Objective： Although the development of trastuzumab has improved the outlook for women with human epidermal growth factor receptor 2 （HER2）-positive breast cancer, the resistance to anti-HER2 therapy is a growing cl...Objective： Although the development of trastuzumab has improved the outlook for women with human epidermal growth factor receptor 2 （HER2）-positive breast cancer, the resistance to anti-HER2 therapy is a growing clinical dilemma. We aim to determine whether HER2-specific T cells generated from dendritic cells （DCs） modified with HER2 gene could effectively kill the HER2-positive breast cancer cells, especially the trastuzumab-resistant cells. Methods： The peripheral blood mononuclear cells （PBMCs） from healthy donors, whose HLA haplotypes were compatible with the tumor cell lines, were transfected with reconstructive human adeno-association virus （rhAAV/HER2） to obtain the specific killing activities of T cells, and were evaluated by lactate dehydrogenase （LDH） releasing assay. Results： Trastuzumab produced a significant inhibiting effect on SK-BR-3, the IC50 was 100ng/ml. MDA-MB-453 was resistant to trastuzumab even at a concentration of 10,000 ng/ml in vitro. HER2-specific T lymphocytes killed effectively SK-BR-3 [（69.86±13.41）%] and MDA-MB-453 [（78.36±10.68）%] at 40：1 （effector：target ratio, E：T）, but had no significant cytotoxicity against HER2-negative breast cancer cell lines MDA-MB-231 or MCF-7 （less than 10%）. Conclusion： The study showed that HER2-specific T lymphocytes generated from DCs modified by rhAAV/HER2 could kill HER2-positive breast cancer cell lines in a HER2-dependent manner, and result in significantly high inhibition rates on the intrinsic trastuzumab-resistant cell line MDA-MB-453 and the tastuzumab-sensitive cell line SK-BR-3. These results imply that this immunotherapy might be a potential treatment to HER2-positive breast cancer.展开更多
基金supported by the grant from the National"973"Basic Research Program of China(No.2009CB521703)Medical Oncology Leadership of Beijing Municipal Government Health Burean(No.2009-2-16)
文摘Objective： Although the development of trastuzumab has improved the outlook for women with human epidermal growth factor receptor 2 （HER2）-positive breast cancer, the resistance to anti-HER2 therapy is a growing clinical dilemma. We aim to determine whether HER2-specific T cells generated from dendritic cells （DCs） modified with HER2 gene could effectively kill the HER2-positive breast cancer cells, especially the trastuzumab-resistant cells. Methods： The peripheral blood mononuclear cells （PBMCs） from healthy donors, whose HLA haplotypes were compatible with the tumor cell lines, were transfected with reconstructive human adeno-association virus （rhAAV/HER2） to obtain the specific killing activities of T cells, and were evaluated by lactate dehydrogenase （LDH） releasing assay. Results： Trastuzumab produced a significant inhibiting effect on SK-BR-3, the IC50 was 100ng/ml. MDA-MB-453 was resistant to trastuzumab even at a concentration of 10,000 ng/ml in vitro. HER2-specific T lymphocytes killed effectively SK-BR-3 [（69.86±13.41）%] and MDA-MB-453 [（78.36±10.68）%] at 40：1 （effector：target ratio, E：T）, but had no significant cytotoxicity against HER2-negative breast cancer cell lines MDA-MB-231 or MCF-7 （less than 10%）. Conclusion： The study showed that HER2-specific T lymphocytes generated from DCs modified by rhAAV/HER2 could kill HER2-positive breast cancer cell lines in a HER2-dependent manner, and result in significantly high inhibition rates on the intrinsic trastuzumab-resistant cell line MDA-MB-453 and the tastuzumab-sensitive cell line SK-BR-3. These results imply that this immunotherapy might be a potential treatment to HER2-positive breast cancer.
