Turning up the heat: CTLA4 blockade in urothelial cancer

Stockem, Chantal F.; Galsky, Matthew D.; van der Heijden, Michiel S.

doi:10.1038/s41585-023-00801-7

Cited by 5 publications

(2 citation statements)

References 126 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several factors related to CTLA-4 blockade may impact these observations including the dose of CTLA-4 blockade, the particular isotype or FcγR binding of the therapeutic antibody, and the clinical measure of antitumor activity employed. 11 With regard to dose, our study used high dose tremelimumab 750 mg intravenously (analogous to doses of ipilimumab at 10 mg/kg employed in some studies 12 ) given prior work suggesting a possible dose-response relationship and given that this dosing was used in the prior study in metastatic urothelial cancer from Sharma and colleagues. 8 Notably, the pharmacokinetics, exposure-response, and exposure-pharmacodynamics relationships of tremelimumab have since been explored in patients with metastatic hepatocellular cancer including patients treated with the 750 mg dosing strategy.…”

Section: Discussionmentioning

confidence: 99%

“…In nonmelanoma solid tumors, single‐agent CTLA‐4 blockade has had minimal impact on standard treatment approaches compared with PD‐1/PD‐L1 blockade, but has also been less extensively explored. Several factors related to CTLA‐4 blockade may impact these observations including the dose of CTLA‐4 blockade, the particular isotype or FcγR binding of the therapeutic antibody, and the clinical measure of antitumor activity employed 11 . With regard to dose, our study used high dose tremelimumab 750 mg intravenously (analogous to doses of ipilimumab at 10 mg/kg employed in some studies 12 ) given prior work suggesting a possible dose–response relationship and given that this dosing was used in the prior study in metastatic urothelial cancer from Sharma and colleagues 8 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade

Miller,

Rose,

Maughan

et al. 2024

Cancer

View full text Add to dashboard Cite

IntroductionProgrammed death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) blockade has changed the landscape of treatment for metastatic urothelial cancer, but single‐agent cytotoxic T‐lymphocyte–associated protein 4 (CTLA‐4) blockade in metastatic urothelial cancer has been underexplored. A prior phase 2 trial of tremelimumab in PD‐1/PD‐L1–blockade naive patients with metastatic urothelial cancer revealed activity comparable to that observed with PD‐1/PD‐L1 blockade raising the hypothesis that these classes of immune checkpoint inhibitors might be non‐cross‐resistant.MethodsThe current phase 2 trial treated patients with PD‐1/PD‐L1 blockade‐resistant metastatic urothelial cancer with single‐agent tremelimumab (750 mg intravenously every 28 days for up to 7 cycles). The primary end point was objective response rate.ResultsTwenty‐six patients were enrolled and 24 patients were evaluable for response. The objective response rate was 8.3%, composed of a total of two partial responses that lasted 10.9 and 24.0 months. Stable disease was observed in another 20.8% of patients, with a median duration of stable disease of 5.4 months. Diarrhea occurred in 15 patients (58%), elevated hepatic transaminases occurred in seven patients (27%), and adrenal insufficiency occurred in two patients (8%); one patient died after experiencing immune‐related hepatitis.ConclusionsHigh dose CTLA‐4 blockade in patients with PD‐1/PD‐L1–resistant metastatic urothelial cancer has modest activity and is associated with treatment‐related toxicity similar to prior reports.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade

Miller,

Rose,

Maughan

et al. 2024

Cancer

View full text Add to dashboard Cite

show abstract

Integrative analysis of the bladder cancer from a cell cycle NCAM1 perspective at both single cell and bulk resolution

Zeng,

Su,

Liu

et al. 2024

Environmental Toxicology

View full text Add to dashboard Cite

IntroductionBladder cancer (BLCA) is a prevalent and deadly form of urinary cancer, and there is a need for effective therapies, particularly for muscle‐invasive bladder cancer (MIBC). Cell cycle inhibitors show promise in restoring control of the cell cycle in BLCA cells, but their clinical prognosis evaluation is limited.MethodsTranscriptome and scRNA‐seq data were collected from the Cancer Genome Atlas Program (TCGA)‐BLCA and GSE190888 cohort, respectively. R software and the Seurat package were used for data analysis, including cell quality control, dimensionality reduction, and identification of differentially expressed genes. Genes related to the cell cycle were obtained from the genecards website, and a protein–protein interaction network analysis was performed using cytoscape software. Functional enrichment analysis, immune infiltration analysis, drug sensitivity analysis, and molecular docking were conducted using various tools and packages. BLCA cell lines were cultured and transfected for in vitro experimental assays, including RT‐qPCR analysis, and CCK‐8 cell viability assays.ResultsWe identified 32 genes as independent risk or protective factors for BLCA prediction. Functional enrichment analysis revealed their involvement in cell cycle regulation, apoptosis, and various signaling pathways. Using these genes, we developed a nomogram for predicting BLCA survival, which displayed high prognosis stratification efficacy in BLCA patients. Four cell cycle associated key genes identified, including NCAM1, HBB, CKD6, and CTLA4. We also identified the main cell types in BLCA patients and investigated the functional differences between epithelial cells based on their expression levels of key genes. Furthermore, we observed a high positive correlative relationship between the infiltration of cancer‐associated fibroblasts and the risk score value. Finally, we conducted in vitro experiments to demonstrate the suppressive role of NCAM1 in BLCA cell proliferation.ConclusionThese findings suggest that cell cycle associated genes could serve as potential biomarkers for predicting BLCA prognosis and may represent therapeutic targets for the development of more effective therapies. Hopefully, these findings provide valuable insights into the molecular mechanisms and potential therapeutic targets in BLCA from the perspective of cell cycle. Moreover, NCAM1 was a novel cell proliferation suppressor in the BLCA carcinogenesis.

show abstract

Small molecule inhibitors targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for cancer immunotherapy (2020–2024)

Cheng,

Lv,

Xiao

et al. 2025

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Turning up the heat: CTLA4 blockade in urothelial cancer

Cited by 5 publications

References 126 publications

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade

Phase 2 trial of tremelimumab in patients with metastatic urothelial cancer previously treated with programmed death 1/programmed death ligand 1 blockade

Integrative analysis of the bladder cancer from a cell cycle NCAM1 perspective at both single cell and bulk resolution

Small molecule inhibitors targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for cancer immunotherapy (2020–2024)

Contact Info

Product

Resources

About