LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation

Sung, Eun-Sil; Ko, Minkyung; Won, Jaeyeon; Jo, Yunju; Park, Eun‐Young; Kim, Hyun‐Joo; Choi, Eun‐Ji; Jung, Ui-jung; Jeon, Jaehyoung; Kim, Youngkwang; Ahn, Hyejin; Choi, Dong-Whan; Choi, Sang-Haeng; Hong, Youngeun; Park, Hye-Young; Lee, Hanbyul; Son, Yong-Gyu; Park, Kyeongsu; Won, Jonghwa; Oh, Soo Jin; Lee, Seonmin; Kim, Kyu-Pyo; Yoo, Changhoon; Song, Hyun Kyu; Jin, Hyung‐seung; Jung, Jaewoon; Park, Yoon

doi:10.1016/j.ymthe.2022.05.003

Cited by 45 publications

(42 citation statements)

References 75 publications

(105 reference statements)

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“… 84 The bispecific antibody ABL501, which targets both LAG‐3 and PD‐L1, promotes mregDC interaction with T cells and consequently induces efficient CD8 + T‐cell responses. 85 More importantly, blocking the mregDC and Treg interaction could promote their communication with effector T cells. Targeting mregDCs and PD‐1 + T cells yielded a synergistic effect in prostate cancer.…”

Section: Potential Clinical Implicationsmentioning

confidence: 99%

“…Furthermore, TIM‐3 inhibition was found to cause cDC1‐like mregDCs to take up more tumour antigen and activate the cGAS–STING pathway, 83 inducing the release of CXCL9 and IL‐12 from mregDCs and encouraging CD8 + T‐cell colocalisation with DCs to enhance antitumour immunity 84 . The bispecific antibody ABL501, which targets both LAG‐3 and PD‐L1, promotes mregDC interaction with T cells and consequently induces efficient CD8 + T‐cell responses 85 . More importantly, blocking the mregDC and Treg interaction could promote their communication with effector T cells.…”

Section: Potential Clinical Implicationsmentioning

confidence: 99%

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Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

Zhou

Huang

et al. 2023

Clinical & Translational Med

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Background Dendritic cells (DCs) mediate divergent immune effects by activating T cells or negatively regulating the immune response to promote immune tolerance. They perform specific functions determined by their tissue distribution and maturation state. Traditionally, immature and semimature DCs were described to have immunosuppressive effects, leading to immune tolerance. Nonetheless, recent research has demonstrated that mature DCs can also suppress the immune response under certain circumstances. Main body Mature DCs enriched in immunoregulatory molecules (mregDCs) have emerged as a regulatory module across species and tumour types. Indeed, the distinct roles of mregDCs in tumour immunotherapy have sparked the interest of researchers in the field of single‐cell omics. In particular, these regulatory cells were found to be associated with a positive response to immunotherapy and a favourable prognosis. Conclusion Here, we provide a general overview of the latest and most notable advances and recent findings regarding the basic features and complex roles of mregDCs in nonmalignant diseases and the tumour microenvironment. We also emphasise the important clinical implications of mregDCs in tumours.

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Section: Potential Clinical Implicationsmentioning

confidence: 99%

Section: Potential Clinical Implicationsmentioning

confidence: 99%

Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

Zhou

Huang

et al. 2023

Clinical & Translational Med

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“…The dosing interval to be used in the dose-expansion part will be re-evaluated based on the emerging safety and pharmacokinetics data from the dose-escalation part of the study. It promotes enhanced human T cell activation in vitro and potentiates antitumor responses of T cells through DC activation [ 101 , 102 ].…”

Section: Preclinical and Clinical Development Of Opdualagmentioning

confidence: 99%

Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor

Chocarro

Bocanegra

Blanco

et al. 2022

Cells

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Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.

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“…Antagonizing LAG-3 can restore the anti-tumor activity of T cells ( 66 ). LAG-3 as an inhibitory receptor expressed on activated T cells can downregulate T-cell function and participate in T-cell exhaustion and tumor immune escape thus promoting tumor progression ( 67 , 68 ), and this immunoglobulin superfamily gene was also expressed on NK, DCs, and B cells ( 66 , 69 ). T regs cells expressing LAG-3 can suppress tumor-specific T cells and produce high levels of the immunoregulatory cytokines interleukin (IL)-10 and transforming growth factor-beta (TGF-β) ( 70 , 71 ).…”

Section: Lag-3mentioning

confidence: 99%

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

et al. 2022

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Gastric cancer (GC) is a malignancy with a high incidence and mortality, and the emergence of immunotherapy has brought survival benefits to GC patients. Compared with traditional therapy, immunotherapy has the advantages of durable response, long-term survival benefits, and lower toxicity. Therefore, targeted immune cells are the most promising therapeutic strategy in the field of oncology. In this review, we introduce the role and significance of each immune cell in the tumor microenvironment of GC and summarize the current landscape of immunotherapy in GC, which includes immune checkpoint inhibitors, adoptive cell therapy (ACT), dendritic cell (DC) vaccines, reduction of M2 tumor-associated macrophages (M2 TAMs), N2 tumor-associated neutrophils (N2 TANs), myeloid-derived suppressor cells (MDSCs), effector regulatory T cells (eTregs), and regulatory B cells (Bregs) in the tumor microenvironment and reprogram TAMs and TANs into tumor killer cells. The most widely used immunotherapy strategies are the immune checkpoint inhibitor programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibody, cytotoxic T lymphocyte–associated protein 4 (CTLA-4) antibody, and chimeric antigen receptor T (CAR-T) in ACT, and these therapeutic strategies have significant anti-tumor efficacy in solid tumors and hematological tumors. Targeting other immune cells provides a new direction for the immunotherapy of GC despite the relatively weak clinical data, which have been confirmed to restore or enhance anti-tumor immune function in preclinical studies and some treatment strategies have entered the clinical trial stage, and it is expected that more and more effective immune cell–based therapeutic methods will be developed and applied.

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LAG-3xPD-L1 bispecific antibody potentiates antitumor responses of T cells through dendritic cell activation

Cited by 45 publications

References 75 publications

Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

Mature dendritic cells enriched in immunoregulatory molecules (mregDCs): A novel population in the tumour microenvironment and immunotherapy target

Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3 Inhibitor

Therapeutic strategies for gastric cancer targeting immune cells: Future directions

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