期刊
MOLECULAR THERAPY
卷 21, 期 6, 页码 1212-1223出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mt.2013.51
关键词
-
资金
- European Research Council
- American Society of Clinical Oncology Foundation
- Helsinki University Central Hospital Research Funds (EVO)
- Helsinki Biomedical Graduate School
- Orion-Farmos Research Foundation
- Ida Montin Foundation
- Waldemar von Frenckell Foundation
- Sigrid Juselius Foundation
- Academy of Finland
- Biocentrum Helsinki
- Biocenter Finland
- University of Helsinki
- Cancer Organizations Finland
- Oncos Therapeutics, Ltd.
Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Pre-clinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum-a possible indicator of immune response-increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据