SYSTEMIC T CELL-INDEPENDENT TUMOR-IMMUNITY AFTER TRANSPLANTATION OF UNIVERSAL RECEPTOR-MODIFIED BONE-MARROW INTO SCID MICE

Gene modification of hematopoietic stem cells (HSC) with antigen-speci fic, chimeric, or ''universal'' immune receptors (URs) is a novel but untested form of targeted immunotherapy. A human immunodeficiency viru s (HIV) envelope-specific UR consisting of the extracellular domain of human CD4 linked to the zeta chain of the T cell receptor (CD4 zeta) was introduced ex vivo into murine HSC by retroviral transduction. Aft er transplantation into immunodeficient SCID mice, sustained high leve l expression of CD4 zeta was observed in circulating myeloid and natur al killer cells. CD4 zeta-transplanted mice were protected from challe nge with a lethal dose of a disseminated human leukemia expressing HIV envelope. These results demonstrate the ability of chimeric receptors bearing zeta-signaling domains to activate non-T cell effector popula tions in vivo and thereby mediate systemic immunity.