ArticleCancer discovery2020
Tuning the Antigen Density Requirement for CAR T-cell Activity.
Article in Cancer discovery, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 394 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
394 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Mapping the clinical landscape of multifunctional CAR T cells: Targets, trends, and synergies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Pooled it
- Outcomes of Wild Type and TP53-Mutated B Cell Malignancy Patients Receiving CAR-T Cell Therapy: A Systematic Review and Meta-Analysis.Journal of cellular and molecular medicine · 2025Pooled it
- Efficacy and safety of a novel CD19, CD22 dual-targeted fully human loop bi-CAR-T for the treatment of relapsed/refractory B cell non-Hodgkin lymphoma.Journal of translational medicine · 2025Trial
- Preclinical evaluation of homodimeric FAPI target modules for UniCAR-mediated targeting of FAP-expressing tumor and stromal cells.Oncoimmunology · 2026Article
- Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.Cancer letters · 2026Review
- Co-expression of non-signaling CARs enhances EGFRvIII-specific CAR T-cell cytotoxicity against head and neck squamous cell carcinoma.BMC cancer · 2026Article
- IL-15 boosts mesothelin- and CD70-CAR NK cell potency in PDAC without added benefit from dual targeting.Molecular therapy. Oncology · 2026Article
- Structural T-Cell Receptor Analysis in the Age of Machine Learning.Immunological reviews · 2026Review
- IFN-γ-driven iNOS induction in macrophages mediates CAR T cell resistance in B cell lymphoma.Nature communications · 2026Article
- Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy.Leukemia · 2026Article
- Cancer Immunotherapy: Therapeutic Limitations and Next-Generation Precision Strategies.Immune network · 2026Review
- Mechanisms, optimization strategies, and salvage options for CAR-T cell therapy.Biomarker research · 2026Review
- CAR-T and TIL therapies in solid tumors: barriers, clinical lessons, and convergent solutions.Cancer cell international · 2026Review
- Navigating the Therapeutic Landscape of Multiple Myeloma: Immunotherapy, Microenvironment, and Resistance.Biomedicines · 2026Review
- A guide to CAR T cell therapies: development, current status and future prospects.Nature reviews. Immunology · 2026Review
- Fate induction through asymmetric T cell division is modulated by chimeric antigen receptor costimulatory domains.Nature immunology · 2026Article
- Multi-antigen-targeting T cells in pediatric central nervous system tumors: a phase 1 trial.Nature medicine · 2026Article
- Engineering CAR-Tregs with Phage-Selected scFv Enables a New Paradigm for Immune Regulation.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Single-cell genomics links targeted functional manipulations to efficacy-associated chromatin signatures in CAR T cells.Research square · 2026Article
- Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis.Cell · 2026Article
334 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
20 authors.
Funding
Abstract
Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28ζ) outperforms that in tisagenlecleucel (CD19-4-1BBζ) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BBζ CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunologic synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BBζ-CARs with enhanced capacity to recognize antigen-low targets while retaining a superior capacity for persistence. SIGNIFICANCE: Optimal CAR T-cell activity is dependent on antigen density, which is variable in many cancers, including lymphoma and solid tumors. CD28ζ-CARs outperform 4-1BBζ-CARs when antigen density is low. However, 4-1BBζ-CARs can be reengineered to enhance activity against low-antigen-density tumors while maintaining their unique capacity for persistence.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.