Oral Presentation Melbourne Immunotherapy Network Winter Retreat 2018

More than a BTK inhibitor: Ibrutinib impairs T cell function (#34)

Chia Sharpe 1 , Joanne Davis 1 2 , Kylie Mason 1 2 , Rachel Koldej 1 2 , David Ritchie 1 2
  1. Department of Medicine , University of Melbourne, Melbourne, Victoria, Australia
  2. Royal Melbourne Hospital, Brunswick, VICTORIA, Australia

Aim

Ibrutinib is increasingly being incorporated into the clinical management of B cell malignancies. This study aimed to determine if ibrutinib and more selective BTK inhibitors impact the cytotoxic capacity of T cells. Ibrutinib inhibits all Tec family kinases including ITK at clinically meaningful concentrations and may exert a Th1 selective pressure1. However this has not been shown in patients2. More selective BTK inhibitors have also been developed including zanubrutinib and acalabrutinib. However the impact of ibrutinib or other BTK inhibitors on T cell function remains unclear.

Method

PBMC were isolated from six treatment-naive CLL patients at the Royal Melbourne Hospital. Healthy donor NKT cells were FACS sorted from PBMC and ex vivo expanded. Cells were treated in vitro with 1uM ibrutinib, zanubrutinib or acalabrutinib. CD8 T cell and NKT cell response to CD3/CD28 stimulation and NKT response to α-Galactosylceramide loaded CLL cells was assessed by flow cytometry (CD107a, Granzyme B and IFN

  1. 1. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood 2013;122:2539–49
  2. 2. Long M, Beckwith K, Do P, Mundy BL, Gordon A, Lehman AM, et al. Ibrutinib treatment improves T cell number and function in CLL patients. J Clin Invest 2017;127:3052–64.