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Radioimmunotherapy of micrometastases in lung with vascular targeted 213Bi
1Life Sciences Division, Oak Ridge National Laboratory, TN 37831-6101, USA.
Abstract:
A model system has been used to test the efficacy of vascular targeting of alpha-particle emitter 213Bi for therapy of small, 'artificial' metastases in mouse lung. Specific monoclonal antibody (mAb) 201 B was used to deliver greater than 30% of the injected dose to lung where tumours had developed due to intravenous injection of cells. Specific 213Bi-mAb 201B treatment of BALB/c mammary carcinoma EMT-6 tumours in lung resulted in a dose-dependent destruction of tumours and an extended lifespan of treated animals relative to controls. Significant reduction of lung tumour burden was noted in animals treated with 0.93 MBq injected dose or as little as 14 Gy absorbed dose to the lung. Animals treated with higher doses (2.6-6.7 MBq) had nearly complete cure of lung tumours but eventually died of lung fibrosis induced by the treatment. Four other tumour cell types were studied: murine Line 1 lung carcinomas in syngeneic BALB/c mice, rat IC-12 tracheal carcinoma growing in severe combined immune deficient (SCID) mice, and two human tumours--epidermoid carcinoma A431 and lung carcinoma A549--growing in SCID mice. In all cases, the number of lung tumour colonies was reduced in animals treated with specific, labelled mAb relative to those in animals treated with control 213Bi MAb or EDTA complexed 213Bi. Tumours treated in immunodeficient SCID mice were partially destroyed or at least retarded in growth, but ultimately regrew and proved fatal, indicating that an intact immune function is necessary for complete cure. The data show that the short-lived alpha-particle emitter 213Bi can be effectively targeted to lung blood vessels and that tumour cells growing in the lung are killed. The mechanism may involve direct killing of tumour cells from alpha-particle irradiation, killing through destruction of blood supply to the tumour, or a combination of the two.
Insights
Targeted alpha therapy using bismuth-213 (213Bi) delivered via monoclonal antibody (mAb) effectively treated lung metastases in mice. This approach showed dose-dependent tumor destruction and extended survival, though higher doses caused lung fibrosis, highlighting the need for immune function in complete cures.
Area of Science:
- Nuclear Medicine
- Oncology
- Immunology
Background:
- Metastatic lung cancer remains a significant therapeutic challenge.
- Targeted alpha therapy offers a promising approach for localized cancer treatment.
- Bismuth-213 (213Bi) is a short-lived alpha-particle emitter suitable for targeted radionuclide therapy.
Purpose of the Study:
- To evaluate the efficacy of vascular targeting of 213Bi for treating artificial lung metastases.
- To assess the therapeutic potential of 213Bi-labeled monoclonal antibody (mAb) 201B in preclinical models.
- To investigate the role of immune function in achieving complete tumor eradication.
Main Methods:
- A model system was established using intravenous injection of tumor cells to create lung metastases in mice.
- Specific monoclonal antibody (mAb) 201B was radiolabeled with 213Bi for targeted delivery.
- Various tumor cell types, including EMT-6, Line 1, IC-12, A431, and A549, were used in syngeneic and immunodeficient mouse models.
Main Results:
- Specific 213Bi-mAb 201B treatment resulted in dose-dependent tumor destruction and extended lifespan in EMT-6 tumor-bearing mice.
- Significant reduction in lung tumor burden was observed at doses as low as 0.93 MBq (14 Gy absorbed dose).
- Complete tumor cure at higher doses (2.6-6.7 MBq) led to lung fibrosis and mortality, while treatment in immunodeficient mice showed tumor regrowth, indicating the necessity of an intact immune system.
Conclusions:
- Targeted delivery of 213Bi via mAb 201B is effective in killing lung tumor cells, potentially through direct irradiation or vascular disruption.
- The study demonstrates the feasibility of using alpha-particle emitter 213Bi for vascular targeting in lung cancer therapy.
- Complete tumor eradication necessitates an intact host immune response in conjunction with targeted alpha therapy.