A Novel Orthotopic Implantation Technique for Osteosarcoma Produces Spontaneous Metastases and Illustrates Dose-Dependent Efficacy of B7-H3-CAR T Cells
| Autor: | Christopher DeRenzo, Lindsay J. Talbot, Stephen Gottschalk, Amy J. Funk, Aaron Ross, Heather Tillman, Ashley Chabot, Jessica Wagner, Phuong Nguyen, Andrew M. Davidoff |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
B7 Antigens Lung Neoplasms medicine.medical_treatment Immunology Dose dependence Bone Neoplasms Immunotherapy Adoptive 03 medical and health sciences Mice 0302 clinical medicine Antigen Cell Line Tumor medicine Immunology and Allergy Bioluminescence imaging Animals Humans Luciferase orthotopic Original Research Osteosarcoma Lung model Receptors Chimeric Antigen Tibia business.industry Immunotherapy RC581-607 medicine.disease Xenograft Model Antitumor Assays CAR 030104 developmental biology medicine.anatomical_structure Treatment Outcome B7-H3 030220 oncology & carcinogenesis T cell therapy Cancer research Female Car t cells Immunologic diseases. Allergy business |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 12 (2021) |
| ISSN: | 1664-3224 |
| Popis: | The outcome for metastatic pediatric osteosarcoma (OS) remains poor. Thus, there is an urgent need to develop novel therapies, and immunotherapy with CAR T cells has the potential to meet this challenge. However, there is a lack of preclinical models that mimic salient features of human disease including reliable development of metastatic disease post orthotopic OS cell injection. To overcome this roadblock, and also enable real-time imaging of metastatic disease, we took advantage of LM7 OS cells expressing firefly luciferase (LM7.ffLuc). LM7.ffLuc were implanted in a collagen mesh into the tibia of mice, and mice reliably developed orthotopic tumors and lung metastases as judged by bioluminescence imaging and histopathological analysis. Intratibial implantation also enabled surgical removal by lower leg amputation and monitoring for metastases development post-surgery. We then used this model to evaluate the antitumor activity of CAR T cells targeting B7-H3, an antigen that is expressed in a broad range of solid tumors including OS. B7-H3-CAR T cells had potent antitumor activity in a dose-dependent manner and inhibited the development of pulmonary metastases resulting in a significant survival advantage. In contrast T cells expressing an inactive B7-H3-CAR had no antitumor activity. Using unmodified LM7 cells also enabled us to demonstrate that B7-H3-CAR T cells traffic to orthotopic tumor sites. Hence, we have developed an orthotopic, spontaneously metastasizing OS model. This model may improve our ability not only to predict the safety and efficacy of current and next generation CAR T cell therapies but also other treatment modalities for metastatic OS. |
| Databáze: | OpenAIRE |
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