TY - JOUR
T1 - Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant
AU - Lulla, Premal D.
AU - Naik, Swati
AU - Vasileiou, Spyridoula
AU - Tzannou, Ifigeneia
AU - Watanabe, Ayumi
AU - Kuvalekar, Manik
AU - Lulla, Suhasini
AU - Carrum, George
AU - Ramos, Carlos A.
AU - Kamble, Rammurti
AU - Hill, La Quisa
AU - Randhawa, Jasleen
AU - Gottschalk, Stephen
AU - Krance, Robert
AU - Wang, Tao
AU - Wu, Mengfen
AU - Robertson, Catherine
AU - Gee, Adrian P.
AU - Chung, Betty
AU - Grilley, Bambi
AU - Brenner, Malcolm K.
AU - Heslop, Helen E.
AU - Vera, Juan F.
AU - Leen, Ann M.
N1 - Funding Information:
This work was supported by Leukemia and Lymphoma Society Specialized Center of Research (SCOR) awards (H.E.H.), the Leukemia Lymphoma Society/Rising Tide Foundation (A.M.L.), an ASH Scholar Award (P.D.L.), a Leukemia Texas Research grant (P.D.L.), an American Society of Blood and Marrow Transplantation (ASBMT) New Investigator Award (P.D.L.), an Edward P. Evans Foundations Discovery Research Grant (P.D.L.), the Caroline Wiess Law Fund for Research in Molecular Medicine and the L. E. and Josephine S. Gordy Memorial Cancer Research Fund (P.D.L.), the Cancer Prevention and Research Institute of Texas (CPRIT) Texas Access to Cancer Cell Therapies (TACCT) (A.P.G.), a CPRIT Early Career Clinical Investigator Award (P.D.L.), the Frank Stahl gift to Houston Methodist Hospital for leukemia research, and the Dan L. Duncan Comprehensive Cancer Center for application of the shared resources from a support grant from the National Institutes of Health, National Cancer Institute (P30CA125123).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/5/13
Y1 - 2021/5/13
N2 - Relapse after allogeneic hematopoietic stem cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor–derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen–pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 × 107 cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT. This trial is registered at www.clinicaltrials.com as #NCT02494167.
AB - Relapse after allogeneic hematopoietic stem cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor–derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen–pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 × 107 cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT. This trial is registered at www.clinicaltrials.com as #NCT02494167.
KW - Adolescent
KW - Adult
KW - Aged
KW - Allografts
KW - Antigens, Neoplasm/immunology
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Combined Modality Therapy
KW - Female
KW - Graft vs Host Disease/etiology
KW - Graft vs Leukemia Effect
KW - Hematopoietic Stem Cell Transplantation
KW - Humans
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Lymphocyte Transfusion/adverse effects
KW - Male
KW - Middle Aged
KW - Myelodysplastic Syndromes/drug therapy
KW - Recurrence
KW - Salvage Therapy
KW - T-Cell Antigen Receptor Specificity
KW - T-Lymphocytes/immunology
KW - Tissue Donors
KW - Young Adult
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U2 - 10.1182/blood.2020009471
DO - 10.1182/blood.2020009471
M3 - Article
C2 - 33270816
AN - SCOPUS:85105759424
SN - 0006-4971
VL - 137
SP - 2585
EP - 2597
JO - Blood
JF - Blood
IS - 19
ER -