Insights from the bottom-up development of LGR5-targeting immunotherapeutics DOI Creative Commons

Nico Mueller,

Marc Andrew de la Roche,

Maike de la Roche

et al.

Immunotherapy Advances, Journal Year: 2024, Volume and Issue: 5(1)

Published: Dec. 30, 2024

Abstract Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a transcriptional target gene of the Wnt signalling pathway, is overexpressed in multiple cancers, including colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B acute lymphoblastic leukaemia (pre-B ALL) has emerged as promising therapeutic target. Here, we reflect on bottom-up development novel α-LGR5 antibody have recently reported, into palette LGR5-targeting immunotherapeutic modalities: antibody-drug conjugates (ADCs), bispecific T cell engagers (bispecific engagers), chimeric antigen (CAR) cells. The highly specific accurately detects LGR5 protein expression levels, enabling its use prognostic biomarker for identifying LGR5+ tumour types. Preclinical studies road-testing various α-LGR5-based modalities established potent safe elimination LGR5-expressing cells vitro efficacy mouse model human vivo. In this review, discuss utility our building block set immunotherapeutics highlight importance matching to individual type patient characteristics.

Language: Английский

Bispecific and multispecific antibodies in oncology: opportunities and challenges DOI

Maria-Elisabeth Goebeler,

Gernot Stuhler,

Ralf C. Bargou

et al.

Nature Reviews Clinical Oncology, Journal Year: 2024, Volume and Issue: 21(7), P. 539 - 560

Published: May 31, 2024

Language: Английский

Citations

37
Bispecific antibodies: advancing precision oncology DOI Creative Commons

M. Zurita Herrera,

G. Pretelli, Jayesh Desai

et al.

Trends in cancer, Journal Year: 2024, Volume and Issue: 10(10), P. 893 - 919

Published: Aug. 30, 2024

Bispecific antibodies (bsAbs) are engineered molecules designed to target two different epitopes or antigens. The mechanism of action is determined by the bsAb molecular targets and structure (or format), which can be manipulated create variable novel functionalities, including linking immune cells with tumor cells, dual signaling pathway blockade. Several bsAbs have already changed treatment landscape hematological malignancies select solid cancers. However, mechanisms resistance these agents understudied management toxicities remains challenging. Herein, we review principles in engineering, current understanding resistance, data for clinical application, provide a perspective on ongoing challenges future developments this field.

Language: Английский

Citations

17
Immune evasion in ovarian cancer: implications for immunotherapy and emerging treatments DOI
Romi Gupta, Raj Kumar, Courtney A. Penn

et al.

Trends in Immunology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

1
Immune Cell Engagers: Advancing Precision Immunotherapy for Cancer Treatment DOI Creative Commons

H. In,

Minkyoung Park,

H.-K. Lee

et al.

Antibodies, Journal Year: 2025, Volume and Issue: 14(1), P. 16 - 16

Published: Feb. 11, 2025

Immune cell engagers (ICEs) are an emerging class of immunotherapies designed to harness the immune system's anti-tumor potential through precise targeting and activation effector cells. By engaging T cells, natural killer (NK) phagocytes, ICEs overcome challenges such as evasion MHC downregulation, addressing critical barriers in cancer treatment. T-cell (TCEs), led by bispecific (BiTEs), dominate field, with innovations half-life-extended BiTEs, trispecific antibodies, checkpoint inhibitory driving their application hematologic solid malignancies. NK (NKCEs) phagocyte (PCEs) rapidly progressing, drawing on cells' innate cytotoxicity macrophages' phagocytic abilities target tumors, particularly immunosuppressive microenvironments. Since FDA approval Blinatumomab 2014, have transformed oncology landscape, nine FDA-approved products numerous candidates clinical trials. Despite toxicity, resistance, limited efficacy ongoing research into advanced platforms combination therapies highlights growing provide personalized, scalable, effective treatments. This review investigates mechanisms, platforms, trends, progress ICEs, emphasizing pivotal role advancing precision immunotherapy promise a cornerstone next-generation therapies.

