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BCL-2 antisense therapy in patients with non-Hodgkin lymphoma
A Webb1, D Cunningham, F Cotter
1Lymphoma Unit, Royal Marsden Hospital, Sutton, Surrey.
Background:
Overexpression of BCL-2 is common in non-Hodgkin lymphoma and leads to resistance to programmed cell death (apoptosis) and promotes tumorigenesis. Antisense oligonucleotides targeted at the open reading frame of the BCL-2 mRNA cause a specific down-regulation of BCL-2 expression which leads to increased apoptosis. Lymphoma grown in laboratory animals responds to BCL-2 antisense oligonucleotides with few toxic effects. We report the first study of BCL-2 antisense therapy in human beings.
Methods:
A daily subcutaneous infusion of 18-base, fully phosporothioated antisense oligonucleotide was administered for 2 weeks to nine patients who had BCL-2-positive relapsed non-Hodgkin lymphoma. Toxicity was scored by the common toxicity criteria, and tumour response was assessed by computed tomography scan. Efficacy was also assessed by quantification of BCL-2 expression; BCL-2 protein levels were measured by flow cytometry in samples from patients.
Findings:
During the course of the study, the daily dose of BCL-2 antisense was increased incrementally from 4.6 mg/m2 to 73.6 mg/m2. No treatment-related toxic effects occurred, apart from local inflammation at the infusion site. In two patients, computed tomography scans showed a reduction in tumour size (one minor, one complete response). In two patients, the number of circulating lymphoma cells decreased during treatment. In four patients, serum concentrations of lactate dehydrogenase fell, and in two of these patients symptoms improved. We were able to measure BCL-2 levels by flow cytometry in the samples of five patients, two of whom had reduced levels of BCL-2 protein.
Interpretation:
In patients with relapsing non-Hodgkin lymphoma, BCL-2 antisense therapy led to an improvement in symptoms, objective biochemical and radiological evidence of tumour response, and down-regulation of the BCL-2 protein in some patients. Our findings are encouraging and warrant further investigations of BCL-2 antisense therapy in cancer treatment.
Insights
BCL-2 antisense therapy shows promise for relapsed non-Hodgkin lymphoma. This novel treatment demonstrated symptom improvement and tumor response in some patients, with minimal toxicity, warranting further investigation.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Overexpression of BCL-2 is implicated in non-Hodgkin lymphoma pathogenesis, conferring resistance to apoptosis.
- Antisense oligonucleotides targeting BCL-2 mRNA offer a potential strategy to down-regulate BCL-2 expression and induce apoptosis.
- Preclinical studies in animal models indicated BCL-2 antisense oligonucleotides are well-tolerated.
Purpose of the Study:
- To evaluate the safety and efficacy of BCL-2 antisense therapy in human patients with relapsed non-Hodgkin lymphoma.
- To assess the biological effects of BCL-2 antisense oligonucleotides on BCL-2 protein expression in patients.
Main Methods:
- Nine patients with BCL-2-positive relapsed non-Hodgkin lymphoma received daily subcutaneous infusions of an 18-base phosphorothioate antisense oligonucleotide.
- Dose escalation from 4.6 mg/m2 to 73.6 mg/m2 was performed over 2 weeks.
- Toxicity was assessed using common toxicity criteria, and tumor response was evaluated by computed tomography scans and BCL-2 protein levels via flow cytometry.
Main Results:
- No significant treatment-related toxic effects were observed, aside from local inflammation at the infusion site.
- Two patients showed tumor size reduction (one minor, one complete response) on CT scans.
- Some patients experienced decreased circulating lymphoma cells, improved symptoms, and reduced lactate dehydrogenase levels, with two patients showing decreased BCL-2 protein expression.
Conclusions:
- BCL-2 antisense therapy is a potentially safe and effective treatment for relapsing non-Hodgkin lymphoma.
- The therapy demonstrated clinical benefits including symptom improvement and objective tumor response in some patients.
- Down-regulation of BCL-2 protein was observed in a subset of patients, supporting the therapeutic mechanism and encouraging further research.