A new approach for eradication of residual lymphoma cells by host nonreactive anti–third-party central memory CD8 T cells

• Published in: Blood 2013-04, Vol.121 (15), p.3033-3040
• Main Authors: Lask, Assaf, Ophir, Eran, Or-Geva, Noga, Cohen-Fredarow, Adva, Afik, Ran, Eidelstein, Yaki, Reich-Zeliger, Shlomit, Nathansohn, Bar, Edinger, Matthias, Negrin, Robert S., Hagin, David, Reisner, Yair
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - immunology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Bone Marrow Transplantation - methods; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; Cytotoxicity, Immunologic - immunology; Female; Flow Cytometry; Graft vs Host Disease - immunology; Graft vs Leukemia Effect - immunology; Immunologic Memory - immunology; Intercellular Adhesion Molecule-1 - immunology; Intercellular Adhesion Molecule-1 - metabolism; Lymphocyte Function-Associated Antigen-1 - immunology; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphoma - immunology; Lymphoma - metabolism; Lymphoma - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Neoplasm, Residual - immunology; Time Factors; Transplantation; Transplantation, Homologous
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-06-432443

Generation of T cells endowed with graft-versus-leukemia (GVL) and depleted of graft-versus-host (GVH) activity represents a highly desirable goal in bone marrow transplantation (BMT). Here, we demonstrate that donor anti–third-party CD8 T cells with central memory phenotype (Tcm) exhibit marked GVL reactivity through a unique T-cell receptor–independent mechanism. Thus, in a residual disease mouse model, Tcm therapy following autologous BMT led to significant survival prolongation, with 30% to 40% of the treated mice displaying long-term tumor-free survival. A more impressive finding was that infusion of donor Tcm in an allogeneic model rapidly eliminated residual lymphoma cells and led to long-term survival of 100% in the absence of GVH disease. Collectively, the strong GVL reactivity of anti–third-party Tcm, coupled with their demonstrated enhancement of bone marrow allografting, suggests that the use of Tcm therapy in conjunction with allogeneic T-cell–depleted BMT could be of particular benefit in patients with B-cell malignancies who cannot tolerate intensive myeloablative conditioning. •Anti–third-party Tcm kill malignant B cells in a T-cell receptor–independent mechanism while sparing naive B cells.