Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy

Journal of Hematology & Oncology, Год журнала: 2023, Номер 16(1)

Опубликована: Сен. 5, 2023

Abstract In one decade, immunotherapy based on immune checkpoint blockades (ICBs) has become a new pillar of cancer treatment following surgery, radiation, chemotherapy, and targeted therapies. However, not all patients benefit from single or combination therapy with anti-CTLA-4 anti-PD-1/PD-L1 monoclonal antibodies. Thus, an increasing number proteins (ICPs) have been screened their effectiveness evaluated in preclinical clinical trials. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin mucin-domain-containing-3 (TIM-3), immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) constitute the second wave targets that show great promise for use solid tumors leukemia. To promote research application ICBs directed at these targets, we summarize discovery, mechanism, efficiency, trial results this review.

Язык: Английский

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Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Июнь 8, 2023

Abstract Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for substantial number of patients. However, response rates to ICIs vary significantly among individuals types, with notable proportion patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed potential strategy address these challenges. One targets is TIGIT, an inhibitory receptor associated T-cell exhaustion. TIGIT diverse immunosuppressive effects on immunity cycle, including inhibition natural killer cell effector function, suppression dendritic maturation, promotion macrophage polarization M2 phenotype, differentiation T cells regulatory cells. Furthermore, linked PD-1 expression, it can synergize PD-1/PD-L1 blockade enhance tumor rejection. Preclinical studies demonstrated co-inhibition in enhancing anti-tumor improving outcomes several types. Several clinical trials are underway evaluate safety efficacy various results awaited. This review provides overview mechanisms treatment, summarizes latest investigating this therapy, discusses its prospects. Overall, represents promising therapeutic approach that improve treated ICIs.

Язык: Английский

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Targeting TIGIT for cancer immunotherapy: recent advances and future directions

Biomarker Research, Год журнала: 2024, Номер 12(1)

Опубликована: Янв. 16, 2024

Abstract As a newly identified checkpoint, T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is highly expressed on CD4 + cells, CD8 natural killer (NK) regulatory cells (Tregs), tumor-infiltrating lymphocytes (TILs). TIGIT has been associated NK exhaustion in vivo individuals various cancers. It not only modulates survival but also mediates exhaustion. the primary ligand of humans, CD155 may be main target for immunotherapy due to its interaction TIGIT. found that anti-programmed death protein 1 (PD-1) treatment response cancer correlated Anti-TIGIT alone combination anti-PD-1 agents have tested immunotherapy. Although two clinical studies advanced lung had positive results, TIGIT-targeted antibody, tiragolumab, recently failed new trials. In this review, we highlight current developments discuss characteristics functions

Язык: Английский

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Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin's lymphoma: a first-in-human phase I study

EClinicalMedicine, Год журнала: 2023, Номер 60, С. 102010 - 102010

Опубликована: Май 18, 2023

Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate safety efficacy a kind virus-free CAR-T cells (PD1-19bbz), in an anti-CD19 CAR sequence is specifically integrated at PD1 locus clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, adults with relapsed/refractory (r/r) B cell non-Hodgkin's lymphoma (B-NHL).This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz adult patients r/r B-NHL from May 3rd 2020 August 10th 2021. The were recruited treated First Affiliated Hospital, School Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis lymphodepleting chemotherapy before infusion. After including three cohorts: 2 × 106/kg, 4 6 106/kg each dose level, optimal biological was determined be then applied extended cohort nine patients. primary endpoint incidence dose-limiting toxicities (DLT). secondary response survival. This registered www.clinicaltrials.gov as #NCT04213469.Twenty-one received Among patients, 19 (90%) diagnosed stage III or IV disease. Meanwhile, stratified intermediate worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression pre-treatment tumour sample, two extremely high levels (∼80%). There no DLT identified. Fourteen low-grade (1-2) cytokine release syndrome tocilizumab. Four experienced immune effector cell-associated neurotoxicity grade 1-2. most common adverse events hematologic toxicities, anaemia (n = 6), lymphocyte count decreased 19), neutrophil 17), white blood 10), platelet 2). All objective 18 reached complete response. At median follow-up 19.2 months, remained remission, estimated progression-free survival duration 19.5 months (95% confidence interval: 9.9-infinity), overall not reached.In this first-in-human study non-viral products, exhibited promising manageable toxicity profile. A I/II larger patient underway.National Key R&D Program China, National Natural Science Foundation Project Technology Department Province, Shanghai Zhangjiang Independent Innovation Demonstration Area, Projects Special Development Funds.

Язык: Английский

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Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies

Biomarker Research, Год журнала: 2023, Номер 11(1)

Опубликована: Март 29, 2023

The immunosuppressive tumor microenvironment (TME) supports the development of tumors and limits immunotherapy, including hematological malignancies. Hematological malignancies remain a major public health issue with high morbidity mortality worldwide. As an important component regulators, phenotypic characteristics prognostic value myeloid-derived suppressor cells (MDSCs) have received much attention. A variety MDSC-targeting therapeutic approaches produced encouraging outcomes. However, use various MDSC-targeted treatment strategies in hematologic is still difficult due to heterogeneity complexity immune system. In this review, we summarize biological functions MDSCs further provide summary phenotypes suppressive mechanisms MDSC populations expanded types malignancy contexts. Moreover, discussed clinical correlation between diagnosis malignant disease, as well drugs targeting MDSCs, focused on summarizing combination other immunotherapies, such checkpoint inhibitors (ICIs), that are under active investigation. We highlight new direction improve efficacy tumors.

