Influence of interleukin-2 regimens on circulating populations of lymphocytes after adoptive transfer of anti-CD3-stimulated T cells: results from a phase I trial in cancer patients.

Abstract

The adoptive transfer of anti-CD3-stimulated T killer (T-AK) cells was tested with different bolus and infusional interleukin-2 (IL-2) regimens, and anti-CD3 stimulation procedures to determine immunologic and antitumor effects in patients with a variety of advanced cancers. Indium-111 labeling was used to observe traffic patterns of the infused T-AK. Autologous peripheral blood mononuclear cells were obtained by leukapheresis. Cyclophosphamide (300 mg/m2) was given to most patients immediately after leukapheresis. The harvested cells were activated ex vivo with anti-CD3 overnight or for 4 days, at which time cells were reinfused and an IL-2 regimen was begun. Treatment was repeated 28 days later. This treatment regimen induced significant increases in leukocytes, lymphocytes, and eosinophils in patients in most treatment cohorts. Circulating lymphocytes were predominantly CD3+ T cells with preferential expansion of the CD8+ subset. Patients receiving cells stimulated in vitro for 4 days had significant T-cell lymphocytosis with either infusional or bolus plus infusional IL-2 regimens. T-cell viability was decreased in culture after a second 4-day stimulation with anti-CD3 at day 28; this decrease could be prevented by adding IL-2 to the culture media. Cells stimulated overnight required both bolus and infusional IL-2 to show an atypical lymphocytosis in vivo. Overnight-stimulated T-AK did not show decreases in in vitro viability at the day 28 restimulation. Indium-III-labeled cells trafficked to the liver, spleen, and bone marrow. No increase in uptake was observed in tumor deposits. There were 2 patients with partial responses, 5 with minor responses, 19 with stable disease, and 88 with progressive disease. The length of in vitro anti-CD3 stimulation, and the dose and timing of IL-2 administration in vivo results in different circulating leukocyte populations after adoptive T-AK infusion. Generally, the CD8+ T-cell subset was preferentially expanded by this treatment approach. Repeated ex vivo stimulation with anti-CD3 may cause cell death.