Language: Английский

Citations

1
Feeder-cell-free system for ex vivo production of natural killer cells from cord blood hematopoietic stem and progenitor cells DOI Creative Commons

Marta Martin Corredera,

Juliette Paillet, Pierre Gaudeaux

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 20, 2025

Natural Killer (NK) cells hold significant promise as therapeutic agents in immuno-oncology due to their ability target and eliminate cancerous infected without causing graft-versus-host disease or cytokine release syndrome. However, the limited availability of robust, scalable methods for generating clinical-grade NK remains a limiting factor broader clinical application. Here we report development novel feeder-cell-free culture system optimized producing from cord blood-derived CD34+ hematopoietic stem progenitor (HSPCs). Our method eliminates need feeder while achieving high yields that exhibit unique marker expression cytotoxic functions. Cord blood HSPCs were cultured our established hDLL 4 generated large numbers human T lymphoid progenitors (ProTcells) 7 days. ProTcells further hDLL4-free, cell differentiation supplemented with cytokines. Following 7- 14-day culture, this produced highly pure populations (>90% CD3-CD56+). Flow mass cytometric analysis confirmed activating receptors, transcription factors (ID2, T-bet) molecules (perforin, granzyme A/B), all essential ProT-NK functionality. These are an immature state, indicated by absence maturation markers (CD16, KIRs). Functional assays demonstrated these capable degranulation cytokines production (TNFα) upon stimulation K562 showed cytotoxicity against superior Peripheral Blood (PB)-NK. In NSG-Tg(hIL-15) mice, colonize bone marrow, liver, spleen persist mature marrow at least 9 days post-injection. Compared D21, D14 was functional homing potential. vivo, anti-tumor assay uses subcutaneous model has potential cells. ex vivo process supports yields, reducing dependency on mitigating contamination risks. findings demonstrate feasibility large, isolated readily available sources offer efficient alternative PB-NK therapies.

Language: Английский

Citations

1
Multimodal targeting chimeras enable integrated immunotherapy leveraging tumor-immune microenvironment DOI
Lin Feng, Shenyi Yin, Zijian Zhang

et al.

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 1, 2024

Language: Английский

Citations

8
Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges DOI Creative Commons
Jun Kong, Mohammad Auwal Sa’ad,

Hema Manusri Vijayan

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: April 25, 2024

Chimeric antigen receptor-natural killer (CAR-NK) cell therapy is a novel immunotherapy targeting cancer cells via the generation of chimeric receptors on NK which recognize specific antigens. CAR-NK gaining attention nowadays owing to ability release potent cytotoxicity against without side effects such as cytokine syndrome (CRS), neurotoxicity and graft-versus-host disease (GvHD). do not require priming, thus enabling them be used “off-the-shelf” therapy. Nonetheless, still possesses several challenges in eliminating reside hypoxic immunosuppressive tumor microenvironment. Therefore, this review envisioned explore current advancements limitations well discuss strategies overcome faced by This also aims dissect status clinical trials future recommendations for improving effectiveness safety

Language: Английский

Citations

7
The role and novel use of natural killer cells in graft-versus-leukemia reactions after allogeneic transplantation DOI Creative Commons
Ashley Hadjis, Shannon R. McCurdy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 16, 2024

Allogeneic hematopoietic cell transplantation (HCT) has transformed over the past several decades through enhanced supportive care, reduced intensity conditioning (RIC), improved human leukocyte antigen (HLA) typing, and novel graft-versus-host disease (GVHD)-prevention treatment strategies. Most notably, implementation of post-transplantation cyclophosphamide (PTCy) dramatically increased safety availability this life-saving therapy. Given reductions in nonrelapse mortality (NRM) with these advances, HCT community placed even greater emphasis on developing ways to reduce relapse - leading cause death after HCT. When using RIC HCT, protection from relies predominantly graft-versus-leukemia (GVL) reactions. Donor lymphocyte infusion (DLI), adoptive cellular therapy, checkpoint inhibition, post-HCT maintenance strategies represent approaches under study that aim augment or synergize GVL effects Optimizing donor selection algorithms leverage represents another active area research. Many seek harness T cells, which for were felt be primary mediators focus investigation reduction. However, there is growing interest capitalizing ability natural killer (NK) cells yield potent anti-tumor effects. A potential advantage NK cell-based cell-mediated NRM addition relapse. By decreasing infection, without increasing risk GVHD, may mitigate NRM, while still yielding reduction identification clearance cancer cells. cell-focused relapse-prevention must weigh benefits against GVHD. In contrast, have both, potentially tipping scales significantly favor survival. Here, we will review role GVL, optimization match mismatch, burgeoning areas research therapy such as transfer chimeric receptor (CAR)

