ArticleThe Journal of clinical investigation2019
Tumor-conditional anti-CTLA4 uncouples antitumor efficacy from immunotherapy-related toxicity.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers, 2 of them syntheses that pooled it.
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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, 2 syntheses or guidelines pooled it, 141 citations in OpenAlex.
- Pooled safety profiles of bispecific antibodies targeting PD-1/CTLA-4 or PD-1/VEGF in non-small cell lung cancer: a systematic review and single-arm meta-analysis.Journal of the Egyptian National Cancer Institute · 2026Pooled it
- CTLA4-Linked Autoimmunity in the Pathogenesis of Endometriosis and Related Infertility: A Systematic Review.International journal of molecular sciences · 2022Pooled it
- Longitudinal tissue analysis reveals microenvironmental changes correlate with combined immunotherapy and targeted therapy response in metastatic breast cancer.Journal for immunotherapy of cancer · 2025Trial
- Bioinformatics-based analysis of the relationship between disulfidptosis and prognosis and treatment response in pancreatic cancer.Scientific reports · 2023Trial
- IL-12p40 drives oral squamous cell carcinoma progression via MMPs and IL-12Rβ1/STAT3 signaling.Cancer cell international · 2026Article
- Development and validation of a cuproptosis-immune prognostic signature for risk stratification and personalized therapy in cutaneous melanoma.Discover oncology · 2026Article
- Cancer therapy-induced ototoxicity: Current challenges and emerging management strategies.Animal models and experimental medicine · 2026Review
- Immune-epigenetic-metabolic crosstalk: attempting to unravel the multidimensional mechanisms of immune evasion in endometriosis.Frontiers in immunology · 2026Review
- A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice.Nature communications · 2025Article
- Single-chain Fab chain-exchange (scFab-PACE) converts targeted prodrugs into functional T cell engagers on tumor cells.The Journal of biological chemistry · 2025Article
- Impact of tumor localization on antitumor immunity with conditionally activated CTLA-4 blockade.Journal for immunotherapy of cancer · 2025Article
- Dual-Function RNA Biomarkers: Integrating Relapse Prediction and Immune Profiling in Triple-Negative Breast Cancer.International journal of medical sciences · 2025Article
- Advances of oncolytic vaccinia viruses armed with interleukin in tumor therapy.Frontiers in oncology · 2025Review
- Machine Learning-Based Enhanced MRI Radiomics for PDCD1 Prognostication and Expression Prediction in Breast Cancer.Clinical Medicine Insights. Oncology · 2025Article
- Article
- Multiple omics integrative analysis identifies GARS1 as a novel prognostic and immunological biomarker: from pan-cancer to bladder cancer.Scientific reports · 2024Article
- Targeting cytotoxic lymphocyte antigen 4 (CTLA-4) in breast cancer.European journal of medical research · 2024Review
- Prognostic prediction using a gene signature developed based on exhausted T cells for liver cancer patients.Heliyon · 2024Article
- The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling.Cell communication and signaling : CCS · 2024Review
- Machine learning reveals diverse cell death patterns in lung adenocarcinoma prognosis and therapy.NPJ precision oncology · 2024Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
25 authors at 3 institutions in 1 country.
Funding
Abstract
While immune checkpoint blockade leads to potent antitumor efficacy, it also leads to immune-related adverse events in cancer patients. These toxicities stem from systemic immune activation resulting in inflammation of multiple organs, including the gastrointestinal tract, lung, and endocrine organs. We developed a dual variable domain immunoglobulin of anti-CTLA4 antibody (anti-CTLA4 DVD, where CTLA4 is defined as cytotoxic T lymphocyte-associated antigen-4) possessing an outer tumor-specific antigen-binding site engineered to shield the inner anti-CTLA4-binding domain. Upon reaching the tumor, the outer domain was cleaved by membrane type-serine protease 1 (MT-SP1) present in the tumor microenvironment, leading to enhanced localization of CTLA4 blockade. Anti-CTLA4 DVD markedly reduced multiorgan immune toxicity by preserving tissue-resident Tregs in Rag 1-/- mice that received naive donor CD4+ T cells from WT C57BL/6j mice. Moreover, anti-CTLA4 DVD induced potent antitumor effects by decreasing tumor-infiltrating Tregs and increasing the infiltration of antigen-specific CD8+ T lymphocytes in TRAMP-C2-bearing C57BL/6j mice. Treg depletion was mediated through the antibody-dependent cellular cytotoxicity (ADCC) mechanism, as anti-CTLA4 without the FcγR-binding portion (anti-CTLA4 DANA) spared Tregs, preventing treatment-induced toxicities. In summary, our results demonstrate an approach to anti-CTLA4 blockade that depletes tumor-infiltrating, but not tissue-resident, Tregs, preserving antitumor effects while minimizing toxicity. Thus, our tumor-conditional anti-CTLA4 DVD provides an avenue for uncoupling antitumor efficacy from immunotherapy-induced toxicities.
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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.