Chimeric antigen receptor modified T (CAR-T) cells have been a kind of promising immunotherapeutic strategy for the treatment of malignances, which could target the specific antigen and exert a specific cytotoxic effect by gene modification of T cells. There has been a great stride in B lymphocytic leukemia along with CAR-T therapy. As the essential effector cells of the innate immune system, natural killer (NK) cells play a critical role in host immunity against cancer and have a wide application prospect in the tumor immunotherapy. The potential of CAR modification in NK cells has also attracted much attention. A lot of remarkable results have been obtained in vitro experiments and animal model of CAR-NK targeting hematologic neoplasms. This paper reviews the progress of CAR-NK immunotherapy in hematological malignancies.

Objective:To analyze the influence of CD19 isoforms to the efficacy of CD19/CD3 Bispecific T-cell Engager (BiTE) antibody, and explore the resistance mechanism of BiTE immunotherapy.Methods:Semi-quantitative RT-PCR (qRT-PCR) was used to detect the expression of CD19 mRNA isoforms before and after BiTE treatment in a patient with CD19 + B cell acute lymphoblastic leukemia (ALL) . CD19 isoforms were analyzed by Sanger sequencing. Flow cytometry and transcriptome sequencing were performed to analyze the expression of cell lineage specific molecules before and after BiTE treatment. Results:The expression of CD19 isoform with exon 2 deletion was identified at diagnosis. After relapsed and treatment of BiTE antibody, the patient did not achieve remission and CD19 antigen on leukemic cells turned negative detected by flow cytometry after BiTE treatment. However the expression ratio of CD19 isoform with exon 2 deletion was not increased. Flow cytometry phenotype and transcriptome sequencing confirmed that no linage switching developed, which suggested the expression of CD19 isoform caused by exon alternative splicing and lineage switching was not related to CD19 epitope loss in this patient. This patient achieved complete remission by sequential administration of self-developed CD22 CAR-T and CD19 CAR-T after disease progression.Conclusion:Targeting or combining an alternative antigen specific CAR-T may be a promising treatment option after losing CD19 expression in relapsed ALL.