Selective targeting of human lymphokine-activated killer cells by CD3 monoclonal antibody against the interferon-inducible high-affinity Fc gamma RI receptor (CD64) on autologous acute myeloid leukemic blast cells.
The potential of the CD3 monoclonal antibody (MoAb) OKT3 to selectively target lymphokine-activated killer (LAK) cells and T-cell clones in vitro against autologous tumor cells was studied using material from patients with acute leukemias (19 acute myeloid leukemias [AML], and 3 acute lymphoblastic leukemias [ALL]). Cytotoxicity mediated by patient LAK cells against AML blasts, but not against ALL cells and autologous Epstein-Barr virus-transformed B cells, was enhanced 1.5-fold to 9.3-fold by OKT3 in all AML patients studied. The following findings suggest that the major target molecule on AML cells for OKT3-coated LAK cells is the high-affinity Fc receptor for IgG (Fc gamma RI; CD64): (1) susceptibility to killing by OKT3-coated effector LAK cells segregated with target cell expression of CD64; (2) preincubation of AML blasts with monomeric OKT3 (murine IgG2a), the Fc portion of which is known to have preferential binding affinity to CD64, resulted in lysis by autologous T cells that were not spontaneously cytotoxic; (3) OKT3-dependent increase in lysis of primary and relapsed AML cells by autologous T-cell clones correlated with the amount of target cell expression of CD64; (4) anti-leukemic cytotoxicity of OKT3-coated T cells could partially be inhibited by monomeric human Ig, the natural ligand of CD64; and (5) expression of CD64 (Fc gamma RI) on fresh AML cells could be increased by interferon-gamma (IFN-gamma) and IFN-alpha translating into further enhancement of lysis by autologous OKT3-coated LAK cells. Nonmalignant CD34+ cells sorted from peripheral blood were found to lack expression of CD64 and hence were not affected by OKT3-triggered T-cell targeting, as detected by colony formation assays. In conclusion, the in vitro data presented provide a rationale for the combined clinical use of recombinant interleukin-2, IFN-gamma, and low doses of CD3 MoAb to eliminate AML cells while sparing nonmalignant hematopoietic progenitor cells, for example, in the setting of purging procedures for autologous bone marrow transplantation.
Notter
M
M
Department of Hematology and Oncology, Free University of Berlin, Klinikum Steglitz, Germany.
Ludwig
W D
WD
Bremer
S
S
Thiel
E
E
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006412:Hematopoietic Stem Cells / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D016853:Muromonab-CD3 / Q000276:immunology*; D017452:Receptors, IgG / Q000032:analysis / Q000502:physiology*
D015703:Antigens, CD; D018952:Antigens, CD34; D016853:Muromonab-CD3; D017452:Receptors, IgG; D007371:Interferon-gamma