A phase I trial of autologous cytokine-induced killer cells for the treatment of relapsed Hodgkin disease and non-Hodgkin lymphoma.
We have previously reported on the ex vivo generation of cytotoxic effector cells, termed cytokine-induced killer (CIK) cells, that have both in vitro and in vivo antitumor activity in murine models. We now report on our efforts for the large-scale expansion of CIK cells and also present preliminary results from a phase I clinical trial. Nine patients with advanced Hodgkin disease (n = 7) and non-Hodgkin lymphoma (n = 2), all of whom had relapsed after an autologous transplantation, were treated with escalating doses of CIK cells (3 patients at each dose level of 1 x 10(9) , 5 x 10(9) , or 1 x 10(10) cells). The CIK cells were produced by culturing unselected cells from steady-state apheresis products with interferon gamma, OKT3, and interleukin 2. After 21 days in culture, with the addition of fresh media and interleukin 2 every 3 to 4 days, the median culture was 97% viable (range, 61%-100%), 98% CD3 + (range, 66%-99%), 76% CD8 + (range, 27%-96%), 23% CD4 + (range, 6%-78%), 20% CD3 + CD56 + (range, 8%-58%), and <1% CD16 + 56 + (range, 0.2%-7.7%). The CD3 + CD56 + cells have previously been shown to exhibit the most cytotoxic activity. The absolute number of CD3 + CD56 + cells typically expanded 290-fold (range, 3- to 4000-fold) under these culture conditions. In vitro cytotoxic activity was measured against a human B-cell tumor line (OCI-Ly8). At a 40:1 effector-target cell ratio, CIK cells killed 32% (range, 2%-69%) of the target cells. A total of 21 infusions were administered to 9 patients. The number of CIK cells infused ranged from 1.0 x 10(9) to 1.0 x 10(10) per treatment. Toxicity was minimal, and there were no immediate adverse reactions to the infusions. Two patients had partial responses, and 2 patients had stabilization of disease: 1 for more than 18 months. Considering that these were heavily pretreated patients with advanced hematologic malignancies, we believe that CIK cells expanded in this fashion may have utility for the treatment of high-risk patients with evidence of minimal residual disease after autologous transplantation.
Leemhuis
Thomas
T
Division of Bone Marrow Transplantation, Stanford University Medical Center, California, USA.
Wells
Sandra
S
Scheffold
Christian
C
Edinger
Matthias
M
Negrin
Robert S
RS
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D006689:Hodgkin Disease / Q000150:complications / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000637:transplantation*; D017710:Lymphocyte Transfusion / Q000009:adverse effects / Q000379:methods; D008228:Lymphoma, Non-Hodgkin / Q000150:complications / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D016879:Salvage Therapy / Q000379:methods; D014182:Transplantation, Autologous; D016896:Treatment Outcome
D015703:Antigens, CD