We determined the safety, immune activating effects, and potential efficacy of i.v. infusion of ex vivo
interleukin-2 (IL-2) activated natural killer (NK) cells (part I) or
IL-2 boluses (part II) during daily s.c.
IL-2 administration following hematopoietic recovery from
autologous transplantation. In all, 57 patients with relapsed
lymphoma (n=29) or metastatic
breast cancer (n=28) were enrolled. In part I of the study, 34 patients were enrolled at three dose levels of ex vivo IL-2-activated NK cells. Lymphaphereses were performed on days 28 and 42 of s.c.
IL-2 administration. Following overnight ex vivo
IL-2 activation of the
pheresis product, the cells were reinfused the following day. In part II, 23 patients were enrolled at three dose levels of supplemental i.v.
IL-2 bolus infusions, given on days 28 and 35 during s.c.
IL-2 administration. Toxicities were generally mild, and no patient required hospitalization. Lytic function was markedly enhanced for fresh peripheral blood mononuclear cells (PBMNCs) obtained 1 day postinfusion of either IL-2-activated cells or
IL-2 boluses.
IL-2 boluses transiently increased the levels of
IL-6, IFN-gamma,
TNF-alpha and IL1-beta, with increases in
IL-6 and IFN-gamma being dose dependent. A total of 37 patients (19 patients with
lymphoma, 18 with
breast cancer) treated with an optimum dose of post-transplant
immunotherapy (defined as having received 1.75 x 10(6) IU/m(2)/day of s.c. IL-2 plus at least one of the planned ex vivo IL-2-activated cell infusions/IL-2 boluses) could be matched with controls from the Autologous Blood and Marrow Transplant Registry database. The matched-pairs analysis demonstrated no improvement in disease outcomes of survival and relapse. We conclude that IL-2-activated cells/IL-2 boluses can be safely administered, generate PBMNCs with enhanced cytotoxicity against NK-resistant targets, and increase
cytokine levels. With this dose and schedule of administration of
IL-2, no improvement in patient disease outcomes was noted. Alternative strategies will be needed to exploit the immunotherapeutic potential of IL-2-activated NK cells.