A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma

Meo, Francesco; Iyer, Anjushree; Akama, Keith; Cheng, Rujin; Yu, Christina Y.; Cesarano, Annamaria; Kurihara, Noriyoshi; Tenshin, Hirofumi; Aljoufi, Arafat; Marino, Silvia; Soni, Rajesh Kumar; Roda, Julie M.; Sissons, James; Vu, Ly; Guzmán, Mónica L.; Huang, Kun; Laskowski, Tamara; Broxmeyer, Hal E.; Roodman, David; Perna, Fabiana

doi:10.1016/j.xcrm.2023.101110

Cited by 7 publications

(1 citation statement)

References 22 publications

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“…Concordant with its expression in certain B lineage cells, it was reported that LILRB4 is expressed in myeloma cells [ 40 , 46 ]. However, it is unknown whether LILRB4 is functional in myeloma pathogenesis.…”

Section: Introductionmentioning

confidence: 87%

LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway

Wang,

Luan

et al. 2024

J Exp Clin Cancer Res

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Background Leukocyte Ig-like receptor B family 4 (LILRB4) as an immune checkpoint on myeloid cells is a potential target for tumor therapy. Extensive osteolytic bone lesion is the most characteristic feature of multiple myeloma. It is unclear whether ectopic LILRB4 on multiple myeloma regulates bone lesion. Methods The conditioned medium (CM) from LILRB4-WT and -KO cells was used to analyze the effects of LILRB4 on osteoclasts and osteoblasts. Xenograft, syngeneic and patient derived xenograft models were constructed, and micro-CT, H&E staining were used to observe the bone lesion. RNA-seq, cytokine array, qPCR, the activity of luciferase, Co-IP and western blotting were used to clarify the mechanism by which LILRB4 mediated bone damage in multiple myeloma. Results We comprehensively analyzed the expression of LILRB4 in various tumor tissue arrays, and found that LILRB4 was highly expressed in multiple myeloma samples. The patient’s imaging data showed that the higher the expression level of LILRB4, the more serious the bone lesion in patients with multiple myeloma. The conditioned medium from LILRB4-WT not -KO cells could significantly promote the differentiation and maturation of osteoclasts. Xenograft, syngeneic and patient derived xenograft models furtherly confirmed that LILRB4 could mediate bone lesion of multiple myeloma. Next, cytokine array was performed to identify the differentially expressed cytokines, and RELT was identified and regulated by LILRB4. The overexpression or exogenous RELT could regenerate the bone damage in LILRB4-KO cells in vitro and in vivo. The deletion of LILRB4, anti-LILRB4 alone or in combination with bortezomib could significantly delay the progression of bone lesion of multiple myeloma. Conclusions Our findings indicated that LILRB4 promoted the bone lesion by promoting the differentiation and mature of osteoclasts through secreting RELT, and blocking LILRB4 singling pathway could inhibit the bone lesion.

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Section: Introductionmentioning

confidence: 87%

LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway

Wang,

Luan

et al. 2024

J Exp Clin Cancer Res

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Targeting myeloma essential genes using NOT Gated CAR T-cells, a computational approach

Walker,

Roy,

Anderson

et al. 2024

Leukemia

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Beyond BCMA: newer immune targets in myeloma

Tan,

Chen,

Smith

2024

Blood Advances

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The identification and targeting of B cell maturation antigen (BCMA) through immunotherapeutic strategies such as antibody-drug conjugates (ADC), chimeric antigen receptor T-cells (CAR T-cells), and T-cell engagers (TCE) have revolutionized the care of patients with multiple myeloma (MM). These treatment modalities have improved survival outcomes of relapsed and/or refractory (R/R) MM patients compared to previously established strategies and are moving into earlier lines of therapy (LOT). Despite their efficacy, the majority of patients eventually relapse, necessitating additional therapeutic targets for salvage. G-protein-coupled receptor class 5 member D (GPRC5D), Fc receptor-homolog 5 (FcRH5), and SLAMF7 are some examples of novel targets in development. This expanding armamentarium of immunotherapeutic agents will be crucial to address the unmet need for relapses following BCMA-targeting therapies, particularly antigen-negative relapses. The utilization of sequential T-cell redirective therapies including agents targeting different tumor-associated antigens and combination therapies appears feasible paves the way for effective chemotherapy-free regimes. Deliberate consideration of treatment timing, preserving T-cell health, overcoming antigenic loss, and comprehension of the complex tumor microenvironment would be key to maximizing therapeutic benefits and minimizing adverse effects. This review summarizes novel targets in development for myeloma beyond BCMA, presenting pivotal safety and efficacy data derived from clinical trials where available and the considerations vital for navigating this expanding landscape of immunotherapeutic options.

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A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma

Cited by 7 publications

References 22 publications

LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway

LILRB4 on multiple myeloma cells promotes bone lesion by p-SHP2/NF-κB/RELT signal pathway

Targeting myeloma essential genes using NOT Gated CAR T-cells, a computational approach

Beyond BCMA: newer immune targets in myeloma

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