ArticleScience translational medicine2021
Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 85 papers, 1 of them a synthesis that pooled it.
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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.
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Who cites it
85 citing papers in PubMed, 1 synthesis or guideline pooled it, 115 citations in OpenAlex.
- 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
- Fine-tuning affinity and spacer design enhances T cell potency in DLL3 and BCMA CAR T cells.mAbs · 2026Article
- Co-expression of non-signaling CARs enhances EGFRvIII-specific CAR T-cell cytotoxicity against head and neck squamous cell carcinoma.BMC cancer · 2026Article
- Computational design of optimized and preferentially paired human TCR constant regions for improved T cell function.Science advances · 2026Article
- ICAM1-targeted costimulation extends HER2 CAR T cytotoxicity to HER2-low and HER2-negative tumors through synergy with TCR signaling.Molecular therapy. Oncology · 2026Article
- The development of novel chimeric antigen receptor gamma-delta T cells against multiple myeloma and single-cell RNA sequencing analysis.British journal of haematology · 2026Article
- A conserved basic motif mediates membrane anchoring and TRAF2 recruitment across costimulatory TNFRs.The EMBO journal · 2026Article
- An ICAM1-Targeting Chimeric Costimulatory Receptor Mimics the Immune Synapse and Enhances Tumor-Specific T-cell Function.Cancer immunology research · 2026Article
- Humanized biparatopic nanobody-based CAR-T cells overcome antigen-heterogeneity in multiple myeloma.Journal of translational medicine · 2026Article
- Necroptotic cell death and immunomodulator release induced by T-cell engaging anti-lymphoma therapies.Cell death & disease · 2026Article
- Bispecific Ligand-Based EphB4 CAR-T Cells Generated Using Ephrin-B2 Show Potent Antitumor Activity Against Lung Adenocarcinoma.Cancer science · 2026Article
- Challenges and advances in CAR-T cell therapy for B-ALL.Biomarker research · 2026Review
- CD39Science translational medicine · 2026Article
- IDR-induced CAR condensation improves the cytotoxicity of CAR-Ts against low-antigen cancers.Nature chemical biology · 2026Article
- CC-DenseSTORM: deep learning enables colorimetry camera-based simultaneous two-color single-molecule localization microscopy with dense emitters.Biomedical optics express · 2026Article
- Enhancing CAR- and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor.Nature communications · 2026Article
- Next-generation CAR-T therapy for acute myeloid leukemia: bridging innovation with clinical translation.Annals of hematology · 2026Review
- Chimeric antigen receptor T‑cell therapy in chronic viral infections: a review.Journal of translational medicine · 2026Review
- Optimization of a parallel CAR for B-cell lymphoma via ITAM attenuation and target specificity validation.Clinical and experimental immunology · 2026Article
- Cis- and trans-binding chimeric costimulatory receptors enhance T-cell fitness and tumor control.Cellular & molecular immunology · 2026Article
25 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
24 authors at 6 institutions in 4 countries.
Funding
Abstract
Despite the high remission rates achieved using T cells bearing a chimeric antigen receptor (CAR) against hematogical malignancies, there is still a considerable proportion of patients who eventually experience tumor relapse. Clinical studies have established that mechanisms of treatment failure include the down-regulation of target antigen expression and the limited persistence of effective CAR T cells. We hypothesized that dual targeting mediated by a CAR and a chimeric costimulatory receptor (CCR) could simultaneously enhance T cell cytotoxicity and improve durability. Concomitant high-affinity engagement of a CD38-binding CCR enhanced the cytotoxicity of BCMA-CAR and CD19-CAR T cells by increasing their functional binding avidity. In comparison to second-generation BCMA-CAR or CD19-CAR T cells, double-targeted CAR + CD38-CCR T cells exhibited increased sensitivity to recognize and lyse tumor variants of multiple myeloma and acute lymphoblastic leukemia with low antigen density in vitro. In addition, complimentary costimulation by 4-1BB and CD28 endodomains provided by the CAR and CCR combination conferred increased cytokine secretion and expansion and improved persistence in vivo. The cumulatively improved properties of CAR + CCR T cells enabled the in vivo eradication of antigen-low tumor clones, which were otherwise resistant to treatment with conventional CAR T cells. Therefore, multiplexing targeting and costimulation through the combination of a CAR and a CCR is a powerful strategy to improve the clinical outcomes of CAR T cells by enhancing cytotoxic efficacy and persistence, thus preventing relapses of tumor clones with low target antigen density.
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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.