The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF.
The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF.
复制标题
免疫细胞因子 L19-IL2 与 CTLA-4 阻断剂或 L19-TNF 联合使用可根除癌症。
DOI：
--
复制
发表时间：
2013
影响因子：
6.5
通讯作者：
D. Neri
中科院分区：
文献类型：
--
作者：
K. Schwager;T. Hemmerle;D. Aebischer;D. Neri
全身性高剂量IL 2促进转移性黑色素瘤患者亚组的长期生存，但这种治疗伴随着严重的毒性。免疫细胞因子L19-IL 2，其中IL 2融合到能够在肿瘤新生血管上选择性积累的人L19抗体，最近在转移性黑素瘤患者中显示出令人鼓舞的临床活性。在这项研究中，我们研究了L19-IL 2的治疗性能，与鼠抗CTLA-4抗体或与第二临床阶段的免疫细胞因子（L19-TNF）在两个同基因免疫活性小鼠模型的癌症，全身联合给药。当L19-IL 2与CTLA-4阻断剂联合使用时，我们观察到完全的肿瘤根除。有趣的是，从F9肿瘤治愈的小鼠在治疗后用肿瘤细胞再攻击时发展出新的病变，而从CT 26肿瘤治愈的小鼠对肿瘤再攻击具有抗性。类似地，当与L19-TNF组合以单次瘤内注射施用时，L19-IL 2诱导完全缓解，而当作为单一药剂施用时，两种组分不导致治愈。这些发现为黑色素瘤的联合试验提供了理论依据，因为在临床试验中已对单个治疗药物进行了广泛研究，并且L19抗体识别的抗原在小鼠和人中具有相同的序列。
Systemic high-dose IL2 promotes long-term survival in a subset of metastatic melanoma patients, but this treatment is accompanied by severe toxicities. The immunocytokine L19-IL2, in which IL2 is fused to the human L19 antibody capable of selective accumulation on tumor neovasculature, has recently shown encouraging clinical activity in patients with metastatic melanoma. In this study, we have investigated the therapeutic performance of L19-IL2, administered systemically in combination with a murine anti-CTLA-4 antibody or with a second clinical-stage immunocytokine (L19-TNF) in two syngeneic immunocompetent mouse models of cancer. We observed complete tumor eradications when L19-IL2 was used in combination with CTLA-4 blockade. Interestingly, mice cured from F9 tumors developed new lesions when rechallenged with tumor cells after therapy, whereas mice cured from CT26 tumors were resistant to tumor rechallenge. Similarly, L19-IL2 induced complete remissions when administered in a single intratumoral injection in combination with L19-TNF, whereas the two components did not lead to cures when administered as single agents. These findings provide a rationale for combination trials in melanoma, as the individual therapeutic agents have been extensively studied in clinical trials, and the antigen recognized by the L19 antibody has an identical sequence in mouse and man.
通过抗体-白细胞介素 2 融合蛋白疗法消除已建立的小鼠结肠癌转移。
影响因子：
11.2
作者：
Xiang,R;Lode,HN;Dolman,CS;Dreier,T;Varki,NM;Qian,X;Lo,KM;Lan,Y;Super,M;Gillies,SD;Reisfeld,RA
通讯作者：
Reisfeld,RA