Harnessing antibody-mediated recognition of the intracellular proteome with T cell receptor-like specificity DOI Creative Commons

Maya Haus‐Cohen,

Yoram Reiter

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

Published: Nov. 22, 2024

The clinical success of cancer immunotherapy has driven ongoing efforts to identify novel targets that can effectively guide potent effector functions eliminate malignant cells. Traditionally, immunotherapies have focused on surface antigens; however, these represent only a small fraction the proteome, limiting their therapeutic potential. In contrast, majority proteins within human proteome are intracellular, yet they represented cell as short peptides presented by MHC class I molecules. These peptide-MHC complexes offer vast and largely untapped resource for targets. intracellular including neo-antigens, presents an exciting opportunity development cell-based soluble immunotherapies. Targeting intracellular-derived molecules surfaces be achieved using specific T-cell receptors (TCRs) or TCR-mimicking antibodies, known TCR-like (TCRL) antibodies. Current strategies under investigation include adoptive transfer TCR-engineered TCRL-T cells CAR-T target complexes, well TCR- TCRL-based agents like bispecific T engagers. Recent developments in targeting TCRL- TCR-based shown promising results, with two therapies recently receiving FDA approval treatment unresectable metastatic uveal melanoma synovial sarcoma. This review focuses processes selecting isolating moieties, emphasis pre-clinical studies explore potential immunotherapy.

Language: Английский

From TCR fundamental research to innovative chimeric antigen receptor design DOI
Susana Minguet, Marcela V. Maus, Wolfgang W. Schamel

et al.

Nature reviews. Immunology, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 21, 2024

Language: Английский

Citations

5
Tailoring CAR surface density and dynamics to improve CAR-T cell therapy DOI Creative Commons

Ana Hinckley-Boned,

Carmen Barbero-Jiménez,

María Tristán‐Manzano

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(4), P. e010702 - e010702

Published: April 1, 2025

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment landscape for relapsed and/or refractory B-cell neoplasms, garnering Food and Drug Administration/European Medicines Agency approval six commercial products. Despite this success, challenges persist, including a relapse rate of 30–50% in hematologic tumors, limited clinical efficacy solid severe side effects. This review addresses critical need therapeutic enhancement by focusing on often-overlooked strategy modulating CAR protein density membrane. We delve into key factors influencing surface expression, such as downmodulation following encounter antigen-related factors. The dynamics remain underexplored; however, recent data point to its modification useful tool improving functionality. Notably, transcriptional control expression incorporation specific elements design have emerged interesting strategies tailor profiles. Therefore, controlling dynamic may represent an attractive achieving optimal outcomes.

Language: Английский

Citations

0
7. EBMT-EHA European CAR-T-Cell Meeting - Die Evolution der CAR-T-Zelltherapien DOI

Alexander Kretzschmar

Onkologische Welt, Journal Year: 2025, Volume and Issue: 16(03), P. 131 - 132

Published: April 29, 2025

Zusammenfassung Adoptive T-Zell-Therapien mit chimären Antigenrezeptoren (CARs) haben sich erfolgreich in der Behandlung einiger fortgeschrittener hämatologischer Tumorerkrankungen etabliert. Derzeit arbeitet die CAR-T-Zellforschung an einer Optimierung Therapie, für solider Tumoren notwendig sind. Auf dem 7. EBMT-EHA European CAR-T-Cell Meeting umrisss Prof. Hinrich Abken vom Leibniz-Institut Immuntherapie (LIT) Regensburg Entwicklung, den aktuellen Stand sowie Zukunft CAR-T-Zelltherapie.

Citations

0
Antigen-independent activation is critical for the durable antitumor effect of GUCY2C-targeted CAR-T cells DOI Creative Commons
Changsong Qi, D Y Liu, Chang Liu

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(10), P. e009960 - e009960

Published: Oct. 1, 2024

Chimeric antigen receptor (CAR)-T cells face many obstacles in solid tumor therapy, including heterogeneous expression and inefficient T cell persistence. Guanylyl cyclase C (GUCY2C) has been identified as a suitable for targeted therapy due to its intestinal-restricted pattern normal tissues steady overexpression gastrointestinal tumors, especially colorectal cancer. An antigen-sensitive long-lasting CAR-T targeting GUCY2C was investigated this study.

Language: Английский

Citations

3
Trogocytosis in CAR immune cell therapy: a key mechanism of tumor immune escape DOI Creative Commons

Yizhao Chen,

Qianling Xin,

Mengjuan Zhu

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Oct. 28, 2024

Immune cell therapy based on chimeric antigen receptor (CAR) technology platform has been greatly developed. The types of CAR immune have expanded from T cells to innate such as NK and macrophages, the diseases treated hematological malignancies non-tumor fields infectious autoimmune diseases. Among them, CAR-T CAR-NK observed examples rapid remission in approved clinical trials, but efficacy is unstable plagued by tumor resistance. Trogocytosis a special phenomenon intercellular molecular transfer that common system achieved recipient through acquisition internalization donor cell-derived molecules mediates effects. Recently, novel short-term drug resistance mechanism trogocytosis proposed, bidirectional exchange between triggered partially explains long-term relapse after treatment with cells. In this review, we summarize research progress immunotherapy, discuss influencing factors its direct indirect interference emphasize can further release potential therapy.

