Early Infusion Of Donor-Derived CIK Cells As Consolidative Immunotherapy Following Non-Myeloablative Allogeneic Transplantation: Safety and Feasibility

Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative option for patients with Myelodysplastic syndromes (MDS). MDS is primarily a disease of older patients for whom ablative allo HCT is often not feasible. We have treated patients greater than 50 years with high risk MDS with a non-myeloablative conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (ATG) and have found very low incidences of acute graft versus host disease (GVHD) and non-relapse mortality (NRM). Relapse remains the main cause of treatment failure. We initiated a combined phase I/II trial of prophylactic post-transplantation infusion of donor-derived Cytokine Induced Killer (CIK) cells as consolidative therapy after TLI-ATG conditioning for patients with MDS. CIK cells are ex vivo expanded CD3⁺CD8⁺NKG2D⁺ cells that are cytotoxic to multiple cancers in vitro yet appear not to cause GVHD. A previous Phase I/II trial of CIK infusions for patients with relapsed malignancy after allogeneic HCT demonstrated that matched-related donor derived CIK cells, at a dose of 1x10⁸ CD3+ cells/kg was well tolerated¹. The MTD of unrelated donor derived CIK cells was unknown. Four patients were treated on a Phase I dose escalation trial of unrelated donor derived CIK cells. Expansion of unrelated donor cells was feasible and there were no infusional toxicities or adverse events at any CIK dose tested. Fourteen patients, including 9 with unrelated donors, were treated on a Phase II trial of prophylactic CIK infusion with a goal dose of 1 x 10⁸ CD3⁺ cells/kg. The median age was 60 years (range 54-69). Three patients had prior evolution to AML. Two patients did not receive CIK cells because the CD34⁺ cell dose from unrelated donors did not meet the pre-specified threshold for culture inoculation. One patient did not receive CIK cells because of active uncontrolled infection at the time of scheduled CIK cell infusion. The remaining 11 patients received the target dose of 1x10^8 CD3⁺cells/kg between days 21 and 35 post PBSC infusion. The median CD3⁺ and CD3⁺ CD8⁺ NKG2D⁺ cell content of the bulk cultures was 96% (range 70-99%) and 63 (13.6-81%), respectively. The median follow up time of living patients is 264 days. There were no infusional toxicities and no patient experienced acute GVHD grades II-IV. There has been no NRM. Of the 11 patients treated on the Phase II trial and that received CIK cells, 3 patients relapsed (at days 74, 147, and 174) and two patients with relapse died. Two year actuarial relapse free survival (RFS) and overall survival (OS) was 62% and 71%, respectively, which compares favorably to our experience without allo CIK after TLI-ATG (2-year RFS 38% and OS 41%). All three of the patients that did not receive CIK cells died; two of relapse, and one of GVHD at day 195. Therefore, by intention-to-treat analysis of all 14 patients, the 2-year actuarial RFS and OS was 52% and 65%. In summary, allo CIK cells administered early in the post-transplant period appear to be safe without increasing the risk of acute GVHD. Further, the infusion of allo CIK cells may improve outcome although additional patients and further follow-up are needed.