Clinical expansion of cytokine induced killer (CIK) cells

Abstract

Cytokine induced killer (CIK) cells are polyclonal T cells that can be expanded from marrow or peripheral blood lymphocytes with potent non‐MHC‐restricted cytotoxicity against a variety of tumor target cells. Earlier work had established the superiority of CIK cells over LAK cells in terms expansion and cytotoxicity. It has been studied extensively both in vitro and in murine experiments with promising killing activity against a wide range of haematological malignancies. Early clinical trials of CIK cells have reported safety and feasibility data as well as possible efficacy and have provided the framework for further clinical studies. As a robust and easily expandable cell population, its role in clinical adoptive immunotherapy should be investigated for translation into a good manufacturing practice (GMP) manufacturing process. Large scale culture to generate adequate number of CIK cells for clinical use involves up‐scaling from flasks to culture bags carried out in a GMP compliant cell therapy facility, use of GMP compliant materials and reagents, efficient harvesting procedures to remove foreign elements and strict release criteria with respect to viability, sterility and potency of the product. All the steps should preferably to be done in a closed system, in order to minimize the chance of contamination. A phase I/II clinical study on the use of allogeneic CIK cells has been conducted to define the role of CIK cells in the management of relapse post stem cell transplant with the aim of looking at feasibility of GMP expansion, toxicity and efficacy. A separate trial looking at autologous CIK cells was also conducted. Allogeneic CIK cells were successfully generated for a total of 24 patients including from patients’ own leukepheresed cells in 5 patients who have no access to further donor cells. The median CD3 + T cell expansion was 9·33 (1·3–38·97) fold and CD3 + CD56 + NK‐like T cells expansion was 27·77 (2·59–438·93) fold. CIK cells were infused into 16 patients who have either failed or progressed after initial response to various individualized chemotherapy regimen and donor lymphocyte infusion (DLI), for a total of 55 infusions at doses ranging from 10 to 200 million CD3/kg. Evidence of efficacy as defined by a demonstrable response attributable to CIK cell infusion was observed in five patients with minimal toxicity. Other published examples to augment CIK efficacy include co‐culture of CIK with myeloma idiotype or CA19‐9 peptide‐pulsed autologous dendritic cells. Redirecting CIK cells by bispecific antibodies to target has been shown for ovarian carcinoma and B cell lymphoma, as well as B cell ALL by engineering CIK cells to express anti‐CD19 receptor. Exploiting the heterogeneous subsets within the bulk CIK cell culture is another avenue for enhancing its potency.