IL-2 activated cell-mediated immunotherapy: Control of minimal residual disease in malignant disorders by allogeneic lymphocytes and IL-2

The present experiments were designed to investigate whether it might be possible to combine ther therapeutic benefits of autologous BMT and allogeneic BMT following administration of T-lymphocyte deplete marrow allografts with additional immunotherapy following BMT. The tumor model used for investigating graft vs leukemia (GVL) effects was the muring B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. Immunotherapy with high dose recombinant human interleukin-2 (IL2) (10⁵ Cetus units x 3/day intraperitoneally (IP) for 5 days) produced significant anti-tumor effects in BCL1-bearing mice. BALB/c mice inoculated with 10³ BCL1 leukemia cells received were treated on day -1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. Highdose IL2 (100,000 Cetus Units x 3/day IP x 5 consecutive days) was initiated on day +1, +7, or +21 following BMT. Optimal time for administration of IL2 was noted at 3 weeks post-BMT with 90% of the mice surviving with no evidence of disease >1 year. An experimental model designed to study GVL effects in a state of minimal residual disease following T-cell depleted allogeneic BMT indicated that mice receiving low dose of BCL1 challenge (10⁴) were successfully treated by either IL2 (2x10⁴ Cetus units x 2/day IP x 3 days), allogeneic spleen cells (10⁶ on day +1, 10⁷ on day +5 and 5x10⁷ on day +9) alone and certainly following a combination of both. Mice inoculated with 10⁵ BCL1 cells following BMT developed leukemia after IL2 treatment alone, but remained disease-free following administration of allogneneic spleen cells or both allogeneic spleen cells and IL2. In contrast, mice inoculatd with a high dose of BCL1 (10⁶) showed no longterm antileukemia effects following combination of IL2 and allogeneic spleen cells. Our data suggests that allogeneic immunocompetent lymphocytes may be used as a therapeutic tool against leukemic relapse even following initial reconstitution with T cell depleted bone marrow allograft in minimal residual disease state and that these GVL effects mediated by allogeneic lymphocytes may be augmented by IL2. A similar approach may prove beneficial in conjunction with autologous and allogeneic BMT in man as long as GVHD may be prevented or controlled.