Combining Local Immunotoxins Targeting Mesothelin with CTLA-4 Blockade Synergistically Eradicates Murine Cancer by Promoting Anticancer Immunity.
Combining Local Immunotoxins Targeting Mesothelin with CTLA-4 Blockade Synergistically Eradicates Murine Cancer by Promoting Anticancer Immunity.
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DOI：
10.1158/2326-6066.cir-16-0330
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发表时间：
2017-08
影响因子：
10.1
通讯作者：
Pastan I
中科院分区：
文献类型：
--
作者：
Leshem Y;O'Brien J;Liu X;Bera TK;Terabe M;Berzofsky JA;Bossenmaier B;Niederfellner G;Tai CH;Reiter Y;Pastan I
使用针对细胞毒性T淋巴细胞相关抗原4（CTLA-4）的抗体的免疫检查点阻断使有限数量的癌症患者受益。SS 1 P和LMB-100是靶向间皮素的免疫毒素。我们观察到间皮瘤患者对SS 1 P的延迟反应，表明诱导了抗肿瘤免疫。我们的目标是通过将SS 1 P或LMB-100与抗CTLA-4组合来刺激抗肿瘤免疫。我们构建了表达人间皮素（66 C14-M）的BALB/c乳腺癌细胞系，将其植入一个或两个位置。将SS 1 P或LMB-100直接注射到已建立的肿瘤中，并腹膜内施用抗CTLA-4。在具有两个肿瘤的小鼠中，一个肿瘤注射免疫毒素，另一个不注射。注射肿瘤的完全消退率为86%，未注射肿瘤的完全消退率为53%。当药物单独给药时，没有发生完全消退。在退化的肿瘤中，垂死和死亡的肿瘤细胞与中性粒细胞混合在一起，并被混合的嗜酸性粒细胞和单核细胞包围。肿瘤消退与肿瘤浸润性CD 8+细胞数量增加相关，并通过给予CD 8抗体阻断。存活的小鼠通过不表达间皮素的66 C14细胞保护免于肿瘤再攻击，表明抗肿瘤免疫的发展。当使用突变的非细胞毒性变体代替LMB-100时，消除了抗肿瘤作用，表明抗肿瘤应答不是由识别外源细菌蛋白介导的。我们的研究结果支持为患者开发由免疫毒素和检查点抑制剂组成的疗法。
Immune checkpoint blockade using antibodies to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) benefits a limited number of cancer patients. SS1P and LMB-100 are immunotoxins that target mesothelin. We observed delayed responses to SS1P in patients with mesothelioma suggesting that anti-tumor immunity was induced. Our goal was to stimulate anti-tumor immunity by combining SS1P or LMB-100 with anti-CTLA-4. We constructed a BALB/c breast cancer cell line expressing human mesothelin (66C14-M) which was implanted in one or two locations. SS1P or LMB-100 was injected directly into established tumors and anti-CTLA-4 administered i.p. In mice with two tumors, one tumor was injected with immunotoxin and the other was not. The complete regression rate was 86% for the injected tumors and 53% for the uninjetced tumors. No complete regressions occurred when drugs were given separately. In regressing tumors, dying and dead tumor cells were intermingled with PMNs and surrounded by a collar of admixed eosinophils and mononuclear cells. Tumor regression was associated with increased numbers of tumor infiltrating CD8+ cells and blocked by administration of antibodies to CD8. Surviving mice were protected from tumor rechallenge by 66C14 cells not expressing mesothelin, indicating the development of anti-tumor immunity. The anti-tumor effect was abolished when a mutant non-cytotoxic variant was used instead of LMB-100, showing that the anti-tumor response is not mediated by recognition of a foreign bacterial protein. Our findings support developing a therapy composed of immunotoxins and checkpoint inhibitors for patients.