Taking advantage of the immune system to exert an antitumor effect is currently a novel approach in cancer therapy. Adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) targeting a desired antigen has shown extraordinary antitumor activity, especially in refractory and relapsed B-cell malignancies. The most representative in this respect, as well as the most successful example, is CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia (B-ALL). However, with the widespread use of CAR T-cell therapy, problems of resistance and relapse are starting to be considered. This review provides a comprehensive picture of the mechanisms of resistance to CAR T-cell therapy from three aspects, namely, CAR T-cell factors, tumor factors, and tumor microenvironment factors, offering insights for improving CAR T-cell therapy.

SummaryEpstein-Barr virus (EBV) T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells, including chronic active EBV infection of T/NK-cell type (CAEBV+T/NK), EBV-associated hemophagocytic lymphohistiocytosis (EBV+HLH), extranodal NK/T-cell lymphoma of nasal type (ENKTL), and aggressive NK-cell leukemia (ANKL). However, the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown. A total of 171 nonimmunosuppressed patients with EBV+T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed. The 94 gene variants, mostly located in UNC13D, LYST, ITK, and PRF1 genes were detected, and mutations covered 28/50 (56.00%) of CAEBV-T/NK, 31/51 (60.78%) of EBV+HLH, 13/28 (46.42%) of ENKTL, and 13/48 (27.09%) of ANKL. Most mutations represented monoallelic and missense. Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations (P=0.0284, P=0.0137). Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV+T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.

High-grade B cell lymphoma with MYC, BCL2, and BCL6 rearrangements (HGBL-TH) is rare and often portends poor outcome after standard chemoimmunotherapy. Adoptive chimeric antigen receptor (CAR) T cell therapy is a new paradigm for the treatment of refractory/relapsed (r/r) lymphomas, but its therapeutic effects in treating HGBL-TH remain inconclusive. Here, we report a patient with HGBL-TH who failed to achieve complete remission (CR) and progressed rapidly after first-line and second-line therapies. Furthermore, he was resistant to the CAR19 and CAR22 T cell cocktail therapy following autologous hematopoietic stem cell transplantation (ASCT), and disease progressed again after the anti-B cell maturation antigen (BCMA) CAR T cell immunotherapy. Comprehensive analyses were performed to explore the inherent mechanism for resistance, which indicated that tumorderived antigen escape, clonal evolution, and T cell defects were involved in it. This is the first report of an HGBL-TH patient with TP53 deletion and additional germline (PIM1) and somatic mutations (TP53, KMT2D, and IGLL5) who was treated with ASCT, CD19/22 CAR T cell cocktail therapy and BCMA CAR T cell immunotherapy. The clinical evolution and genetic features of this case may help to explain the underlying mechanism of treatment resistance and provide novel insights into lymphoma treatment. Trial registration: ChiCTR-OPN-16009847