Preclinical studies have shown that anti-CD3
antibodies can enhance the in vitro activation of human T lymphocytes in combination with low-dose
interleukin-2 (IL-2) and induce the in vivo rejection of murine
tumors. A Phase IA/IB trial combining a murine
monoclonal antibody, anti-CD3 antibody (
OKT3), with low-dose continuous-infusion
IL-2 was conducted in
cancer patients to define the toxicity and immunologic effects of this combination.
OKT3 administered weekly as a 15-min infusion at dose levels of 10, 100, 200, 400, and 600 micrograms/m2 was followed 18 h later by a 100-h infusion of
IL-2 at 3 MIU/m2/day for 3 consecutive weeks. When feasible, patients also received the
IL-2 course without
OKT3 to assess the effects of
OKT3 on the
IL-2 regimen within the same patient. Thirty patients were enrolled onto the study, with 24 completing the
OKT3/IL-2 course and 18 completing both
OKT3/IL-2 and
IL-2 alone courses.
OKT3 administration was associated with acute
hypotension with
fevers of > 40 degrees C and in two patients cerebral vascular
infarcts. At 600 micrograms/m2
OKT3, these toxicities were dose limiting. In a dose-dependent manner,
OKT3 induced the transient release of
tumor necrosis factor (TNF) and
IL-6 into the serum and a profound
lymphopenia.
OKT3 did not significantly enhance the toxicity of this schedule of
IL-2 administration. All solid
tumor patients treated at 100-600 micrograms/m2
OKT3 showed induction of a human anti-murine antibody response prior to the third week of treatment. A patient with
renal cell cancer treated at the 600-micrograms/m2
OKT3 dose level experienced a 4-month partial remission, and two mixed responses were observed in a
sarcoma and a
melanoma patient treated at 100- and 400-micrograms/m2
OKT3 dose levels, respectively. Most importantly, we were unable to demonstrate that the addition of
OKT3 enhanced immune activation within peripheral blood based upon the magnitude of rebound
lymphocytosis, increase in CD56+ or CD3+, CD25+ lymphocytes, induction of natural killer, lymphokine activated killer, or cytolytic T lymphocyte cytotoxicity, or release of serum
cytokines (TNF, IL-6) or soluble CD25 (as assayed 24 h following IL-2 infusion). Therefore, this approach was ineffective at enhancing the immunologic effects of a low-dose continuous-infusion
IL-2 regimen and will not be pursued further in clinical trials.