Tri-specific tribodies targeting 5T4, CD3, and immune checkpoint drive stronger functional T-cell responses than combinations of antibody therapeutics DOI Creative Commons
Margherita Passariello,

Lorenzo Manna,

Rosa Rapuano Lembo

et al.

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: Feb. 10, 2025

Abstract One of the most promising cancer immunotherapies is based on bi-specific T-cell engagers (BiTEs) that simultaneously bind with one arm to a tumor-associated antigen tumor cells and other CD3 complex T form TCR-MHC independent immune synapse. We previously generated four novel tri-specific tribodies made up Fab targeting 5T4, an oncofetal expressed several types tumors, scFv cells, additional specific for checkpoint (IC), such as PD-1, PD-L1 or LAG-3. To verify their advantages over combinations BiTEs (CD3/TAA) IC inhibitors, recently used overcome immunosuppressive environment, here we tested functional properties in comparison clinically validated mAbs same ICs, alone combination control devoid immunomodulatory scFvs, called 53 P. found activated human peripheral blood mononuclear more efficiently than (atezolizumab, pembrolizumab, relatlimab) either P, leading stronger cytotoxicity cytokines release. In particular, 53L10 tribody displayed much potent effects P all led complete regression vivo, showing higher efficacy atezolizumab. shed light molecular basis this potentiated anti-tumor activity by evidencing insertion anti-PD-L1 moiety not only binding but also blocked increased induced IFNγ secretion due activation. These results are important design antigens.

Language: Английский

Lung cancer immunotherapy: progress, pitfalls, and promises DOI Creative Commons

Aritraa Lahiri,

Avik Maji, Pravin D. Potdar

et al.

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Feb. 21, 2023

Abstract Lung cancer is the primary cause of mortality in United States and around globe. Therapeutic options for lung treatment include surgery, radiation therapy, chemotherapy, targeted drug therapy. Medical management often associated with development resistance leading to relapse. Immunotherapy profoundly altering approach owing its tolerable safety profile, sustained therapeutic response due immunological memory generation, effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground cancer. Recent advances adoptive cell therapy (CAR T, TCR, TIL), clinical trials on cancer, hurdles discussed this review. patients (without targetable oncogenic driver alteration) reveal significant responses when treated programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that loss effective anti-tumor immunity tumor evolution. vaccines combined immune inhibitors (ICI) can achieve better effects. To end, present article encompasses detailed overview recent developments immunotherapeutic landscape targeting small (SCLC) non-small (NSCLC). Additionally, review also explores implication nanomedicine immunotherapy as well combinatorial application traditional along regimens. Finally, ongoing trials, obstacles, future outlook strategy highlighted boost further research field.

Language: Английский

Citations

526
Designing antibodies as therapeutics DOI Creative Commons
Paul J. Carter,

Arvind Rajpal

Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2789 - 2805

Published: July 1, 2022

Language: Английский

Citations

141
Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy DOI Creative Commons
Letong Cai, Yuchen Li, Jiaxiong Tan

et al.

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: Sept. 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.

Language: Английский

Citations

129
Advances in antibody-based therapy in oncology DOI

Sacha Zinn,

Rodrigo Vazquez-Lombardi,

Carsten Zimmermann

et al.

Nature Cancer, Journal Year: 2023, Volume and Issue: 4(2), P. 165 - 180

Published: Feb. 20, 2023

Language: Английский

Citations

120
Combination cancer immunotherapies: Emerging treatment strategies adapted to the tumor microenvironment DOI
Nicole Kirchhammer, Marcel P. Trefny, Priska Auf der Maur

et al.

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(670)

Published: Nov. 9, 2022

Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, resistance to ICB occurs frequently due tumor-intrinsic alterations or extrinsic factors in the tumor microenvironment. This Viewpoint aims give an update on recent developments immunotherapy for solid tumors and highlights progress translational research clinical practice.

Language: Английский

Citations

117
Cancer treatments: Past, present, and future DOI
Dmitriy Sonkin, Anish Thomas, Beverly A. Teicher

et al.

Cancer Genetics, Journal Year: 2024, Volume and Issue: 286-287, P. 18 - 24

Published: June 17, 2024

Language: Английский

Citations

98
Targeting macrophages in hematological malignancies: recent advances and future directions DOI Creative Commons
Wei Li, Fang Wang, Rongqun Guo

et al.

