Immune modulation in autologous bone marrow transplantation: cyclosporine and gamma-interferon trial

Abstract

Summary:From March 1994 to November 1994, 16 patients with high risk hematological malignancies were entered in a phase I clinical trial, designed to confirm the toxicity of cyclosporine and gamma interferon given to induce autologous graft-versus-host disease (GVHD) after autologous bone marrow transplantation (ABMT). This trial was based on the results in a rodent model, in which cyclosporine given after ABMT induces an autoimmune syndrome (autologous GVHD) identical to allogeneic GVHD. Further, this autologous GVHD is associated with a graft-versus-tumor effect augmented by interferon that upregulates MHC class II expression on normal and tumor cells, the target of the cytolytic T cells in autologous GVHD. In this trial, cyclosporine 1 mg/kg/day was given from the day of bone marrow reinfusion until the completion of the interferon and gamma-interferon. Gamma-interferon at 0.025 mg/m 2 every other day was started when the total white cell count was Ͼ200 cells/ml for 2 consecutive days and continued for a total of 10 doses after ABMT. The preparative regimens were busulfan and cyclophosphamide, or cyclophosphamide with total body irradiation. All patients received 4HC-purged marrow grafts. Median age was 45 years (range 19-68). The diagnoses included chemo-resistant non-Hodgkin's lymphoma (10), acute lymphoblastic leukemia (two), chemo-resistant Hodgkin's disease (two), acute myeloid leukemia (one), and multiple myeloma (one). Median absolute neutrophil count recovery was 25.5 days (range 19-46 days). Median platelet count recovery was 40.5 days (range 28-279 days). There were nine deaths, two were related to transplant toxicity (infection), while the other seven were due to relapse. Event-free survival with a median of 964 days (range 19-1441 days of follow-up was 44%. In conclusion, treatment with cyclosporine, and gammainterferon after ABMT was well tolerated and did not impair engraftment. Further studies with a larger number of patients are required to document any beneficial anti-tumor effect of autologous GVHD induction after ABMT.

Autologous graft-versus-host disease: harnessing anti-tumor immunity through impaired self-tolerance

“…Vogelsang et al 24 investigated the effect of marrow purging on auto-GVHD. Sixteen high-risk hematologic malignancy patients were conditioned with either Bu-Cy or Cy-TBI followed by infusion of 4-HC-purged bone marrow and then were given CsA 1 mg/kg/day as well as IFN-g 0.025 mg/m 2 every other day for 10 doses after early engraftment.…”

“…10,14,19,21,22,24,26 Auto-GVHD generally appears within the first several weeks after auto-HCT, typically manifesting as a localized or more generalized erythematous maculopapular rash involving the face, trunk, extremities, palms and soles. The histopathologic appearance is inseparable from classic acute GVHD and rarely is greater than grade II in appearance.…”

“…Phase I and II studies were performed to evaluate the potential efficacy of post transplant immune modulation using CsA with or without IFN-g to induce auto-GVHD. 10,14,[21][22][23][24][25][26] We will review these data from a clinical and mechanistic perspective and speculate as to how auto-GVHD might be more effectively harnessed in future clinical trials.…”

Randomized trial of low-dose interleukin-2 vs cyclosporine A and interferon-γ after high-dose chemotherapy with peripheral blood progenitor support in women with high-risk primary breast cancer

“…8 Several studies, both preclinical and clinical, have demonstrated that a syndrome similar to GVHD can in fact be induced in the autologous setting by using immunomodulation. [9][10][11][12][13][14][15][16][17][18] Based on this work, we tested the effect of two methods of immunotherapy following HDC with SCS in high-risk primary breast cancer. We hypothesized that the addition of immunomodulation would improve DFS when compared with historical controls.…”

Enhancement of cyclosporin A-induced autologous graft-versus-host disease after peripheral blood stem cell transplantation by utilizing selected CD34+ cells

“…10,11 Several clinical trials in patients with hematologic malignancies suggest that the induction of autologous GVHD can reduce relapse rate. [12][13][14][15] Disease-free survival among lymphoma patients who develop autologous GVHD is higher than in those who do not develop this autoaggression syndrome. 14,15 Autologous GVHD can be induced in 70-80% of autologous bone marrow (BM) recipients by administration of CsA in the early post autologous SCT period.…”