Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors.
Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors.
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DOI：
10.1158/2326-6066.cir-15-0089
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发表时间：
2015-12
影响因子：
10.1
通讯作者：
Chiarle R
中科院分区：
文献类型：
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作者：
Voena C;Menotti M;Mastini C;Di Giacomo F;Longo DL;Castella B;Merlo MEB;Ambrogio C;Wang Q;Minero VG;Poggio T;Martinengo C;D'Amico L;Panizza E;Mologni L;Cavallo F;Altruda F;Butaney M;Capelletti M;Inghirami G;Jänne PA;Chiarle R
含有间变性淋巴瘤激酶(ALK)基因染色体重排的非小细胞肺癌(NSCLC)可以用ALK酪氨酸激酶抑制剂(TKIs)治疗，但仅在有限的时间内有效；大多数病例由于产生耐药性而复发。在这里，我们展示了针对ALK的疫苗诱导了强烈和特异的免疫反应，在预防和治疗方面都损害了ALK阳性小鼠模型中肺肿瘤的生长。ALK疫苗与ALK TKI联合治疗也是有效的，并显著延迟了TKI暂停治疗后的肿瘤复发。我们发现，含有ALK重排的肺肿瘤诱导了免疫抑制微环境，调节了肺肿瘤细胞表面PD-L1的表达。PD-L1的高表达降低了ALK疫苗的效力，这种作用可以通过给予抗PD-1免疫治疗来恢复。因此，ALK疫苗与TKIs和免疫检查点阻断疗法的结合可能是治疗ALK驱动的NSCLC的有效策略。
Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKIs), but is successful for only a limited amount of time; most cases relapse due to the development of drug resistance. Here we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC.