Prolonged Cytopenia Following CD19 Car T Cell Therapy Is Linked With Bone Marrow Infiltration of Clonally Expanded Ifnγ-Expressing CD8 T Cells

Authors

Paolo Strati
Xubin Li
Qing Deng
Mario L Marques-Piubelli
Jared Henderson
Grace Watson
Laurel Deaton
Taylor Cain
Haopeng Yang
Vida Ravanmehr
Luis E Fayad
Swaminathan P Iyer
Loretta J Nastoupil
Frederick B Hagemeister
Edwin R Parra
Neeraj Saini
Koichi Takahashi
Nathan H Fowler
Jason R Westin
Raphael E Steiner
Ranjit Nair
Christopher R Flowers
Linghua Wang
Sairah Ahmed
Gheath Al-Atrash
Francisco Vega
Sattva S Neelapu
Michael R Green

Publication Date

8-15-2023

Journal

Cell Reports Medicine

Abstract

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine signaling gene sets, associated with prolonged cytopenia. In line with this, we found that hematopoietic stem cells from these patients expressed IFN-γ response signatures. IFN-γ deregulates hematopoietic stem cell self-renewal and differentiation and can be targeted with thrombopoietin agonists or IFN-γ-neutralizing antibodies, highlighting a potential mechanism-based approach for the treatment of CAR T-associated prolonged cytopenia.

Keywords

Humans, Immunotherapy, Adoptive, Receptors, Chimeric Antigen, Bone Marrow, Lymphoma, B-Cell, CD8-Positive T-Lymphocytes, Antigens, CD19, Interferon-gamma

Comments

Supplementary Materials

PMID: 37586321