Page 60 - 2021_10-Haematologica-web

Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2588-2597
Engineered type 1 regulatory T cells designed for clinical use kill primary pediatric acute myeloid leukemia cells
Brandon Cieniewicz,1* Molly Javier Uyeda,1,2* Ping (Pauline) Chen,1
Ece Canan Sayitoglu,1 Jeffrey Mao-Hwa Liu,1 Grazia Andolfi,3
Katharine Greenthal,1 Alice Bertaina,1,4 Silvia Gregori,3 Rosa Bacchetta,1,4 Norman James Lacayo,1 Alma-Martina Cepika1,4#
and Maria Grazia Roncarolo1,2,4#
1Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 2Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy and 4Center for Definitive and Curative Medicine, Stanford School of Medicine, Stanford, CA, USA
*BC and MJU contributed equally as co-first authors #AMC and MGR contributed equally as co-senior authors
ABSTRACT
Type 1 regulatory (Tr1) T cells induced by enforced expression of interleukin-10 (LV-10) are being developed as a novel treatment for chemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft-versus-host disease while mediating graft-versus-leukemia effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature. Overlaying the signatures of sensitive and resistant pAML onto the pub- lic NCI TARGET pAML dataset revealed that sensitive pAML clustered with M5 monocytic pAML and pAML with MLL rearrangement. Resistant pAML clustered with myelomonocytic leukemias and those bearing the core binding factor translocations inv(16) or t(8;21)(RUNX1- RUNX1T1). Furthermore, resistant pAML upregulated the membrane glycoprotein CD200, which binds to the inhibitory receptor CD200R1 on LV-10 cells. In order to examine if CD200 expression on target cells can impair LV-10 cell function, we overexpressed CD200 in myeloid leukemia cell lines ordinarily sensitive to LV-10 killing. Indeed, LV-10 cells degranulated less and killed fewer CD200-overexpressing cells com- pared to controls, indicating that pAML can utilize CD200 expression for immune evasion. Altogether, the majority of pAML are killed by LV-10 cells in vitro, supporting further LV-10 cell development as an innovative cell therapy for pAML.
Introduction
Pediatric acute myeloid leukemia (pAML) affects over 700 children in the US every year. While pAML comprises only 25% of all pediatric acute leukemias, it accounts for almost half of pediatric leukemia-related deaths. Five-year survival rates for pAML have risen to over 60%, in part due to improved risk-stratification, supportive care, and post-relapse treatment.1 However, between 30-55% of patients eventually relapse,2,3 and relapse remains the most frequent cause of death. Current treatment for relapsed or treatment-refractory pAML is allogeneic hematopoietic stem cell transplantation (allo-HSCT).4 Unfortunately, allo-HSCT carries the significant risk of inducing life-threatening graft-versus-host disease (GvHD) mediated by donor- derived T cells. GvHD is the major cause of transplant-related morbidity and mortal- ity, and the second leading cause of death in AML patients.5,6 GvHD can be treated
Acute Myeloid Leukemia
Correspondence:
MARIA GRAZIA RONCAROLO
mg1@stanford.edu
Received: June 15, 2020.
Accepted: September 17, 2020. Pre-published: September 28, 2020.
https://doi.org/10.3324/haematol.2020.263129 ©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
2588
haematologica | 2021; 106(10)
ARTICLE