Repetitive Infusions of Cytokine-Induced Killer (CIK) Cells for Treatment of Impending Relapse in High-Risk Leukemia Patients after Allogeneic Stem Cell Transplantation

Introduction:

Allogeneic stem cell transplantation (SCT) is an established treatment option for patients with high-risk leukemias. But the success of this approach is still limited by patients’ relapse. Evidence was presented, that minimal residual disease (MRD) status in principle could be treated by donor lymphocyte infusion (DLI). However, T cells within DLI raise the risk for severe graft versus host disease (GvHD). Cytokine-induced killer (CIK) cells, mainly T cells sharing in part characteristics of natural killer (NK) cells, demonstrated potent non major histocompatibility complex (MHC)-restricted cytotoxicity against hematological malignancies, but displayed negligible alloreactivity in vitro and caused minimal GvHD in vivo.

Here, we report our single center experience of repetitive, dose-escalating CIK cell infusions in 12 leukemia patients with impending (n=10) or overt relapse (n=2) after allogeneic SCT.

Patients and Methods:

Between August 11, 2011 and July 31, 2014 CIK cell infusions approved by the regulatory authorities (Regierungspräsidium Darmstadt, Germany) were given repetitively on compassionate used basis to 12 patients (<18 years of age, n=11, median age 9, range 1-16 years; >18 years of age, n=1, age 69 years) with haematological malignancies (AML, n=6; ALL, n=5; CML, n=1) and evidence of relapse in the absence of acute GvHD >grade I after allogeneic SCT. CIK cells obtained from peripheral blood mononuclear cells of original stem cell donors were generated within 10 days under good manufacturing practice (GMP)-conditions in the presence of interferong, anti-CD3 antibody, interleukin-2 and -15.

Results:

Altogether 53 CIK cell infusions (median number 3.5, range 1-10 per patient) from matched unrelated (n=6) or haploidentical (n=6) stem cell donors were offered at a minimum of three weeks after allogeneic SCT and an interval of 4-6 weeks between infusions (median follow up after 1^st CIK cell infusion 8, range 3-22 months). Patients with overt relapse underwent cytoreductive chemotherapy before infusions. Based on our cumulative experience starting doses of CIK cell infusions were 5x10⁶ CD3⁺CD56^- CIK cells/kg in pediatric and 1x10⁶ CD3⁺CD56^- CIK cells/kg in adult patients. Regardless of donor type, dose escalation continued until a maximal dose of 100x10⁶ CD3⁺CD56^- CIK cells/kg was reached(median dose 10x10⁶, range 0.1-100x10⁶ CD3⁺CD56^- CIK cells/kg). Acute GvHD grade I occurred in two patients after infusions of 1x10⁶ or 5x10⁶ CD3⁺CD56^- CIK cells/kg. Another two patients developed acute GvHD grade III after infusion of 10x10⁶ CD3⁺CD56^-CIK cells/kg, respectively. In 3 patients with relapsed AML CIK cell infusions provided transient remission, but ultimately all three patients relapsed and succumbed to their diseases 8-9 months after first CIK cell infusion. Two patients with ALL and one patient with AML relapsed 2, 5, and 12 months after first CIK cell infusion, respectively. All patients were offered further anti-leukemic treatment including allogeneic SCT. Two AML patients died due to infections 9 and 12 months after the last CIK cell infusion. Both patients were in complete remission at the time of death. Three high-risk patients with ALL and one CML-patient with impending relapse indicated by MRD or BCR/ABL are still in complete remission.

Conclusion:

In conclusion, allogeneic CIK cell infusions seemed to be very promising and may improve cell-based immune therapies especially in leukemia patients with impending relapse after allogeneic SCT.