Anti-CD3-enhanced interleukin-2 immunotherapy of pulmonary metastases

A newly developed monoclonal rat IgG 2b antibody which in vitro can activate both helper and cytolytic T-lymphocytes by binding to the CD3 epsilon subunit of the T-cell receptor complex was tested alone and in combination with Interleukin-2, a growth factor for activated T-cells, for ability to reduce established pulmonary metastases in a murine model. C57BL/6 mice injected iv with a tumor cell suspension of a weakly immunogenic fibrosarcoma, MCA106, were randomly assigned to 1 of 15 treatment groups for intraperitoneal injections with YCD3 (0, 0.1, 1, 10, or 100 micrograms) on Days 3, 5, 7, 10, 12, 17, and 19 or with IL-2 (0, 1000, or 50,000 units bid) on Days 3 through 7, 10 through 12, and 17 through 19. On Day 21 all mice were sacrificed for enumeration of metastases. Pooled splenocytes of three randomly selected mice from each group were assayed for surface expressions of T-cell markers Thy-1, Ly2, and L3T4.

High-dose IL-2 (50,000 units bid) in combination with low-dose YCD3 (1 microgram) reduced metastases 60% (P less than 0.005). YCD3 or IL-2 alone was ineffective. Combined high-dose IL-2 (50,000 units) and high-dose YCD3 (100 micrograms) resulted in 100% mortality. Phenotypically, YCD3 induced a dose-dependent depletion of T-cells from 25 to 2.4% (0.1 to 100 micrograms, respectively). These results suggest potential clinical applicability of low-dose anti-CD3 monoclonal antibody to enhance antitumor efficacy of high-dose IL-2. However, the toxicity of high-dose anti-CD3 and high-dose IL-2 cautions for care in selection of dose.