Palbociclib impairs the proliferative capacity of activated T cells while retaining their cytotoxic efficacy

Frontiers in Pharmacology

Pharmacology

Stefanie Koristka¹  Anja Feldmann¹  Liliana R. Loureiro¹  Claudia Arndt²  Michael Philipp Bachmann³  Torsten Tonn⁴  Eleni Kourtellari⁵  Stephanie Luttosch⁵  Katharina Hannemann⁵  Jan Dominik Kuhlmann⁶  Theresa Link⁶  Pauline Wimberger⁶  Antje Tunger⁷  Rebecca Rothe⁷  Rebekka Wehner⁸  Marc Schmitz⁸ 

[1] Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany;Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany;National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany;Tumor Immunology, University Cancer Center (UCC), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany;German Red Cross Blood Donation Service North-East, Institute for Transfusion Medicine, Dresden, Germany;Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany;Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany;National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany;Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany;National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany;Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany;German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany;

关键词: cancer immunotherapy;    CDK4/6;    palbociclib;    fulvestrant;    bispecific antibody;    CAR T cell;    adoptive T cell therapy;   

DOI  :  10.3389/fphar.2023.970457

 received in 2022-06-16, accepted in 2023-01-20,  发布年份 2023

来源: Frontiers

【 摘 要 】

The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib is an emerging cancer therapeutic that just recently gained Food and Drug Administration approval for treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor (Her)2-negative breast cancer in combination with the ER degrader fulvestrant. However, CDK4/6 inhibitors are not cancer-specific and may affect also other proliferating cells. Given the importance of T cells in antitumor defense, we studied the influence of palbociclib/fulvestrant on human CD3+ T cells and novel emerging T cell-based cancer immunotherapies. Palbociclib considerably inhibited the proliferation of activated T cells by mediating G0/G1 cell cycle arrest. However, after stopping the drug supply this suppression was fully reversible. In light of combination approaches, we further investigated the effect of palbociclib/fulvestrant on T cell-based immunotherapies by using a CD3-PSCA bispecific antibody or universal chimeric antigen receptor (UniCAR) T cells. Thereby, we observed that palbociclib clearly impaired T cell expansion. This effect resulted in a lower total concentration of interferon-γ and tumor necrosis factor, while palbociclib did not inhibit the average cytokine release per cell. In addition, the cytotoxic potential of the redirected T cells was unaffected by palbociclib and fulvestrant. Overall, these novel findings may have implications for the design of treatment modalities combining CDK4/6 inhibition and T cell-based cancer immunotherapeutic strategies.

【 授权许可】

Unknown   
Copyright © 2023 Arndt, Tunger, Wehner, Rothe, Kourtellari, Luttosch, Hannemann, Koristka, Loureiro, Feldmann, Tonn, Link, Kuhlmann, Wimberger, Bachmann and Schmitz.