Язык: Английский

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Cancer cell-intrinsic PD-1: Its role in malignant progression and immunotherapy

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 167, С. 115514 - 115514

Опубликована: Сен. 15, 2023

Programmed cell death protein-1 (PD-1), also called CD279, is coded by the PDCD1 gene and constitutively expressed on surface of immune cells. As a receptor checkpoint, PD-1 can bind to programmed ligand-1/programmed ligand-2 (PD-L1/PD-L2) in tumor cells, leading evasion. Anti-PD-1 anti-PD-L1 are important components therapy. as an intrinsic variant (iPD-1) cancer cells where it plays roles malignant progression proposed recent studies. However, iPD-1 has received much less attention compared although there unmet medical need for fully elucidating mechanisms actions achieve best response immunotherapy. suppresses tumorigenesis non-small lung (NSCLC) colon cancer, whereas promotes melanoma, hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), thyroid (TC), glioblastoma (GBM), triple-negative breast (TNBC). In this review, we focus role development its molecular mechanisms. We deeply discuss nivolumab-based combined therapy common may explain different therapeutic effects anti-PD-1 treatment provide critical information use anti-tumor approaches.

Язык: Английский

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The potential and promise for clinical application of adoptive T cell therapy in cancer

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Май 1, 2024

Abstract Adoptive cell therapy has revolutionized cancer treatment, especially for hematologic malignancies. T cells are the most extensively utilized in adoptive therapy. Currently, tumor-infiltrating lymphocytes, receptor-transgenic and chimeric antigen receptor three main therapies. Tumor-infiltrating lymphocytes kill tumors by reinfusing enlarged that naturally target tumor-specific antigens into patient. have ability to specifically destroy tumor via precise recognition of exogenous receptors with major histocompatibility complex. Chimeric transfer genes specific structural domains activation signals cells, allowing attack without assistance Many barriers been demonstrated affect clinical efficacy therapy, such as heterogeneity loss, hard trafficking infiltration, immunosuppressive microenvironment exhaustion. Several strategies improve explored, including multispecific combination immune checkpoint blockade, targeting microenvironment, etc. In this review, we will summarize current status application, followed bottlenecks addition, discuss promising result even more incredible advancements solid if aforementioned problems can be handled. Graphical abstract

Язык: Английский

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Interactions between LAMP3+ dendritic cells and T-cell subpopulations promote immune evasion in papillary thyroid carcinoma

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(5), С. e008983 - e008983

Опубликована: Май 1, 2024

The incidence of papillary thyroid cancer (PTC) continues to rise all over the world, 10-15% patients have a poor prognosis. Although immunotherapy has been applied in clinical practice, its therapeutic efficacy remains far from satisfactory, necessitating further investigation mechanism PTC immune remodeling and exploration novel treatment targets. This study conducted single-cell RNA sequencing (scRNA-seq) analysis using 18 surgical tissue specimens procured 14 diagnosed with adjacent tissues, non-progressive or progressive PTC. Key findings were authenticated through spatial transcriptomics sequencing, immunohistochemistry, multiplex an independent bulk RNA-seq data set containing 502 samples. A total 151,238 individual cells derived underwent scRNA-seq analysis. We found that exhibits following characteristics: significant decrease overall cells, enhanced evasion tumor disrupted antigen presentation function. Moreover, we identified subpopulation lysosomal associated membrane protein 3 (LAMP3+) dendritic (DCs) exhibiting heightened infiltration advanced T stage prognosis LAMP3+ DCs promote CD8+ exhaustion (mediated by NECTIN2-TIGIT) increase abundance regulatory chemokine (C-C motif) ligand 17 (CCL17)-chemokine receptor 4 (CCR4)) establishing immune-suppressive microenvironment. Ultimately, unveiled facilitate retention within microenvironment NECTIN3-NECTIN2 interactions, thereby rendering more susceptible evasion. Our expound valuable insights into role interaction between T-cell subpopulations offer new effective ideas strategies for

Язык: Английский

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Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Май 6, 2023

Abstract Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding immunology oncology. In this review, we summarize recent applications single-cell technologies CAR therapy, including biological characteristics, latest response adverse events, promising strategies that contribute to development target selection. Generally, propose a multi-omics research mode guide potential future on therapy.

Язык: Английский

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The CAR‐HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL

American Journal of Hematology, Год журнала: 2023, Номер 98(11), С. 1699 - 1710

Опубликована: Авг. 16, 2023

Abstract CD19‐directed CAR T‐cell therapy with brexucabtagene autoleucel (brexu‐cel) has substantially improved treatment outcomes for patients relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common clinically relevant side effects. In this multicenter observational study, we describe in 103 r/r MCL receiving brexu‐cel. Furthermore, report associations between the baseline CAR‐HEMATOTOX (HT) score toxicity events, non‐relapse mortality (NRM), progression‐free/overall survival (PFS/OS). At lymphodepletion, 56 were HT low (score 0–1) while 47 high ≥2). The cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) an increased rate of severe (30% 5%, = .001). Overall, 1‐year NRM was 10.4%, primarily attributed to infections, differed by (high low: 17% 4.6%, .04). experienced inferior 90‐day complete response (68% 93%, .002), PFS 9 months not‐reached, .0001), OS 26 .0001). Multivariable analyses showed that scores independently associated hematotoxicity, poor PFS/OS. conclusion, hematotoxicity are after brexu‐cel contribute NRM. identified at risk outcomes.

Язык: Английский

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