Advances in chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Abstract

B-cell non-Hodgkin lymphoma (B-NHL) is a group of heterogeneous disease which remains incurable despite developments of standard chemotherapy regimens and new therapeutic agents in decades. Some individuals could have promising response to standard therapy while others are unresponsive to standard chemotherapy or relapse after autologous hematopoietic stem-cell transplantation (ASCT), which indicates the necessity to develop novel therapies for refractory or relapsed B-NHLs. In recent years, a novel cell therapy, chimeric antigen receptor T-cell therapy (CAR-T), was invented to overcome the limitation of traditional treatments. Patients with aggressive B-NHL are considered for CAR-T cell therapy when they have progressive lymphoma after second-line chemotherapy, relapse after ASCT, or require a third-line therapy. Clinical trials of anti-CD19 CAR-T cell therapy have manifested encouraging efficacy in refractory or relapsed B-NHL. However, adverse effects of this cellular therapy including cytokine release syndrome, neurotoxicity, tumor lysis syndrome and on-target, off-tumor toxicities should attract our enough attention despite the great anti-tumor effects of CAR-T cell therapy. Although CAR-T cell therapy has shown remarkable results in patients with B-NHL, the outcomes of patients with B-NHL were inferior to patients with acute lymphoblastic leukemia. The inferior response rate may be associated with physical barrier of lymphoma, tumor microenvironment and low quality of CAR-T cells manufactured from B-NHL patients. Besides, some patients relapsed after anti-CD19 CAR-T cell therapy, which possibly were due to limited CAR-T cells persistence, CD19 antigen escape or antigen down-regulation. Quite a few new antigen-targeted CAR-T products and new-generation CAR-T, for example, CD20-targeted CAR-T, CD79b-targeted CAR-T, CD37-targeted CAR-T, multi-antigen-targeted CAR-T, armored CAR-T and four-generation CAR-T are developing rapidly to figure out these deficiencies.

Effectiveness and Safety of Anti-CD19 Chimeric Antigen Receptor-T Cell Immunotherapy in Patients With Relapsed/Refractory Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis

“…One of the latest developments in cell immunotherapy is chimeric antigen receptor T (CAR-T) cells, demonstrating remarkable achievements in B-cell NHL ( Kersten et al, 2020 ; Yin et al, 2021 ). CAR-T cell therapy involves autologous or allogeneic genetically engineered T cells to fight cancer and appears to be effective even in r/r patients ( Kersten et al, 2020 ; Yin et al, 2021 ).…”

“…One of the latest developments in cell immunotherapy is chimeric antigen receptor T (CAR-T) cells, demonstrating remarkable achievements in B-cell NHL ( Kersten et al, 2020 ; Yin et al, 2021 ). CAR-T cell therapy involves autologous or allogeneic genetically engineered T cells to fight cancer and appears to be effective even in r/r patients ( Kersten et al, 2020 ; Yin et al, 2021 ). Indeed, CAR-T cells engineered to target CD19 have shown remarkable efficacy in patients with r/r CD19 + B-cell malignancies ( Lee et al, 2015 ; Turtle et al, 2016 ; Locke et al, 2017 ; Kersten et al, 2020 ).…”

Treatment of Classic Hairy Cell Leukemia: Targeting Minimal Residual Disease beyond Cladribine

“…Chimeric antigen receptor-engineered (CAR) T-cell therapy has emerged as the most complex immunotherapeutic approach in recent years, primarily directed against CD19+ B-cell malignancies [ 63 ]. CARs are genetically engineered synthetic constructs transfected into immunocompetent T cells of the patients to recognize a specific antigen on the surface of tumor cells [ 63 ]. Several clinical trials have demonstrated the efficacy of CD19-directed CAR T-cell therapy, leading to FDA and EMA approval in certain B-cell lymphomas [ 64 , 65 ].…”

Management of Aggressive Non-Hodgkin Lymphomas in the Pediatric, Adolescent, and Young Adult Population: An Adult vs. Pediatric Perspective

“…CAR T-cell therapy relies on the modification of a patient’s T lymphocytes in order to express a cell surface receptor, most commonly for CD19, that can recognize leukemia cells expressing the CD19 surface antigen and thereby lead to on-target cytotoxicity with minimal off-target effects [ 171 ]. While four different anti-CD19 CAR T-cell products have been approved for use in adults, none have been approved yet for pediatric patients with NHL [ 172 ]. Various CAR T-cell products such as tisagenlecleucel, KTE-X19, and axicabtagene clioleucel have been tested in phase 2 and 3 trials in adult patients with R/R LBCL and have shown ORRs ranging from 50 to 80% and complete response rates (CRRs) of 40–50%, in some cases indicating improvements in response over other salvage treatment options [ 173 , 174 , 175 , 176 ].…”