Use of recombinant human interleukin-2 in conjunction with syngeneic bone marrow transplantation in mice as a model for control of minimal residual disease in malignant hematologic disorders

Abstract

Unlike allogeneic bone marrow transplantation (BMT), autologous BMT is not accompanied by immune-mediated graft-versus-leukemia (GVL) effects; hence, the relapse rate observed after autologous BMT in malignant hematologic disorders is higher than that observed after allogeneic BMT. Autologous BMT represents a much safer medical procedure available for many patients in need in situations where allogeneic BMT is not feasible or risky. The present experiments were designed to investigate whether it might be possible to combine the therapeutic benefits of autologous BMT with additional immunotherapy after BMT. The tumor model used for investigating GVL effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. BALB/c mice inoculated with 10(3) BCL1 leukemia cells were treated on day-1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. High-dose recombinant interleukin-2 (rIL-2) (100,000 Cetus units x 3/day intraperitoneally x 5 consecutive days) was initiated on day +1, +7, or +21 after BMT. Kinetics of lymphocyte reconstitution after syngeneic BMT indicated a steep increase in the absolute number of peripheral blood lymphocytes on days 17 through 24. All experimental groups were observed for relapse. Mice receiving no rIL-2 therapy relapsed and died within 50 days after BMT, whereas mice receiving rIL-2 showed long-term disease-free survival. Optimal time for administration of rIL-2 was noted at 3 weeks post-BMT, with 90% of the mice surviving with no evidence of disease for more than 1 year. Similarly, when 10(4) BCL1 cells were given 1 day after syngeneic BMT to simulate minimal residual disease after syngeneic BMT, rIL-2 therapy administered at 14 days post-BMT seemed effective in prolonging disease-free survival in contrast to the same regimen given at 1 day after BMT. Our data suggest that immunotherapy with rIL-2 should be further investigated as a new immunotherapeutic tool for decreasing the relapse rate after BMT for hematologic malignancies.

Clinical Analysis and Optimization of Post-Remission Therapy for Acute Myeloid Leukemia Patients With Minimal Residual Disease as Determined by Flow Cytometry

“…All of these factors other than sex were previously suggested as unfavorable prognostic factors in Japanese patients. 18 We were obliged to reduce the treatment intensity for 9 and 5 patients in Group A and B, respectively. Allogeneic stem-cell transplantation (allo-SCT) was performed in 6 patients of Group A and 6 of Group B, without statistical significance.…”

Interleukin 2 in the management of acute leukaemia

“…In mice with AML, allotransplants with syngeneic marrows activated in vitro for 24 h with IL2 and followed by further IL2 given immediately after the transplant lead to a GVL effect (Charak et al, 1991). It has also been reported that in a situation of minimal residual disease following murine syngeneic bone marrow transplantation the optimal anti-leukaemic effect is obtained when IL2 is started 2-3 weeks after the transplant (Ackerstein et al, 1991). In allogeneic transplants it has been reported that IL2 may induce allospecific CTL, without aggravating GVHD, in a murine minor histoincompatibility model (Merluzzi et al, 1985).…”

Immunotherapy of multi-drug resistant hematologic malignancies with IL-2-activated intentionally mismatched lymphocytes

“…We have used a spontaneous murine B cell leukemia (BCL1) (9) in an attempt to develop new approaches for improving the anti-cancer effects inducible by naïve donor lymphocytes. First, we documented that even the GvL effects induced by syngeneic donor lymphocytes could be ampli ed by treatment with interleukin 2 (IL-2) (10,11). Similarly, the opportunity to document similar enhancement of GvL effects by IL-2-activated DLI following super-myeloablative conditioning and allogeneic SCT from a fully matched sibling was already con rmed in late 1986 when a patient with fully resistant relapsed ALL following super-myeloablative conditioning was rescued with IL-2 activated DLI after failing to respond to treatment with naïve donor lymphocytes (2,3).…”