Frontiers in Pharmacology (Feb 2023)

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

  • Claudia Arndt,
  • Claudia Arndt,
  • Antje Tunger,
  • Antje Tunger,
  • Rebekka Wehner,
  • Rebekka Wehner,
  • Rebekka Wehner,
  • Rebecca Rothe,
  • Rebecca Rothe,
  • Eleni Kourtellari,
  • Stephanie Luttosch,
  • Katharina Hannemann,
  • Stefanie Koristka,
  • Liliana R. Loureiro,
  • Anja Feldmann,
  • Torsten Tonn,
  • Torsten Tonn,
  • Torsten Tonn,
  • Theresa Link,
  • Theresa Link,
  • Theresa Link,
  • Jan Dominik Kuhlmann,
  • Jan Dominik Kuhlmann,
  • Jan Dominik Kuhlmann,
  • Pauline Wimberger,
  • Pauline Wimberger,
  • Pauline Wimberger,
  • Michael Philipp Bachmann,
  • Michael Philipp Bachmann,
  • Michael Philipp Bachmann,
  • Michael Philipp Bachmann,
  • Marc Schmitz,
  • Marc Schmitz,
  • Marc Schmitz

DOI
https://doi.org/10.3389/fphar.2023.970457
Journal volume & issue
Vol. 14

Abstract

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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.

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