ArticleMolecular cancer2024
Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects.
Article in Molecular cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 41 citations in OpenAlex.
- Chimeric antigen receptor (CAR)-T cell therapy for solid tumors in pediatric patients: current breakthroughs, dilemmas, and strategies.Experimental hematology & oncology · 2026Review
- Repurposing Seleno-L-Methionine as a Pleiotropic Immunomodulatory Agent to Overcome TGF-β1/HIF-Driven Immune Evasion in Clear Cell Renal Cell Carcinoma: Mechanistic Insights and Translational Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.Molecular biology reports · 2026Review
- Chimeric Antigen Receptor-Immune Cell-Based Therapies for Clear Cell Renal Cell Carcinoma: Latest Advancements and Directions.Cancers · 2026Review
- Targeting the immunological synapse in multiple myeloma.Discover oncology · 2026Review
- Rapid CAR screening and circRNA-driven CAR-NK cells for persistent shed-resistant immunotherapy.Signal transduction and targeted therapy · 2026Article
- Optimizing next-generation CAR-macrophages against solid tumors: challenges and potential strategies.Journal of hematology & oncology · 2026Review
- Bridging biomaterials and immunotherapy: hydrogel strategies for next-generation CAR-T cell treatment.Stem cell research & therapy · 2026Review
- TIM-3 in AML: pathogenic roles and therapeutic targetability.Clinical and experimental medicine · 2026Review
- Therapeutic targeting of cancer stem cell-specific surface glycans and glycoproteins.Discover oncology · 2026Review
- Targeting urological cancers with CAR-T cell therapy: current landscape and future directions.Journal of translational medicine · 2026Review
- Article
- A new era in CAR-NK cell therapy: from technological innovations to clinical applications.World journal of pediatrics : WJP · 2026Review
- Imaging CRISPR-edited CAR-T cell therapies with optical and positron emission tomography reporters.Theranostics · 2026Article
- Why CAR T cell therapy fails in renal cell carcinoma.Frontiers in immunology · 2026Review
- A Hidden Checkpoint: Bidirectional pH Remodeling of the Immunological Synapse in Cancer, Methods, and Therapeutic Opportunities.Journal of immunology research · 2026Review
- CAR-T cell signaling dynamics, rational design principles and artificial intelligence for next-generation chimeric antigen receptors.Frontiers in immunology · 2026Review
- Carbonic Anhydrase IX and Cyclooxygenase-2 Regulation in Renal Cell Carcinoma and Impact on Therapeutic Efficiency of Anti-CAIX CAR T cells.Current topics in medicinal chemistry · 2026Article
- Peripheral nerve remodeling in the tumor microenvironment: neuro-immune crosstalk, molecular mechanisms, and precision therapeutic.Frontiers in immunology · 2026Review
- Engineering CAR T NK and NKT cell therapies to target cancer stem cells and overcome stem like resistance.Discover oncology · 2025Review
Corrections and comments
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Authors and funding
29 authors at 4 institutions in 2 countries.
Funding
Abstract
One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target.
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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.