TGF-β1 Inhibition, Cytokine Modulation, and Clinical Response to Seleno-L-Methionine Plus Axitinib and Pembrolizumab in Treatment-Naïve Clear Cell Renal Cell Carcinoma
- 1Division of Hematology, Oncology and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
- 2Division of Hematology and Medical Oncology, Mayo Clinic Arizona, Phoenix, AZ 85054, USA
- 3Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
Abstract
Metastatic clear cell renal cell carcinoma (ccRCC) remains largely incurable, and the efficacy of pembrolizumab plus axitinib may be limited by hypoxia-associated signaling, immunosuppressive cytokines, and metabolic reprogramming involving the TGF-β1/HIF axis. Seleno-L-methionine (SLM) is a pharmacologic inhibitor of this axis and its downstream effectors, including PD-L1 and VEGF. In a phase I/II pilot study (ClinicalTrials.gov NCT05363631), patients with newly diagnosed metastatic ccRCC received SLM twice daily for 14 days, then once daily with standard-dose axitinib; pembrolizumab was added on day 15. Endpoints included circulating (plasma) TGF-β1, plasma selenium, circulating cytokines, efficacy, and safety. Twelve patients were treated and evaluable for safety (six at 5000 µg, six at 6000 µg SLM); ten were evaluable for response. The objective response rate was 70% (complete response 40%, partial response 30%). Of the four patients with CR, two had favorable and two had intermediate International Metastatic Renal Cell Carcinoma Database Consortium disease. Grade 3 hypertension was documented in 58.3%, about twice the pivotal-trial rate, without treatment discontinuations or new toxicities. SLM increased plasma selenium and produced time-dependent inhibition of TGF-β1 and modulation of immune-related cytokines (CXCL13, IFN-γ, TNF-α, IL-6, IL-8). In this pilot study, SLM combined with axitinib and pembrolizumab showed time-dependent TGF-β1 inhibition, cytokine modulation, and encouraging antitumor activity without treatment-limiting toxicity, supporting further investigation of SLM for targeting the TGF-β1/HIF-driven immunosuppressive microenvironment in ccRCC.
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BibTeX
@article{kroll2026tgfβ1,
title = {{TGF-β1 Inhibition, Cytokine Modulation, and Clinical Response to Seleno-L-Methionine Plus Axitinib and Pembrolizumab in Treatment-Naïve Clear Cell Renal Cell Carcinoma}},
author = {Matthew R. Kroll and Yousef Zakharia and Fernando Maciel Barbosa and Vitor Fiorin de Vasconcellos and John M. Rieth and Mohammed Milhem and Mariana Pilon Capella and Youcef M. Rustum},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219825},
url = {https://www.mdpi.com/1422-0067/27/21/9825},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TGF-β1 Inhibition, Cytokine Modulation, and Clinical Response to Seleno-L-Methionine Plus Axitinib and Pembrolizumab in Treatment-Naïve Clear Cell Renal Cell Carcinoma
AU - Matthew R. Kroll
AU - Yousef Zakharia
AU - Fernando Maciel Barbosa
AU - Vitor Fiorin de Vasconcellos
AU - John M. Rieth
AU - Mohammed Milhem
AU - Mariana Pilon Capella
AU - Youcef M. Rustum
PY - 2026
DA - 2026/11/02
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219825
UR - https://www.mdpi.com/1422-0067/27/21/9825
AB - Metastatic clear cell renal cell carcinoma (ccRCC) remains largely incurable, and the efficacy of pembrolizumab plus axitinib may be limited by hypoxia-associated signaling, immunosuppressive cytokines, and metabolic reprogramming involving the TGF-β1/HIF axis. Seleno-L-methionine (SLM) is a pharmacologic inhibitor of this axis and its downstream effectors, including PD-L1 and VEGF. In a phase I/II pilot study (ClinicalTrials.gov NCT05363631), patients with newly diagnosed metastatic ccRCC received SLM twice daily for 14 days, then once daily with standard-dose axitinib; pembrolizumab was added on day 15. Endpoints included circulating (plasma) TGF-β1, plasma selenium, circulating cytokines, efficacy, and safety. Twelve patients were treated and evaluable for safety (six at 5000 µg, six at 6000 µg SLM); ten were evaluable for response. The objective response rate was 70% (complete response 40%, partial response 30%). Of the four patients with CR, two had favorable and two had intermediate International Metastatic Renal Cell Carcinoma Database Consortium disease. Grade 3 hypertension was documented in 58.3%, about twice the pivotal-trial rate, without treatment discontinuations or new toxicities. SLM increased plasma selenium and produced time-dependent inhibition of TGF-β1 and modulation of immune-related cytokines (CXCL13, IFN-γ, TNF-α, IL-6, IL-8). In this pilot study, SLM combined with axitinib and pembrolizumab showed time-dependent TGF-β1 inhibition, cytokine modulation, and encouraging antitumor activity without treatment-limiting toxicity, supporting further investigation of SLM for targeting the TGF-β1/HIF-driven immunosuppressive microenvironment in ccRCC.
SN - 1422-0067
ER -