Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL.
Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs. Engineered TCM-derived CD19 CAR T cells were infused 2 days after HSCT at doses of 25 to 200 × 10(6) in a single infusion. In NHL1, 8 patients safely received T-cell products engineered from enriched CD8(+) TCM subsets, expressing a first-generation CD19 CAR containing only the CD3ζ endodomain (CD19R:ζ). Four of 8 patients (50%; 95% confidence interval [CI]: 16-84%) were progression free at both 1 and 2 years. In NHL2, 8 patients safely received T-cell products engineered from enriched CD4(+) and CD8(+) TCM subsets and expressing a second-generation CD19 CAR containing the CD28 and CD3ζ endodomains (CD19R:28ζ). Six of 8 patients (75%; 95% CI: 35-97%) were progression free at 1 year. The CD4(+)/CD8(+) TCM-derived CD19 CAR T cells (NHL2) exhibited improvement in expansion; however, persistence was ≤28 days, similar to that seen by others using CD28 CARs. Neither cytokine release syndrome nor delayed hematopoietic engraftment was observed in either trial. These data demonstrate the safety and feasibility of CD19 CAR TCM therapy after HSCT. Trials were registered at www.clinicaltrials.gov as #NCT01318317 and #NCT01815749.
Department of Hematology and Hematopoietic Cell Transplantation.
Xiuli
X
Wang
Department of Hematology and Hematopoietic Cell Transplantation.
Leslie L
LL
Popplewell
Department of Hematology and Hematopoietic Cell Transplantation.
Jamie R
JR
Wagner
Department of Hematology and Hematopoietic Cell Transplantation.
Araceli
A
Naranjo
Department of Information Sciences.
M Suzette
MS
Blanchard
Clinical Trials Unit, and.
Michelle R
MR
Mott
Clinical Trials Unit, and.
Adam P
AP
Norris
Department of Hematology and Hematopoietic Cell Transplantation.
ChingLam W
CW
Wong
Department of Hematology and Hematopoietic Cell Transplantation.
Ryan Z
RZ
Urak
Department of Hematology and Hematopoietic Cell Transplantation.
Wen-Chung
WC
Chang
Department of Hematology and Hematopoietic Cell Transplantation.
Samer K
SK
Khaled
Department of Hematology and Hematopoietic Cell Transplantation.
Tanya
T
Siddiqi
Department of Hematology and Hematopoietic Cell Transplantation.
Lihua E
LE
Budde
Department of Hematology and Hematopoietic Cell Transplantation.
Jingying
J
Xu
Department of Hematology and Hematopoietic Cell Transplantation.
Brenda
B
Chang
Department of Radiology, City of Hope, Duarte, CA;
Nikita
N
Gidwaney
Department of Hematology and Hematopoietic Cell Transplantation.
Sandra H
SH
Thomas
Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX;
Laurence J N
LJ
Cooper
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA; and.
Stanley R
SR
Riddell
Department of Hematology and Hematopoietic Cell Transplantation.
Christine E
CE
Brown
Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute and School of Medicine, Seattle, WA.
Michael C
MC
Jensen
Department of Hematology and Hematopoietic Cell Transplantation.
Stephen J
SJ
Forman
D000328:Adult; D000368:Aged; D018941:Antigens, CD19 / Q000378:metabolism; D002452:Cell Count; D003131:Combined Modality Therapy / Q000009:adverse effects; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D014182:Transplantation, Autologous; D055815:Young Adult
D018941:Antigens, CD19; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins