ABSTRACT
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.
ABSTRACT
BACKGROUND Splenic aneurysms are rare, asymptomatic, and usually derive from previous surgical interventions. Endovascular repair is the best option, but when A-V shunt is present, open repair might be more suitable. CASE REPORT A 43-year-old man presented to the Internal Medicine Department of AHEPA University Hospital with symptoms of fever and ascites. He was an ex-medical student with a history of sickle cell anemia, who had undergone urgent splenectomy and cholecystectomy 26 years ago and had a transit ischemic attack at the age of 21 years. Diagnostic imaging control revealed a giant splenic aneurysm 9.8 cm in diameter and 5 cm in length, with a concomitant A-V shunt (due to common ligation of the vessels after splenectomy and long stump presence with concomitant erosion of arterial wall). The patient underwent open surgery and cross-clamping the orifice of the splenic artery, also including the splenic vein, and the vessels were ligated. Post-operatively, the patient remained in the Intensive Care Unit for 48 h and suffered a portal vein thrombosis treated with appropriate anticoagulants. One month later, he had acute hemorrhagic pancreatitis and paralytic ileus and underwent laparotomy performed by general surgeons. CONCLUSIONS Giant splenic aneurysms are rare and are usually caused by previous splenectomy and preservation of a long-vessel stump. Immediate surgical repair is mandatory because of the high risk of rupture.
