Abstract
Relapse or refractory B-cell malignancies have been reported in multiple clinical trials after treatment of Anti-CD19 Chimeric Antigen Receptor (CAR) T-cells. Many clinical studies have demonstrated the potential immune escape mechanism for B-cell malignancies like genetic mutation, transcriptional deregulation, lineage switch, loss of CAR T-cells, and trogocytosis. The study of these mechanisms can provide us insights in designs of future immunotherapies regarding both B-cell malignancies and even other solid tumors. The potential solution for the immune escape mechanisms regarding CAR T-cell treatment is engineering multispecific CARs. In this article, I review most of the upto- date immune escape mechanism studies and some multispecific CAR T-cell treatment clinical studies and trials that may prevent the escape route and have to potential to cure B-cell malignancies.
Highlights
Despite significant medical treatment advances on B-cell malignancies like B-cell acute lymphoblastic leukemias(B-ALL), relapsed or refractory disease cases in adults is still highly probable and result lower than 50% long-term event-free survival
One of the most innovative treatment against B-ALL is the use of AntiCD19 Chimeric Antigen Receptor (CAR) T-cells
Lineage-switch for the first patient is caused by cell reprogramming of a previously committed lymphoid lineage, but the other can only be explained with myeloid differentiation of a noncommitted precursor or selection of a pre-existing myeloid clone [10]. In conjunction with this clinical study, a recent experiment on murine ALL have demonstrated that the immune pressure from CD19 CAR T-cell therapy can induce either a rapid relapsing leukemia resulting previously discussed CD19 Δex2 isoforms, or a lineage-switched leukemia which is caused by reprogramming of PAX5 and EBF1(important B-cell regulatory transcription factors), resulting CD19 CAR resistant tumor [11, 12]
Summary
Despite significant medical treatment advances on B-cell malignancies like B-cell acute lymphoblastic leukemias(B-ALL), relapsed or refractory disease cases in adults is still highly probable and result lower than 50% long-term event-free survival. One of the most innovative treatment against B-ALL is the use of AntiCD19 CAR T-cells. There are still relapsed or refractory disease cases after CAR T cell therapy. In a phase 1 clinical study of CD19-specific CAR T cells in patients with B-ALL, there were four CD19+ relapse cases, while CD19- disease relapses were not seen [1]. The relapsed cases were not limited to the treatment of B-ALL. In clinical trial treating patients with B-Cell Lymphomas using CTL019 cells (autologous T cells that express a CD19-directed CAR), both the loss of the CD19 expression and continued expression of CD19 were observed [2]. Recent clinical studies have concluded that relapsed or refractory cases are mostly caused by either the loss of CD19 target protein or the loss of CAR T-cells in blood [3]
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