Use of a Lethally Irradiated Major Histocompatibility Complex Nonrestricted Cytotoxic T-Cell Line for Effective Purging of Marrows Containing Lysis-Sensitive or -Resistant Leukemic Targets

Abstract

Improved marrow purging protocols are needed in autologous bone marrow transplantation (BMT) to achieve complete eradication of minimal residual disease. This study investigates the potential of a human major histocompatibility complex (MHC) nonrestricted killer T-cell line (TALL-104) as a new marrow purging agent in a clinical setting. TALL-104 cells can be irradiated without losing cytotoxic activity against tumor targets in vitro. In vivo, the irradiated killers can be adoptively transferred into immunodeficient and immunocompetent leukemia-bearing mice, and reverse their disease even in advanced stages. The present study shows that gamma-irradiated TALL-104 cells, cultured for 18 hours with marrows from healthy donors, do not impair the viability and long-term growth of committed and pluripotent hematopoietic progenitors. However, as determined by polymerase chain reaction (PCR) and colony assays, TALL-104 cells could completely purge marrows containing up to 50% lysis-susceptible myelomonocytic leukemia cells (U937). When marrows were admixed with a pre-B leukemia cell line (ALL-1), which is fairly resistant to TALL-104 cell lysis in longterm 51Cr-release assays but can be totally growth inhibited by TALL-104 cells in proliferation assays, residual ALL-1 cells were detectable by PCR after TALL-104 purging. However, importantly, these PCR+ marrows were devoid of tumorigenic activity when transplanted into the human hematopoietic microenvironment of human severe combined immunodeficient (SCID) chimeras. These data indicate the strong potential of the TALL-104 cell line in future marrow purging strategies against lysis-susceptible and -resistant leukemias.