Immunotherapy of established tumors using bone marrow transplantation with antigen gene--modified hematopoietic stem cells.
A major focus of cancer immunotherapy is to develop strategies to induce T-cell responses through presentation of tumor antigens by dendritic cells (DCs). Current vaccines are limited in their ability to efficiently transfer antigens to DCs in vivo. Ex vivo-generated DCs can be efficiently loaded with antigen but after reinjection, few DCs traffic to secondary lymphoid organs, the critical sites for antigen presentation. To enhance efficiency and durability of antigen presentation by DCs, we transduced hematopoietic stem-progenitor cells (HSCs) with a model tumor antigen and then transplanted the gene-modified cells into irradiated recipient mice, which resulted in efficient expression of the transgene in a large proportion of donor derived DCs in lymphoid organs. The combination of bone marrow transplantation (BMT) using transduced HSCs, systemic agents that generate and activate DCs, and mature T-cell infusion resulted in substantial expansion and activation of antigen-specific T cells. This tripartite strategy provided potent antigen-specific immunotherapy for an aggressive established tumor.
Cui
Yan
Y
Immunology & Hematopoiesis Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Kelleher
Erin
E
Straley
Erin
E
Fuchs
Ephraim
E
Gorski
Kevin
K
Levitsky
Hyam
H
Borrello
Ivan
I
Civin
Curt I
CI
Schoenberger
Stephen P
SP
Cheng
Linzhao
L
Pardoll
Drew M
DM
Whartenby
Katharine A
KA
D000818:Animals; D000941:Antigens / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology; D006384:Hemagglutination / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D013154:Spleen / Q000166:cytology; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D014161:Transduction, Genetic; D014182:Transplantation, Autologous
D000941:Antigens; D019013:CD40 Antigens; D007371:Interferon-gamma