Fischer Jeannette, Paret Claudia, El Malki Khalifa, Alt Francesca, Wingerter Arthur, Neu Marie A, Kron Bettina, Russo Alexandra, Lehmann Nadine, Roth Lea, Fehr Eva-M, Attig Sebastian, Hohberger Alexander, Kindler Thomas, Faber Jörg
*Section of Pediatric Oncology, Children's Hospital, University Medical Center of the Johannes Gutenberg University, Mainz, Germany ‡Third Department of Medicine, University Medical Center of the Johannes Gutenberg University §Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg University †University Cancer Center of the Johannes Gutenberg University, Mainz, Germany.
J Immunother. 2017 Jun;40(5):187-195. doi: 10.1097/CJI.0000000000000169.
B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer and the prognosis of children with relapsed or therapy refractory disease remains a challenge. Treatment with chimeric antigen receptor-modified T cells targeting the CD19 antigen (CART-19 therapy) has been presented as a promising approach toward improving the outcome of relapsed or refractory disease. However, 10%-20% of the patients suffer another relapse. Epitope-loss under therapy pressure has been suggested as a mechanism of tumor cells to escape the recognition from CART-19 therapy. In this work, we analyzed the expression of CD19 isoforms in a cohort of 14 children with CD19 B-ALL and 6 nonleukemia donors. We showed that an alternatively spliced CD19 mRNA isoform lacking exon 2, and therefore the CART-19 epitope, but not isoforms lacking the transmembrane and cytosolic domains are expressed in leukemic blasts at diagnosis in children and in the bone marrow of nonleukemia donors. Furthermore, we clarified the sequence of a further isoform lacking the epitope recognized by CART-19 therapy and disclosed the presence of new isoforms. In comparison with the children, we showed that alternatively spliced CD19 mRNA isoforms affecting exon 2 are also expressed in 6 adult patients with CD19 B-ALL. On top of that, one of the adults expressed an isoform lacking the CD19 transmembrane and cytosolic domains. In conclusion, we proved that some of the CD19 isoforms contributing to CART-19 escape already preexist at diagnosis and could evolve as a dominant clone during CART-19 therapy suggesting the application of combined treatment approaches.
B 细胞急性淋巴细胞白血病（B-ALL）是最常见的儿童癌症，复发或难治性疾病患儿的预后仍然是一个挑战。靶向 CD19 抗原的嵌合抗原受体修饰 T 细胞治疗（CART-19 疗法）已被视为改善复发或难治性疾病预后的一种有前景的方法。然而，10%-20%的患者会再次复发。治疗压力下的表位丢失被认为是肿瘤细胞逃避 CART-19 疗法识别的一种机制。在这项研究中，我们分析了 14 例 CD19 B-ALL 患儿和 6 名非白血病供者队列中 CD19 异构体的表达情况。我们发现，一种缺失外显子 2 因而缺失 CART-19 表位的可变剪接 CD19 mRNA 异构体在儿童白血病原始细胞以及非白血病供者的骨髓中表达，但缺失跨膜和胞质结构域的异构体不表达。此外，我们阐明了另一种缺失 CART-19 疗法识别表位的异构体的序列，并发现了新的异构体。与儿童相比，我们发现影响外显子 2 的可变剪接 CD19 mRNA 异构体在 6 例成人 CD19 B-ALL 患者中也有表达。除此之外，一名成人表达了一种缺失 CD19 跨膜和胞质结构域 的异构体。总之，我们证明了一些导致 CART-19 逃逸的 CD19 异构体在诊断时就已存在，并可能在 CART-19 治疗过程中演变为优势克隆，这表明应采用联合治疗方法。
