Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma
Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma
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DOI：
10.1182/blood-2012-05-432393
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发表时间：
2013-01-10
期刊：
影响因子：
20.3
通讯作者：
Illidge, Timothy M.
中科院分区：
文献类型：
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作者：
Dovedi, Simon J.;Melis, Monique H. M.;Illidge, Timothy M.
单克隆抗体的被动免疫治疗改善了B细胞恶性肿瘤患者的预后，尽管许多患者仍然复发，T细胞恶性肿瘤的进展甚微。在这种疾病背景下，显然需要新的治疗方法。最近，人们对开发使用新型免疫调节剂与标准护理治疗组合来增强抗肿瘤免疫应答的治疗方法产生了很大兴趣。在这里，我们报告，静脉注射Toll样受体7（TLR 7）激动剂，R848与放射治疗（RT）相结合，导致长期清除T细胞和B细胞淋巴瘤荷瘤小鼠的肿瘤。TLR 7/RT联合治疗可扩增肿瘤抗原特异性CD 8（+）T细胞并提高生存率。此外，在TLR 7/RT治疗后实现肿瘤长期清除的那些小鼠通过产生肿瘤特异性记忆免疫应答而免受随后的肿瘤再攻击。我们的研究结果表明，通过与全身给药的TLR 7激动剂联合使用，有可能提高常规细胞毒性抗癌治疗的疗效，以改善抗肿瘤免疫应答并提供持久的缓解。（血。2013;121（2）：251-259）
Passive immunotherapy with monoclonal antibodies has improved outcome for patients with B-cell malignancies, although many still relapse and little progress has been made with T-cell malignancies. Novel treatment approaches are clearly required in this disease setting. There has been much recent interest in developing therapeutic approaches to enhance antitumor immune responses using novel immunomodulatory agents in combination with standard of care treatments. Here we report that intravenous administration of the Toll-like receptor 7 (TLR7) agonist, R848 in combination with radiation therapy (RT), leads to the longstanding clearance of tumor in T- and B-cell lymphoma bearing mice. In combination, TLR7/RT therapy leads to the expansion of tumor antigen-specific CD8(+) T cells and improved survival. Furthermore, those mice that achieve long-term clearance of tumor after TLR7/RT therapy are protected from subsequent tumor rechallenge by the generation of a tumor-specific memory immune response. Our findings demonstrate the potential for enhancing the efficacy of conventional cytotoxic anticancer therapy through combination with a systemically administered TLR7 agonist to improve antitumor immune responses and provide durable remissions. (Blood. 2013;121(2):251-259)