Mechanisms of failure of chimeric antigen receptor T-cell therapy.

Abstract

Although chimeric antigen receptor T (CART)-cell therapy is best recognized for its antitumor effect in relapsed/refractory B-cell hematological cancers, it is still associated with a high relapse rate. We firstly analyzed internal immunological and genetic reasons of CD19+ relapse after treatment for R/R B-cell hematological cancers with CART19 cells. The reasons: murine-derived scFv may limit expansion of CART cells. Repeated antigen exposure leads to T-cell exhaustion. Activation of T cells can cause T-cell senescence and high expression of inhibitive receptors, PD-1, CTLA4, TIGIT, LAG-3, CD244, CD160, TIM3, which might be solved by some external pharmacological intervention methods [for instance, the use of FC (Fludarabine, Cyclophosphamide) lymphodepletion regimen, lenalidomide, PD-1 inhibitor, ibrutinib and humanized CD19-CART cells. Secondly, mechanism of CD19 relapse can be attributed to the preexisting of CD19 subclone, the loss or alternative RNA splicing on exon 2 of chromosome 16 on which CD19 gene is located, B-cell transcript factors - paired-box 5 (PAX5) and early B-cell factor 1 (EBF1) are down-regulated to cause lineage-switch from lymphoid to myeloid. Although different preparation techniques generates various entities of CART 19 cells, these problems could be conquered by novel agents and novel CAR system. Although Chimeric Antigen Receptor T (CART) cell therapy is best recognized for its antitumor effect in Relapsed/Refractory B-cell hematological cancers, it still shows a high relapse rate. We review mechanisms of failure of CART therapy. http://links.lww.com/COH/A18.