Mechanisms of Relapse After CD19 CAR T-Cell Therapy for Acute Lymphoblastic Leukemia and Its Prevention and Treatment Strategies

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is highly effective in the treatment of B-cell acute lymphoblastic leukemia (ALL) or B-cell lymphoma, providing alternative therapeutic options for patients who failed to respond to conventional treatment or relapse. Moreover, it can bridge other therapeutic strategies and greatly improve patient prognosis, with broad applicable prospects. Even so, 30-60% patients relapse after treatment, probably due to persistence of CAR T-cells and escape or downregulation of CD19 antigen, which is a great challenge for disease control. Therefore, understanding the mechanisms that underlie post-CAR relapse and establishing corresponding prevention and treatment strategies is important. Herein, we discuss post-CAR relapse from the aspects of CD19-positive and CD19-negative and provide some reasonable prevention and treatment strategies.

Keywords: CD19 CAR T-cell; mechanisms; prevention; relapse; strategies; treatment.

Figure 1

(A) Alternative splicing. CD19 gene deletion, frameshift, and exon 2 mutations in patient tumor cell samples resulted in the loss of CD19 epitope recognized by FMC63 of CD19 CAR T-cells. The low level of SRSF3, a splicing factor with its function of retaining exon 2, is the main reason for the loss. (B) Selection by immune pressure. A small number of pre-existing CD19-negative tumor cells escape recognition of CD19 CAR T-cells and are transformed to dominant clones under selective therapeutic stress. (C) Lineage switch induced by immune pressure. CD19 CAR T-cells induce cell reprogramming and dedifferentiation of B cells or differentiation of non-targeted pre-B cells. (D) Trogocytosis and cooperative killing. B-ALL cells change CD19 to CD19 CAR T-cells, resulting in antigen escape and fratricide T cell killing.

Figure 2

(A) Improving CAR structure. Replacing murine scFv with humanized scFv, inducing ICOS TM transmembrane domain and using 4-1BB costimulatory molecule can enhance the persistence of CAR T-cells. (B) CRISPR/Cas9 Genome editing in CAR T-cells. Inhibitory receptor co-expression leads to immune cell dysfunction and failure. Using CRISPR/Cas-9 genome editing can downregulate these inhibitory receptors and enhance the activity and persistence of CAR T-cells. (C) Designing artificial antigen-presenting cells. Designed artificial antigen-presenting cells release IL-21 and IL-15, and activate CD19 CAR T-cells after remission induction to stimulate and amplify the number of CAR T-cells. (D) CAR T-cell binding immunological checkpoint inhibitor. PD-1: PD-L1 initiates T cell programmed death, rendering tumors to gain immune escape. Binding PD-1 and PD-L1 inhibitor can enhance the efficacy and persistence of CAR T-cells.

Figure 3

(A) Dual-signaling CAR T. A single vector encodes two independent CAR molecules, each recognizing different targets. (B) Tandem CAR T. A single vector encodes a bivalent CAR molecule that can recognize two different targets. (C) Trivalent CAR T. A single vector encodes three independent CAR molecules or a bivalent CAR molecule plus an independent CAR molecule. (D) CSPG4-Specific CAR T. A single vector encodes a CSPG4 CAR molecule that can target MLL-rearranged B-ALL.

Figure 4

(A) Sequential infusion of two groups of single-targeted CAR T-cells. Infuse CD22 CAR T following the infusion of CD19 CAR T or vice versa. (B) HSCT after CAR T-cell therapy. After CAR T therapy induces CR, hematopoietic stem cell transplantation can be bridged.