A unique expression pattern of <scp><i>LAG3</i></scp> distinct from that of other immune checkpoints in diffuse large B‐cell lymphoma

Lee, Hyunjee; Yoon, Sang Eun; Kim, Seok Jin; Kim, Won Seog; Cho, Junhun

doi:10.1002/cam4.6268

Cancer Medicine

2023

DOI: 10.1002/cam4.6268

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A unique expression pattern of LAG3 distinct from that of other immune checkpoints in diffuse large B‐cell lymphoma

Hyunjee Lee

Sang Eun Yoon

Seok Jin Kim

et al.

Abstract: BackgroundAlthough some patients with diffuse large B‐cell lymphoma (DLBCL) show a response to immunotherapy, there are still many who do not respond. This suggests that various immune checkpoints are complicatedly intertwined in the composition of the tumor microenvironment of DLBCL.Patients and MethodsTo comprehensively understand the expression of various immune checkpoint genes in DLBCL, we performed NanoString assay in 98 patients to investigate 579 genes. In addition, we performed immunohistochemistry fo… Show more

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References 45 publications

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Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen

Esquinas,

Moreno-Sanz,

Sandá

et al. 2024

J Immunother Cancer

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BackgroundInfusion of T cells modified with a chimeric antigen receptor (CAR) targeting CD19 has achieved exceptional responses in patients with non-Hodgkin’s lymphoma (NHL), which led to the approval of CAR targeting CD19 (CART19) (Axi-cel and Liso-cel) as second line of treatment for adult patients with relapsed/refractory NHL. Unfortunately, 60% of patients still relapse after CART19 due to either a loss of expression of the target antigen (CD19) in the tumor cell, observed in 27% of relapsed patients, a limited CAR-T persistence, and additional mechanisms, including the suppression of the tumor microenvironment. Clinic strategies to prevent target antigen loss include sequential treatment with CARs directed at CD20 or CD22, which have caused loss of the second antigen, suggesting targeting other antigens less prone to disappear. CD79b, expressed in NHL, is a target in patients treated with antibody-drug conjugates (ADC). However, the limited efficacy of ADC suggests that a CAR therapy targeting CD79b might improve results.MethodsWe designed three new CARs against CD79b termed CAR for Lymphoma (CARLY)1, 2 and 3. We compared their efficacy, phenotype, and inflammatory profiles with CART19 (ARI0001) and CARTBCMA (ARI0002h), which can treat NHL. We also analyzed the target antigen’s expression loss (CD79b, CD19, and B-cell maturation antigen(BCMA)).ResultsWe found that CARLY2 and CARLY3 had high affinity and specificity towards CD79b on B cells. In vitro, all CAR-T cells had similar anti-NHL efficacy, which was retained in an NHL model of CD19−relapse. In vivo, CARLY3 showed the highest efficacy. Analysis of the loss of the target antigen demonstrated that CARLY cells induced CD79b and CD19 downregulation on NHL cells with concomitant trogocytosis of these antigens to T cells, being most notorious in CARLY2, which had the highest affinity towards CD79b and CD19, and supporting the selection of CARLY3 to design a new treatment for patients with NHL. Finally, we created a CAR treatment based on dual targeting of CD79b and BCMA to avoid losing the target antigen. This treatment showed the highest efficacy and did not cause loss of the target antigen.ConclusionsBased on specificity, efficacy, and loss of the target antigen, CARLY3 represents a potential novel CAR treatment for NHL.

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Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen

Esquinas,

Moreno-Sanz,

Sandá

et al. 2024

J Immunother Cancer

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Checkpoint inhibition in hematologic malignancies

Tsumura,

Levis,

Tuscano

2023

Front. Oncol.

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Checkpoint inhibitor therapy has emerged as an effective therapeutic strategy for many types of malignancies, especially in solid tumors. Within the last two decades, numerous monoclonal antibody drugs targeting the CTLA-4 and PD-1/PD-L1 checkpoint pathways have seen FDA approval. Within hematologic malignancies, Hodgkin Lymphoma has seen the greatest clinical benefits thus far with more recent data showing efficacy in the front-line setting. As our understanding of checkpoint inhibition expands, using these pathways as a therapeutic target has shown some utility in the treatment of other hematologic malignancies as well, primarily in the relapsed/refractory settings. Checkpoint inhibition also appears to have a role as a synergistic agent to augment clinical responses to other forms of therapy such as hematopoietic stem cell transplant. Moreover, alternative checkpoint molecules that bypass the well-studied CTLA-4 and PD-1/PD-L1 pathways have emerged as exciting new therapeutic targets. Most excitingly is the use of anti-CD47 blockade in the treatment of high risk MDS and TP-53 mutated AML. Overall, there has been tremendous progress in understanding the benefits of checkpoint inhibition in hematologic malignancies, but further studies are needed in all areas to best utilize these agents. This is a review of the most recent developments and progress in Immune Checkpoint Inhibition in Hematologic Malignancies in the last decade.

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A unique expression pattern of LAG3 distinct from that of other immune checkpoints in diffuse large B‐cell lymphoma

Cited by 2 publications

References 45 publications

Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen

Preclinical development of three novel CARs targeting CD79b for the treatment of non-Hodgkin’s lymphoma and characterization of the loss of the target antigen

Checkpoint inhibition in hematologic malignancies

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