Targeting CD19 in diffuse large B‐cell lymphoma: An expert opinion paper

Bailly, Sarah; Cartron, Guillaume; Chaganti, Sridhar; Corradini, Paolo; Düll, Johannes; Ferrarini, Isacco; Osborne, Wendy; Rosenwald, Andreas; Sancho, Juan‐Manuel; Tilly, Hervé; Neste, Eric W Van Den; Viardot, Andreas; Visco, Carlo

doi:10.1002/hon.3013

Cited by 10 publications

(12 citation statements)

References 152 publications

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“…Our investigation centered on the CD19 and CD20 antigens in ALL. CD19, a single-pass transmembrane immunoglobulin-like molecule, resides external to the cell membrane, while CD20, a multi-pass transmembrane molecule, is identified by membrane markers [ 37 , 38 ]. Due to these structural distinctions, targeting CD20 necessitates an elongated extracellular CAR domain, whereas CD19 requires a shorter one.…”

Section: Discussionmentioning

confidence: 99%

CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia

Yang,

Zhang,

Zhang

et al. 2024

J Transl Med

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Background Chimeric antigen receptor natural killer (CAR-NK) cells represent a promising advancement in CAR cell therapy, addressing limitations observed in CAR-T cell therapy. However, our prior study revealed challenges in CAR-NK cells targeting CD19 antigens, as they failed to eliminate CD19+ Raji cells in NSG tumor-bearing mice, noting down-regulation or loss of CD19 antigen expression in some Raji cells. In response, this study aims to enhance CD19 CAR-NK cell efficacy and mitigate the risk of tumor recurrence due to target antigen escape by developing CD19 and CD20 (CD19/CD20) dual-targeted CAR-NK cells. Methods Initially, mRNA encoding anti-CD19 CARs (FMC63 scFv-CD8α-4-1BB-CD3ζ) and anti-CD20 CARs (LEU16 scFv-CD8α-4-1BB-CD3ζ) was constructed via in vitro transcription. Subsequently, CD19/CD20 dual-targeted CAR-NK cells were generated through simultaneous electrotransfection of CD19/CD20 CAR mRNA into umbilical cord blood-derived NK cells (UCB-NK). Results Following co-electroporation, the percentage of dual-CAR expression on NK cells was 86.4% ± 1.83%, as determined by flow cytometry. CAR expression was detectable at 8 h post-electric transfer, peaked at 24 h, and remained detectable at 96 h. CD19/CD20 dual-targeted CAR-NK cells exhibited increased specific cytotoxicity against acute lymphoblastic leukemia (ALL) cell lines (BALL-1: CD19+CD20+, REH: CD19+CD20−, Jurkat: CD19−CD20−) compared to UCB-NK, CD19 CAR-NK, and CD20 CAR-NK cells. Moreover, CD19/CD20 dual-targeted CAR-NK cells released elevated levels of perforin, IFN-γ, and IL-15. Multiple activation markers such as CD69 and cytotoxic substances were highly expressed. Conclusions The creation of CD19/CD20 dual-targeted CAR-NK cells addressed the risk of tumor escape due to antigen heterogeneity in ALL, offering efficient and safe 'off-the-shelf' cell products. These cells demonstrate efficacy in targeting CD20 and/or CD19 antigens in ALL, laying an experimental foundation for their application in ALL treatment.

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Section: Discussionmentioning

confidence: 99%

CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia

Yang,

Zhang,

Zhang

et al. 2024

J Transl Med

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“…ADCs enable targeted delivery of potent warheads into tumor cells using antibodies against tumor antigens. Due to its pattern of expression and its biological role in lymphocytes, the B cell marker CD19 has been heavily exploited for antibody-based therapies, including ADCs, and, more recently, for cellular therapies (4,(6)(7)(8)(9)(10). Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the CD19specific antibody is stochastically conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199) (11).…”

Section: Introductionmentioning

confidence: 99%

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

Tarantelli,

Wald,

Munz

et al. 2024

haematol

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Antibody-drug conjugates (ADCs) represent one of the most successful therapeutic approaches introduced in clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19 targeting ADC, in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine (PBD) dimer warhead (SG3199). Based on the results of a phase 2 study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with CD19 expression levels, and identified combination partners providing synergy with loncastuximab tesirine. Loncastuximab tesirine was tested across 60 lymphoma cell lines. Loncastuximab tesirine had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with CD19 expression level and intrinsic sensitivity of cell lines to the ADC’s warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADCs (coltuximab ravtansine, huB4-DGN462), albeit the pattern of activity across cell lines was correlated. Loncastuximab tesirine activity was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.

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“…In addition of being a cell lineage defining marker, CD19 is also involved in the activation and differentiation of B cells 6 . Most B‐cell malignancies retain CD19 expression, making it an excellent and preferred target for immunotherapy 7–11 . CD19‐targeting therapies represent a new armamentarium of drugs with high activity against R/R DLBCL including chimeric antigen receptor (CAR) T‐cell therapy (CAR T cells), but lately also monoclonal antibodies, bispecific antibodies and targeting antibody‐drug conjugates (ADC) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…6 Most B-cell malignancies retain CD19 expression, making it an excellent and preferred target for immunotherapy. [7][8][9][10][11] CD19-targeting therapies represent a new armamentarium of drugs with high activity against R/R DLBCL including chimeric antigen receptor (CAR) T-cell therapy (CAR T cells), but lately also monoclonal antibodies, bispecific antibodies and targeting antibody-drug conjugates (ADC) (Figure 1). The optimal sequencing and choice among these different immunotherapeutic options remain unknown and is not based on evidence.…”

mentioning

confidence: 99%

How to integrate CD19 specific chimeric antigen receptor T cells with other CD19 targeting agents in diffuse large B‐cell lymphoma?

de Ramon Ortiz,

Wang,

Stathis

et al. 2023

Hematological Oncology

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About one third of patients with diffuse large B‐cell lymphoma (DLBCL) have a relapsing/refractory (R/R) disease after first line chemo‐immunotherapy, with particularly poor outcomes observed in patients with primary refractory disease and early relapse. CD19 specific chimeric antigen receptor (CAR) T cell therapy is a game changer that results in durable and complete response rates in almost half of the patients with R/R DLBCL. Other emerging CD19‐targeting therapies include monoclonal antibodies, bispecific antibodies and targeting antibody‐drug conjugates, which also show encouraging results. However, the timing and sequencing of different anti‐CD19‐targeting agents and how they might interfere with subsequent CAR T cell treatment is still unclear. In this review, we summarize the results of the pivotal clinical trials as well as evidence from real‐world series of the use of different CD19‐targeting approved agents. We discuss the effect of various therapies on CD19 expression and its implications for treatment sequencing.

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Targeting CD19 in diffuse large B‐cell lymphoma: An expert opinion paper

Cited by 10 publications

References 152 publications

CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia

CD19/CD20 dual-targeted chimeric antigen receptor-engineered natural killer cells exhibit improved cytotoxicity against acute lymphoblastic leukemia

Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy

How to integrate CD19 specific chimeric antigen receptor T cells with other CD19 targeting agents in diffuse large B‐cell lymphoma?

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