr Blood Cancer. 2021;68 Suppl 2:e28352. doi:10.1002/pbc.28352
2. Li S, Zhang H, Shang G. Current status and future challenges of CAR-T cell therapy for osteosarcoma. Front Immunol. 2023;14:1290762. Published 2023 Dec 22. doi:10.3389/fimmu.2023.1290762
3. Lin Z, Wu Z, Luo W. Chimeric Antigen Receptor T-Cell Therapy: The Light of Day for Osteosarcoma. Cancers (Basel). 2021;13(17):4469. Published 2021 Sep 5. doi:10.3390/cancers13174469
4. Majzner RG, Theruvath JL, Nellan A, et al. CAR T Cells Targeting B7-H3, a Pan- Cancer Antigen, Demonstrate Potent Preclinical Activity Against Pediatric Solid Tumors and Brain Tumors. Clin Cancer Res. 2019;25(8):2560-2574. doi:10.1158/1078-0432.CCR-18-0432
5. Zarghooni K, Bratke G, Landgraf P, Simon T, Maintz D, Eysel P. The Diagnosis and Treatment of Osteosarcoma and Ewing’s Sarcoma in Children and Adolescents. Dtsch Arztebl Int. 2023;120(24):405-412. doi:10.3238/arztebl.m2023.0079
6. Mensali N, Köksal H, Joaquina S, et al. ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma. Nat Commun. 2023;14(1):3375. Published 2023 Jun 8. doi:10.1038/s41467-023-39097-x
7. Wang, Y., Yu, W., Zhu, J. et al. Anti-CD166/4-1BB chimeric antigen receptor T cell therapy for the treatment of osteosarcoma. J Exp Clin Cancer Res 38, 168 (2019). https://doi.org/10.1186/s13046-019-1147-6
8. Kaczanowska S, Murty T, Alimadadi A, et al. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell. 2024;42(1):35-51.e8. doi:10.1016/j.ccell.2023.11.011
9. Yang Q, Hu J, Jia Z, et. al. Membrane-Anchored and Tumor-Targeted IL12 (attIL12)- PBMC Therapy for Osteosarcoma. Clin Cancer Res 2022; 28 (17): 3862–3873. https://doi.org/10.1158/1078-0432.CCR-22-0721
10. Li S, Zhang H, Shang G. Current status and future challenges of CAR-T cell therapy for osteosarcoma. Front Immunol. 2023;14:1290762. Published 2023 Dec 22. doi:10.3389/fimmu.2023.1290762
11. Goldstein SD, Hayashi M, Albert CM, Jackson KW, Loeb DM. An orthotopic xenograft model with survival hindlimb amputation allows investigation of the effect of tumor microenvironment on sarcoma metastasis. Clin Exp Metastasis. 2015;32(7):703-715. doi:10.1007/s10585-015-9738-x