Language: Английский

Citations

6
Natural killer cell engagers: From bi‐specific to tri‐specific and tetra‐specific engagers for enhanced cancer immunotherapy DOI Creative Commons
An Zhu, Yu Bai,

Yanyang Nan

et al.

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(11)

Published: Oct. 29, 2024

Abstract Natural killer cell engagers (NKCEs) are a specialised subset of antibodies capable simultaneously targeting endogenous NK cells and tumour cells, generating precise effective cytolytic responses against cancer. This review systematically explores as rising star in NK‐mediated immunotherapy, specifically focusing on multi‐specific engagers. It examines the diverse configuration NKCEs how certain biologics could be employed to boost activity, including activating receptor engagement cytokine incorporation. Some challenges future perspectives current therapy also discussed, optimising pharmacokinetics, addressing immunosuppressive microenvironment exploring potential combinatorial approaches. By offering an in‐depth analysis landscape trajectories cancer treatment, this serves valuable resource for understanding promising field immunotherapy. Highlights Innovative : represent new class immunotherapeutics tumours by cells. Multi‐specific formats The transition from bi‐specific enhances their versatility therapeutic efficacy. Mechanisms action have improve activation engaging receptors incorporating cytokines. Clinical Current clinical trials demonstrate safety efficacy various across different types. Future research directions Optimising NKCE designs combination therapies essential overcoming treatment.

Language: Английский

Citations

6
Bispecific immune cell engager enhances the anticancer activity of CD16+ NK cells and macrophages in vitro, and eliminates cancer metastasis in NK humanized NOG mice DOI Creative Commons
Shahryar Khoshtinat Nikkhoi, Ge Yang,

Hajar Owji

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(3), P. e008295 - e008295

Published: March 1, 2024

Background In a prior report, we detailed the isolation and engineering of bispecific killer cell engager, referred to as BiKE:E5C1. The BiKE:E5C1 exhibits high affinity/specificity for CD16a activating receptor on natural (NK) cells human epidermal growth factor 2 (HER2) cancer cells. vitro studies have demonstrated that can activate NK induce killing HER2+ ovarian breast cells, surpassing performance best-in-class monoclonal antibody, Trazimera (trastuzumab). To advance this BiKE technology toward clinical application, objective research was demonstrate ability CD16+ immune such macrophages kill eradicate metastatic tumors in humanized NOG mice. Methods We assessed BiKE:E5C1’s potential CD16-expressing peripheral blood (PB)-NK laNK92 THP-1-CD16A monocyte-macrophages through flowcytometry antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC) assays. Subsequently, were selected effector genetically modified express nanoluciferase gene, enabling monitoring their viability mice using quantitative bioluminescent imaging (qBLI). evaluate functionality vivo, introduced firefly luciferase-expressing via intraperitoneal injection into hIL-15 hIL-2 mice, creating model metastasis. Once tumor establishment confirmed, treated with plus response therapy qBLI. Results Our data activates not only but also PB-NK macrophages, significantly enhancing anticancer activities. ADCC assay IgG 1 Fc region had no impact activity. vivo results reveal both mouse models support proliferation Furthermore, it observed leading eradication metastasis models. Conclusions Collectively, our findings underscore an engager capable elimination, thereby expanding arsenal available BiKEs immunotherapy.

Language: Английский

Citations

5