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Aug. 17, 2022

Abstract Emerging evidence indicates that the detection and clearance of cancer cells via phagocytosis induced by innate immune checkpoints play significant roles in tumor-mediated escape. The most well-described are “don’t eat me” signals, including CD47/signal regulatory protein α axis (SIRPα), PD-1/PD-L1 axis, CD24/SIGLEC-10 MHC-I/LILRB1 axis. Molecules have been developed to block these pathways enhance phagocytic activity against tumors. Several clinical studies investigated safety efficacy CD47 blockades, either alone or combination with existing therapy hematological malignancies, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), lymphoma. However, only a minority patients responses treatments alone. Combining blockades other treatment modalities studies, early results suggesting synergistic therapeutic effect. Targeting macrophages bispecific antibodies being explored blood therapy. Furthermore, reprogramming pro-tumor anti-tumor macrophages, CAR (CAR-M) demonstrate activities. In this review, we elucidated distinct types macrophage-targeted strategies from preclinical experiments trials, outlined potential approaches developed.

Language: Английский

Citations

97
Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives DOI Creative Commons

Hao Lin,

Chaxian Liu,

An-Kang Hu

et al.

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: May 8, 2024

Abstract Glioblastoma (GBM), the predominant and primary malignant intracranial tumor, poses a formidable challenge due to its immunosuppressive microenvironment, thereby confounding conventional therapeutic interventions. Despite established treatment regimen comprising surgical intervention, radiotherapy, temozolomide administration, exploration of emerging modalities such as immunotherapy integration medicine engineering technology therapy, efficacy these approaches remains constrained, resulting in suboptimal prognostic outcomes. In recent years, intensive scrutiny inhibitory milieu within GBM has underscored significance cellular constituents microenvironment their interactions with cells neurons. Novel immune targeted therapy strategies have emerged, offering promising avenues for advancing treatment. One pivotal mechanism orchestrating immunosuppression involves aggregation myeloid-derived suppressor (MDSCs), glioma-associated macrophage/microglia (GAM), regulatory T (Tregs). Among these, MDSCs, though constituting minority (4–8%) CD45 + GBM, play central component fostering evasion propelling tumor progression, angiogenesis, invasion, metastasis. MDSCs deploy intricate mechanisms that adapt dynamic (TME). Understanding interplay between provides compelling basis This review seeks elucidate inherent explore existing targets, consolidate insights into MDSC induction contribution immunosuppression. Additionally, comprehensively surveys ongoing clinical trials potential strategies, envisioning future where targeting could reshape landscape GBM. Through synergistic other modalities, this approach can establish multidisciplinary, multi-target paradigm, ultimately improving prognosis quality life patients

Language: Английский

Citations

62
Cytokine release syndrome and cancer immunotherapies – historical challenges and promising futures DOI Creative Commons
Deep Shah,

Brian W. Soper,

Lindsay S. Shopland

et al.

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 25, 2023

Cancer is the leading cause of death worldwide. immunotherapy involves reinvigorating patient's own immune system to fight against cancer. While novel approaches like Chimeric Antigen Receptor (CAR) T cells, bispecific cell engagers, and checkpoint inhibitors have shown promising efficacy, Cytokine Release Syndrome (CRS) a serious adverse effect remains major concern. CRS phenomenon hyperactivation that results in excessive cytokine secretion, if left unchecked, it may lead multi-organ failure death. Here we review pathophysiology CRS, its occurrence management context cancer immunotherapy, screening can be used assess de-risk drug discovery earlier clinical setting with more predictive pre-clinical data. Furthermore, also sheds light on potential immunotherapeutic overcome associated activation.

Language: Английский

Citations

43
Beyond checkpoint inhibitors: the three generations of immunotherapy DOI Creative Commons

J. Schaub,

Shou‐Ching Tang

Clinical and Experimental Medicine, Journal Year: 2025, Volume and Issue: 25(1)

Published: Jan. 21, 2025

Anti-tumor immunotherapy was rediscovered and rejuvenated in the last two decades with discovery of CTLA-4, PD-1 PD-L1 roles inhibiting immune function tumor evasion anti-tumor response. Following approval first checkpoint inhibitor ipilimumab against CTLA-4 melanoma 2011, there has been a rapid development immunotherapy. Furthermore, additional positive negative molecules among T-cell regulatory systems have identified that to fine tune stimulatory or inhibitory cells modulate their functions (checkpoint modulators). Many strategies are being explored target macrophages, NK-cells, cytotoxic T-cells, fibroblasts, endothelial cells, cytokines involved tolerance microbiome. Similar agents modulators, these newer targets potential synergize other classes immunotherapeutic importantly may overcome resistance immunotherapies. In order better understand mechanism action all major immunotherapy, design clinical trials taking advantage different types use them rationally practice either combination sequence, we propose group immunotherapies into three generations: inhibitors as generation, modulators second while those TME third generation. This review discusses generations oncology, actions, trial results indication, for future designs rational applications.

Language: Английский

Citations

2