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

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Palbociclib, a CDK4/6 inhibitor, is approved for ER+/HER2- breast cancer treatment with fulvestrant.
• CDK4/6 inhibitors can affect proliferating non-cancerous cells, including T cells.
• T cells are vital for anti-tumor immunity and emerging T cell-based immunotherapies.

Purpose of the Study:

• To investigate the impact of palbociclib/fulvestrant on human T cells and T cell-based immunotherapies.
• To assess the reversibility of palbociclib's effects on T cell proliferation.
• To evaluate the influence of palbociclib/fulvestrant on T cell expansion and function in combination therapies.

Main Methods:

• Assessing palbociclib's effect on activated human CD3+ T cell proliferation and cell cycle.
• Investigating the reversibility of T cell suppression after drug withdrawal.
• Evaluating palbociclib/fulvestrant's impact on T cell expansion using bispecific antibodies and UniCAR T cells.
• Measuring cytokine release (IFN-γ, TNF) and cytotoxic potential of T cells.

Main Results:

• Palbociclib significantly inhibited T cell proliferation via G0/G1 cell cycle arrest, an effect that was fully reversible.
• Palbociclib/fulvestrant impaired overall T cell expansion in combination therapies.
• Reduced total concentrations of IFN-γ and TNF were observed, but average cytokine release per cell remained unaffected.
• The cytotoxic capacity of T cells, when redirected by bispecific antibodies or UniCARs, was not diminished by palbociclib/fulvestrant.

Conclusions:

• Palbociclib demonstrates reversible inhibition of T cell proliferation.
• Combined CDK4/6 inhibition with T cell-based immunotherapies may lead to reduced T cell expansion and lower overall cytokine production.
• The cytotoxic function of T cells remains intact, suggesting potential for combination strategies with careful consideration of T cell expansion dynamics.