Volume 14 - Issue 2

Mini Review Biomedical Science and Research Biomedical Science and Research CC by Creative Commons, CC-BY

The Molecular Mechanisms of CD19-Negative Relapse in B-Cell Lymphoma after CAR T-Cell Immunotherapy

*Corresponding author: Weihong Chen, Department of Hematology, The First Affiliated Hospital of Shenzhen University/Shenzhen Second People’s Hospital, Shenzhen 518035, China

Received: September 06, 2021; Published: September 13, 2021

DOI: 10.34297/AJBSR.2021.14.001965


The chimeric antigen receptor T cell (CAR T-cell) immunotherapy is the most antitumor ability in relapse/refractory (R/R) hematological malignancies but it still shows a high relapse rate. A few studies have been found that the molecular mechanisms of CD19-negative relapse after CAR T-cell therapy are the CD19 loss or down-regulation in lymphoma, including lineage switching, CD19 gene mutation, selective shearing, and subcloning of CD19-negative cell. The gene rearrangement, fusion genes and IL-6 may be to influent the therapeutic effect of CAR T-cell immunotherapy. The gene mutations of APX5, IKAROS, EBF1, GNA13, SOCS1, TNFALP3, XPO1, FLT3 etc. have been currently found after CAR T-cell therapy relapse. The review reports the molecular mechanisms of CD19-negative relapse in B-cell lymphoma after CAR T-cell immunotherapy.

Keywords: CD19-negative relapse, B-cell lymphoma, CAR T-cell immunotherapy, Molecular mechanisms


CAR T-cell immunotherapy is a great advance in the treatment of hematologic malignancies. Some researches find that the complete remission rate about 70%-90% for relapsed/refractory B-cell acute lymphocytic leukemia [1]. However, a study has also found that relapse rate of lymphoma is about 30-50% after CAR T-cell treatment. We have reported that there are two main causes for CD19-positive and CD19-negative relapse after CAR T-cell immunotherapy [2-4]. CD19-positive relapse is mainly due to low efficiency and persistence, senescence of CAR T-cell in vivo. And there are also some confounding factors such as: different co-stimulatory, the manufacture methods, various categories and dosage of CAR T-cell, tumor heterogeneity and so on [2,3]. The main mechanisms of CD19-negative relapse after CAR T-cell therapy may be the presence of the loss or down-regulation of CD19 expression. The effects of other molecular, still unclear genetic mutations, and the indirect effects of other cytokines may influent the expression of CD19.

Possibly Relevant Molecular Mechanisms

Mutations in ctDNA

The patients of relapse lymphoma have been found some mutated genes after CAR T-cell treatment. In one study, continuous monitoring results of circulating tumor DNA (ctDNA) in the patients revealed mutations of GNA13, SOCS1, XPO1T and TNFALP3 in ctDNA. GNA13, located on chromosome 17, corresponds to a monitoring region of exon1-4. It encodes the Gα13 protein, which acts to regulate cell morphology, contraction, migration and differentiation and maturation [14]. SOCS1, located on chromosome 17, corresponds to a monitoring region of CDS. It is an important member of the suppressor of cytokine signaling (SOCS) protein family. SOCS1 is involved in a variety of acute and chronic inflammatory responses, innate and acquired immune responses, hormone regulation, and the generation and development of many tumors in the body [15]. XPO1, located on chromosome 2, corresponds to a monitoring region of exon15-17 It is an important member of the importinβ family of nuclear export protein receptors, mainly responsible for the nuclear export of some tumor suppressor proteins and growth regulator proteins [16]. TNFALP3 corresponds to a monitoring region of CDS. There are few relevant studies about TNFALP3. The mutations of GNA13, SOCS1, XPO1T and TNFALP3 in ctDNA would exist associated with prognosis after CAR T-cell treatment [17].

Gene Rearrangement and Fusion Genes

Rearrangement of 11q23 occurs to patients with MLL-r, The most common of which is MLL-AF4. At present, fusion gene of ZNF384 in 12q13, as well as internal repeat crosstalk of the FLT3 gene, are also found in patients of relapse with lineage switch. FLT3, located on chromosome 13, encodes a class III receptor tyrosine kinase that regulates hematopoiesis. Activated receptor kinase phosphorylation activates multiple signaling pathways, including apoptosis, proliferation and differentiation of myeloid hematopoietic cells [18]. The gene rearrangement or fusion genes cause relapse of MLL remains to be investigated after CAR T-cell immunotherapy [5,19,20].


The current research on CD19-negative relapse is thought to be the loss of CD19 after CAR T-cell immunotherapy. The lineage switching, CD19 gene mutation, selective shearing, and subcloning of CD19- negative are thought to result in the loss of CD19. Moreover, the IL-6, mutated and fused genes have also been discovered. Further studies are needed for its relapse mechanism.

Future Perspectives

CD19 is the most common target in CAR T-cell immunotherapy. CD22 is a target for salvage therapy after Anti-CD 19 CAR T-cell treatment [22]. The bispecific anti-CD20 and anti-CD19 CAR T-cells are also available to treat lymphoma [23]. The loss of surface antigens may lead to relapse. Therefore, research in the molecular field may be the way forward for CAR T-cell immunotherapy.

Financial Support and Sponsorship

1. The relapse mechanism of genetic mutation for the relapsed/ refractory lymphoma after CAR T-cell therapy has been approved by Shenzhen Science and Technology Innovation Committee. Award Number: JCYJ20180228163509339. Grant Recipient: Weihong Chen.
2. CAR T-38 cell therapy for disease progression/relapse multiple myeloma has been approved by Shenzhen municipal Health Commission. Award Number: 201606021. Grant Recipient: Weihong Chen.


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