Engineering T Cells To Suppress Acute Gvhd and Leukemia Relapse After Allogeneic Hematopoietic Stem Cell Transplantation

Authors

Feiyan Mo
Norihiro Watanabe
Kayleigh I Omdahl
Phillip M Burkhardt
Xiaoyun Ding
Eiko Hayase
Angela Panoskaltsis-Mortari
Robert R Jenq
Helen E Heslop
Leslie S Kean
Malcolm K Brenner
Victor Tkachev
Maksim Mamonkin

Publication Date

3-9-2023

Journal

Blood

Abstract

Acute graft-versus-host disease (aGVHD) limits the therapeutic benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and requires immunosuppressive prophylaxis that compromises antitumor and antipathogen immunity. OX40 is a costimulatory receptor upregulated on circulating T cells in aGVHD and plays a central role in driving the expansion of alloreactive T cells. Here, we show that OX40 is also upregulated on T cells infiltrating GVHD target organs in a rhesus macaque model, supporting the hypothesis that targeted ablation of OX40+ T cells will mitigate GVHD pathogenesis. We thus created an OX40-specific cytotoxic receptor that, when expressed on human T cells, enables selective elimination of OX40+ T cells. Because OX40 is primarily upregulated on CD4+ T cells upon activation, engineered OX40-specific T cells mediated potent cytotoxicity against activated CD4+ T cells and suppressed alloreactive T-cell expansion in a mixed lymphocyte reaction model. OX40 targeting did not inhibit antiviral activity of memory T cells specific to Epstein-Barr virus, cytomegalovirus, and adenoviral antigens. Systemic administration of OX40-targeting T cells fully protected mice from fatal xenogeneic GVHD mediated by human peripheral blood mononuclear cells. Furthermore, combining OX40 targeting with a leukemia-specific chimeric antigen receptor in a single T cell product provides simultaneous protection against leukemia and aGVHD in a mouse xenograft model of residual disease posttransplant. These results underscore the central role of OX40+ T cells in mediating aGVHD pathogenesis and support the feasibility of a bifunctional engineered T-cell product derived from the stem cell donor to suppress both disease relapse and aGVHD following allo-HSCT.

Keywords

Humans, Animals, Mice, Leukocytes, Mononuclear, Epstein-Barr Virus Infections, Macaca mulatta, Herpesvirus 4, Human, Graft vs Host Disease, Leukemia, Chronic Disease, Hematopoietic Stem Cell Transplantation, Recurrence

DOI

10.1182/blood.2022016052

PMID

36044667

PMCID

PMC10023730

PubMedCentral® Posted Date

September 2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes