Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state.
Intermittent chemotherapy can retain the therapeutic potential of anti-CD137 antibody during the late tumor-bearing state.
复制标题
DOI：
10.1111/cas.12568
复制
发表时间：
2015-01
期刊：
影响因子：
5.7
通讯作者：
Harada M
中科院分区：
文献类型：
--
作者：
Tongu M;Harashima N;Tamada K;Chen L;Harada M
免疫调节单克隆抗体（mAb）可以引起抗肿瘤T细胞反应，这种反应被调节性T细胞（Treg）和髓源性抑制细胞（MDSC）减弱。环磷酰胺（CP）和吉西他滨（GEM）治疗可分别减轻Treg和MDSC的免疫抑制作用。在目前的研究中，我们研究了局部注射抗cd137单抗联合使用CP和GEM间歇性低剂量化疗对皮下建立的CT26结肠癌的抗肿瘤作用。虽然在荷瘤期早期（第10天）开始局部抗cd137单抗治疗（5 μg）可观察到显著的抗肿瘤作用，但在荷瘤期后期（第17天）开始单抗治疗时未观察到治疗效果。肿瘤浸润免疫细胞的分析显示，在肿瘤接种后13天，gr -1高/低CD11b+ MDSC的数量开始增加，而注射低剂量（50 mg/kg） CP和GEM则减轻了这种增加。此外，尽管在第10和18天间歇注射低剂量CP和GEM可显著抑制肿瘤生长，但在第19、21和23天额外局部注射抗cd137 mAb可进一步增强治疗效果。我们成功地从肿瘤治愈或肿瘤稳定小鼠的脾脏细胞中诱导出对CT26和肿瘤抗原肽反应的细胞毒性T淋巴细胞。在双侧肿瘤接种模型中，该联合治疗获得了全身性治疗效果，并抑制了单克隆抗体未治疗肿瘤的生长。这些结果表明，使用CP和GEM的间歇免疫化疗可以保留抗cd137单抗的治疗潜力，这种潜力通常在肿瘤晚期受损。间歇化疗和抗cd137抗体治疗。
Immunomodulating monoclonal antibodies (mAb) can evoke antitumor T-cell responses, which are attenuated by regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Treatment with cyclophosphamide (CP) and gemcitabine (GEM) can mitigate the immunosuppression by Treg and MDSC, respectively. In the current study, we examined the antitumor effects of a combination of local injection with anti-CD137 mAb and intermittent low-dose chemotherapy using CP and GEM in subcutaneously established CT26 colon carcinoma. Although a significant antitumor effect was observed when local anti-CD137 mAb therapy (5 μg) was started early in the tumor-bearing stage (day 10), no therapeutic efficacy was observed when the mAb therapy was started at a later tumor-bearing stage (day 17). Analyses of the tumor-infiltrating immune cells revealed that the number of Gr-1high/low CD11b+ MDSC started to increase 13 days after tumor inoculation, whereas injection with low-dose (50 mg/kg) CP and GEM mitigated this increase. In addition, although intermittent injections with low-dose CP and GEM on days 10 and 18 suppressed tumor growth significantly, additional local injections of anti-CD137 mAb on days 19, 21, and 23 further augmented the therapeutic efficacy. Cytotoxic T lymphocytes reactive to CT26 and a tumor antigen peptide were induced successfully from the spleen cells of tumor-cured or tumor-stable mice. In a bilateral tumor inoculation model, this combination therapy achieved systemic therapeutic effects and suppressed the growth of mAb-untreated tumors. These results suggest that intermittent immunochemotherapy using CP and GEM could retain the therapeutic potential of anti-CD137 mAb that is normally impaired during the late tumor-bearing stage. Intermittent chemotherapy and anti-CD137 antibody therapy.
登录
查看更多内容
DOI：
10.4049/jimmunol.1101304
发表时间：
2012-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Shirota Y;Shirota H;Klinman DM
通讯作者：
Klinman DM
影响因子：
20.3
作者：
Lin, Wei;Voskens, Caroline J.;Strome, Scott E.
通讯作者：
Strome, Scott E.
影响因子：
4.4
作者：
Almand, B;Clark, JI;Gabrilovich, DI
通讯作者：
Gabrilovich, DI
影响因子：
28.2
作者：
Palazon, Asis;Martinez-Forero, Ivan;Melero, Ignacio
通讯作者：
Melero, Ignacio
影响因子：
11.2
作者：
Palazon, Asis;Teijeira, Alvaro;Melero, Ignacio
通讯作者：
Melero, Ignacio