Abstract: The invention provides method of depleting endogenous T-cells or NK-cells to facilitate propagation or survival of engineered T-cells introduced into a subject for a therapeutic purpose. The depletion regime involves a co-administration of an immunotherapeutic agent against T-cells and an immunotherapeutic agent that inhibits CD47 interaction with NK-cells. The immunotherapeutic agent against T-cells or NK-cells binds to an antigen on T-cells or NK-cells effecting depletion of the T-cells or NK-cells, which depletion is promoted by the immunotherapeutic agent inhibiting CD47-SIRP? interaction. The genetically engineered T-cells or NK-cells can have a variety of genetic modifications such as a chimeric antigen receptor that targets the T-cells to a target cell.

Abstract: The invention provides co-administration regimes of immunotherapeutic agents specifically binding to c-kit or inhibiting CD47-SIRP? for ablation of endogenous HSPCs. Relatively low levels of anti-c-kit result in saturation of binding to c-kit on HSPCs without significant reduction of the levels HSPCs. Significant reduction of the level of HSPCs can be obtained when the action of anti-c-kit is promoted by an immunotherapeutic agent inhibiting CD47-SIRP?. HSPCs expressing c-kit can thus be reduced to an acceptable level an acceptable level to permit introduction of replacement HSPCs without detrimental delay during which a subject has inadequate HSPCs.