Radiotherapy combined with intratumoral dendritic cell vaccination enhances the therapeutic efficacy of adoptive T-cell transfer.
Radiotherapy combined with intratumoral dendritic cell vaccination enhances the therapeutic efficacy of adoptive T-cell transfer.
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DOI：
10.1097/cji.0b013e3181a95165
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Chang AE
中科院分区：
文献类型：
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作者：
Teitz-Tennenbaum S;Li Q;Davis MA;Wilder-Romans K;Hoff J;Li M;Chang AE
用环磷酰胺（100 mg/kg）和氟达拉滨（200 mg/kg）处理C57 BL/6小鼠可诱导非清髓性淋巴细胞耗竭，但不抑制D5黑色素瘤肿瘤生长。利用该模型，我们发现在过继转移离体抗-CD 3/CD 28活化和IL-2扩增的D5-G6肿瘤引流淋巴结细胞之前诱导淋巴细胞减少增强了输注细胞在肺转移和皮下D5荷瘤小鼠中的抗肿瘤功效。然而，诱导淋巴细胞减少并不促进瘤内或瘤外的增殖或注入的细胞的积累。我们以前已经表明，放疗增强了肿瘤内非脉冲树突状细胞疫苗接种在皮下小鼠肿瘤模型的治疗效果，通过增强诱导抗肿瘤细胞免疫应答。在这里，我们在鼠转移性黑色素瘤肝肿瘤模型中证实了这一发现。此外，局部肿瘤照射联合瘤内树突状细胞给药显著增强了肿瘤反应性T细胞过继转移在该淋巴细胞耗竭的肝肿瘤模型中的治疗功效。这一点通过减小肝脏肿瘤大小、降低自发性腹腔内转移的发生率和延长生存期而得到证明，导致46%的小鼠治愈。这种增强的抗肿瘤活性与CD 4+而不是CD 8+输注细胞的增殖、积累和功能的选择性增加相关。这种多模态方案可能具有用于治疗人类癌症的转化应用。
Treatment of C57BL/6 mice with cyclophosphamide (100 mg/kg) and fludarabine (200 mg/kg) induced non-myeloablative lymphodepletion without inhibiting D5 melanoma tumor growth. Utilizing this model, we found that induction of lymphopenia prior to adoptive transfer of ex vivo anti-CD3/CD28 activated and IL-2 expanded D5-G6 tumor draining lymph node cells enhanced the anti-tumor efficacy of the infused cells in both pulmonary metastases and subcutaneous D5 bearing mice. However, induction of lymphopenia did not promote intratumoral or extratumoral proliferation or accumulation of the infused cells. We have previously shown that radiotherapy enhances the therapeutic efficacy of intratumoral unpulsed dendritic cell vaccination in subcutaneous murine tumor models by augmenting the induction of anti-tumor cellular immune responses. Here, we confirmed this finding in a murine metastatic melanoma liver tumor model. Furthermore, local tumor irradiation combined with intratumoral dendritic cell administration significantly enhanced the therapeutic efficacy of tumor-reactive T cell adoptive transfer in this lymphodepleted liver tumor model. This was evident by reduced liver tumor size, decreased incidence of spontaneous intra-abdominal metastasis, and prolonged survival, resulting in 46% of mice cured. This enhanced anti-tumor activity was associated with a selective increase in proliferation, accumulation, and function of CD4+ rather than CD8+ infused cells. This multimodality regimen may have translational applications for the treatment of human cancers.