Il-2 plus g-csf as a mobilization regimen in advanced breast cancer patients receiving high dose chemotherapy: marked expansion of activated t and nk cells with enhanced cytolyt1c activity within the autograft, without compromise of the hematologic engraftment
Cord Blood Stem Cell Transplantation
Administration of IL- with G-CSF to cancer patients may provide a means of better mobilizing immune effector cells into the stem cell graft, in addition to peripheral blood progenitor cells. The activated immune effector cells may act to eliminate malignant cells remaining in the host, as well as purging cancer cells within the graft. Based on this hypothesis, we have initiated a phase I trial of IL-2 (Amgen) and G-CSF administered prior to peripheral blood harvesting in patients with stage 1MB and IV breast cancer, who then proceed to receive STAMP-V chemotherapy, stem cells and G-CSF. Cohorts of patients were to receive IL-2 immediately after stem cell infusion, once we had shown that the IL-2 plus G-CSF dose level was able to mediate rapid engraftment. Control patients received G-CSF alone for mobilization ( + /- IL-2 post-stem cell infusion). A total of 32 patients have been enrolled onto the trial. Of the 22 patients receiving pretransplant IL-2 (1.8-3.6MIU(Amgen|/m2/d), only 5 patients did not mobilize adequate stem cells O2.0 xlO6 CD34/kg). All five of these patients subsequently mobilized poorly with G-CSF alone. The other 17 patients receiving pre-transplant IL-2 engrafted rapidly with a median (rangel of hématologie recovery of; platelets >20K at day 9 (8-11); >50K at day 14 (9-26); ANC>500/ul at day 10 (8-12); and hospital discharge at day 12 (9-16) which compared favorably to those receiving G-CSF alone for mobilization. Only a single patient (one of those who mobitized poorly) died of transplant-related toxicity (VOD). Patients! 17) mobilized with IL-2 plus G-CSF had greater number of mononuclear cells (20.6 vs. 10.2 x10 /kg ) compared to those (9) receiving G-CSF alone for mobilization, but fewer CD34+ progenitor cells ( 9.8 vs 31.0 x10 /kg ). IL-2 + G-CSF mobilized patients (11) had far greater numbers of activated T cellsJCD3/CD25 + ) (470 vs. 36 xlO /kg ), NK cells (CD56 + M837 vs 151 x10°/kg.|, and activated NK cells (CD56 bright-)-) (282 vs. 22 xlO /kg ) than those patients (5) mobilized with G-CSF alone. In addition, both NK and LAK cytolytic activity was markedly enhanced compared to baseline in the grafts of those mobilized with IL-2 + G-CSF from 43 to 297 NK LU/107 and from 10.2 to 40.7 LAK LU/107, while those mobilized with G-CSF actually had a decline in LU activity. The trial is now being completed with Chiron IL-2, the commercially available form. Studies of changes in minimal residual disease within the BM, blood, and graft are ongoing Overall, these results demonstrate that IL-2 as a component of the mobilization regimen with G-CSF can enhance the number and function of anti-tumor immune effector cells within the autograft without significantly impairing the hématologie engraftment.