Language: Английский

Citations

2
UniCAR T-Cell Potency—A Matter of Affinity between Adaptor Molecules and Adaptor CAR T-Cells? DOI Open Access
Hugo Boutier, Liliana R. Loureiro,

Lydia Hoffmann

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7242 - 7242

Published: June 30, 2024

Although Chimeric Antigen Receptor (CAR) T-cells have shown high efficacy in hematologic malignancies, they can cause severe to life-threatening side effects. To address these safety concerns, we developed adaptor CAR platforms, like the UniCAR system. The redirection of target cells relies on a Target Module (TM), containing E5B9 epitope and tumor-specific binding moiety. Appropriate UniCAR-T activation thus involves two interactions: between TM T-cell, cell. Here, investigate if how alterations amino acid sequence impact interaction TMs UniCAR. We identify new E5B9L, for which monoclonal antibody 5B9 has greatest affinity. then integrate E5B9L peptide previously established directed Fibroblast Activation Protein (FAP) assess such changes affect T-cell potency. Binding properties newly generated anti-FAP-E5B9L their ability redirect were compared side-by-side with ones anti-FAP-E5B9 TMs. Despite substantial variation affinity different UniCAR, no significant differences observed cytotoxic cytokine-release profiles redirected T-cells. Overall, our work indicates that increasing does not play crucial role system, as it significantly potency

Language: Английский

Citations

1
Preclinical evaluation of antigen-sensitive B7-H3-targeting nanobody-based CAR-T cells in glioblastoma cautions for on-target, off-tumor toxicity DOI Creative Commons
Fien Meeus, Cyprine Neba Funeh, Robin Maximilian Awad

et al.

Journal for ImmunoTherapy of Cancer, Journal Year: 2024, Volume and Issue: 12(11), P. e009110 - e009110

Published: Nov. 1, 2024

Background Glioblastoma is the most common lethal primary brain tumor, urging evaluation of new treatment options. Chimeric antigen receptor (CAR)-T cells targeting B7 homolog 3 (B7-H3) are promising because overexpression B7-H3 on glioblastoma but not healthy tissue. Nanobody-based (nano)CARs gaining increasing attention as alternatives to classical single-chain variable fragment-based (scFv)CARs, their single-domain nature and low immunogenicity. Still, nanoCAR-T have been extensively studied in glioblastoma. Methods nanoCAR- scFvCAR-T were developed evaluated human models. NanoCAR-T an irrelevant served control. T cell activation, cytokine secretion killing capacity vitro using ELISA, live imaging flow cytometry. Antigen-specific was assessed by generating knock-out Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9-genome editing. The tumor tracing nanobody first vivo nuclear imaging. Then, therapeutic potential a xenograft model. Results We showed that efficient lysing pos vitro. Lack control lack neg antigen-specificity. nanobody—used for nanoCAR design—in experiments. Evaluation mice treated with contrast progressive disease cells. However, we observed limiting toxicity activated even levels mouse expression. Conclusions promise therapy following characterization, observed. Off-tumor recognition tissue cross-reactive identified cause this toxicity, warranting caution when highly sensitive cells, recognizing low-level expression

Language: Английский

Citations

1
The method for assessing the specificity of developing CAR therapies DOI Creative Commons

Ivan V. Prikhodko,

Georgy Guria

Biophysical Reports, Journal Year: 2024, Volume and Issue: 4(3), P. 100172 - 100172

Published: July 17, 2024

The effectiveness of antitumor chimeric antigen receptor (CAR) therapy mainly dealt with an elevated sensitivity CAR cells to target cells. However, therapies are associated nonspecific side effects: on-target off-tumor toxicity. Sensitivity and specificity the most important properties recognition process among other Current developments concentrated on exploring molecular biology methods for designing highest sensitivity, while problem cell is rarely considered. For assessment specificity, we suggest that, in addition level CAR-antigen affinity, ability CARs clustering should be taken into account. We assume that cytotoxicity determined by clustering. latter treated within framework nucleation theory. master equation probability derived. size a critical cluster found one two essential parameters. conditions necessary sufficient explored. Relevant parametric diagrams Possible applications method assessing developing discussed.

Language: Английский

Citations

0
Integrating Single-Cell and Bulk Rna Sequencing to Identify Disulfidptosis-Related Gene Signature, Immune Landscape, and Immunotherapy Targets in Cutaneous Melanoma DOI
Zhen Yi, Xiaozhen Li, Teng Li

et al.

Published: Jan. 1, 2024

Language: Английский

Citations

0
Logic-gated and contextual control of immunotherapy for solid tumors: contrasting multi-specific T cell engagers and CAR-T cell therapies DOI Creative Commons
Olivier Nolan-Stevaux, Richard Smith

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

Published: Nov. 13, 2024

CAR-T cell and T engager therapies have demonstrated transformational efficacy against hematological malignancies, but achieving in solid tumors has been more challenging, large part because of on-target/off-tumor toxicities sub-optimal anti-tumor cytotoxic functions. Here, we discuss engineering solutions that exploit biological properties to overcome these challenges. Using logic gates as a framework, categorize the numerous approaches leverage two inputs instead one achieve better cancer selectivity or with dual-input CAR-Ts multi-specific TCEs. In addition “OR gate” “AND dual tumor antigen targeting, also review “contextual AND technologies whereby continuous cancer-selective such pH, hypoxia, target density, proteases, immune-suppressive cytokine gradients can be creatively incorporated therapy designs. We introduce notion “output directionality” distinguish strategies mechanistically impact killing fitness. Finally, contrast feasibility potential benefits various using TCE therapeutics why promising “IF/THEN” “NOT” gate types pertain specifically therapies, succeed by integrating both technologies.

Language: Английский

Citations

0