Vyas Maulik, Müller Rolf, Pogge von Strandmann Elke
Experimental Tumor Research, Center for Tumor Biology and Immunology, Clinic for Hematology, Oncology and Immunology, Philipps University , Marburg , Germany.
Institute of Molecular Biology and Tumor Research, Center for Tumor Biology and Immunology, Philipps University , Marburg , Germany.
Front Immunol. 2017 Feb 24;8:175. doi: 10.3389/fimmu.2017.00175. eCollection 2017.
Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.
自20世纪90年代中期以来，癌症免疫治疗领域稳步发展，某些免疫疗法现已成为某些恶性肿瘤的常规且首选治疗方案。主动和被动癌症免疫疗法都利用肿瘤细胞在细胞表面表达特定抗原这一事实，从而引发针对恶性细胞的特异性免疫反应。众所周知，癌细胞通常会在自然或治疗诱导的选择性压力下失去表面抗原，而这些抗原丢失变体往往是导致治疗抵抗性复发的细胞群体。急性淋巴细胞白血病和慢性淋巴细胞白血病中分别出现的CD19和CD20抗原丢失，以及与混合谱系白血病（MLL）基因重排相关的白血病中的谱系转换，都是这方面有充分记录的证据。尽管正在开发越来越多的新型免疫疗法，但其中大多数并未解决对抗原丢失变体的控制问题。在此，我们综述白血病中抗原丢失变体的发生情况，并讨论应对这些变体的治疗策略。我们还提出了一种双靶点免疫配体方法，可有效地将自然杀伤（NK）细胞重新靶向MLL相关白血病中的抗原丢失变体。同时靶向不止一种肿瘤抗原的新型免疫疗法肯定有望完全根除肿瘤并防止治疗抵抗性复发。
