Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation.
Viral infections and leukemic relapse account for the majority of treatment failures in patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving allogeneic hematopoietic stem cell (HSC) or cord blood (CB) transplants. Adoptive transfer of virus-specific cytotoxic T lymphocytes (CTLs) provides protection against common viruses causing serious infections after HSC transplantation without concomitant graft-versus-host disease. We have now generated CTL lines from peripheral blood (PB) or CB units that recognize multiple common viruses and provide antileukemic activity by transgenic expression of a chimeric antigen receptor (CAR) targeting CD19 expressed on B-ALL. PB-derived CAR(+) CTLs produced interferon-gamma (IFNgamma) in response to cytomegalovirus-pp65, adenovirus-hexon, and Epstein-Barr virus pepmixes (from 205 +/- 104 to 1034 +/- 304 spot-forming cells [SFCs]/10(5) T cells) and lysed primary B-ALL blasts in (51)Cr-release assays (mean, 66% +/- 5% specific lysis; effector-target [E/T] ratio, 40:1) and the CD19(+) Raji cell line (mean, 78% +/- 17%) in contrast to nontransduced controls (8% +/- 8% and 3% +/- 2%). CB-derived CAR(+) CTLs showed similar antiviral and antitumor function and both PB and CB CAR(+) CTLs completely eliminated B-ALL blasts over 5 days of coculture. This approach may prove beneficial for patients with high-risk B-ALL who have recently received an HSC or CB transplant and are at risk of infection and relapse.
Micklethwaite
Kenneth P
KP
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
Savoldo
Barbara
B
Hanley
Patrick J
PJ
Leen
Ann M
AM
Demmler-Harrison
Gail J
GJ
Cooper
Laurence J N
LJ
Liu
Hao
H
Gee
Adrian P
AP
Shpall
Elizabeth J
EJ
Rooney
Cliona M
CM
Heslop
Helen E
HE
Brenner
Malcolm K
MK
Bollard
Catherine M
CM
Dotti
Gianpietro
G
D000256:Adenoviridae / Q000276:immunology; D019264:Adoptive Transfer; D000328:Adult; D018941:Antigens, CD19 / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D001773:Blood Cells / Q000276:immunology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor / Q000276:immunology; D002478:Cells, Cultured / Q000276:immunology / Q000637:transplantation; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003587:Cytomegalovirus / Q000276:immunology; D005240:Feasibility Studies; D005312:Fetal Blood / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D015448:Leukemia, B-Cell / Q000276:immunology* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000276:immunology; D011183:Postoperative Complications / Q000517:prevention & control* / Q000821:virology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D011991:Receptors, Virus / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000276:immunology; D012008:Recurrence; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D014777:Virus Diseases / Q000276:immunology / Q000517:prevention & control*
D018941:Antigens, CD19; D000956:Antigens, Viral; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D007371:Interferon-gamma