A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission.

BACKGROUND AIMS: Cytokine-induced killer (CIK) cells have shown remarkable cytotoxicity against various tumors in vitro and in animal studies. We report on the clinical outcome of autologous CIK cells for patients with acute (AML) and chronic (CML) myeloid leukemia in remission. METHODS: Eleven of the 13 recruited AML patients undergoing autologous peripheral blood stem cell transplant (autoPBSCT) were given autologous CIK cell infusion upon engraftment post-transplant and followed-up for disease relapse. Eleven CML patients on Imatinib with residual disease detectable by polymerase chain reaction (PCR) were given infusion and monitored by quantitation of the bcr-abl transcript. RESULTS: Despite the presence of interferon (IFN)-γ-secreting T cells against various AML- and CML-associated peptides at sporadic time-points and demonstration of in vitro cytotoxicity of CIK cells against autologous and allogeneic AML targets, there was no survival benefit in AML patients post-autoPBSCT given CIK cells compared with historical controls. For CML patients, all continued to have a detectable bcr-abl transcript fluctuating within a range comparable to their pre-treatment baseline, although two had a transient but non-sustainable disappearance of bcr-abl transcript. There were no adverse reactions except for fever within the first day of infusion. CONCLUSIONS: Our small series, while confirming safety, failed to demonstrate a clinical benefit of autologous CIK cells given in its current form for AML and CML. Further manipulation of CIK cells to improve anti-leukemic potency and specificity, together with the preparation of patients to create a more conducive milieu for in vivo expansion and persistence of infused CIK cells, should be explored.

CD16 is indispensable for antibody-dependent cellular cytotoxicity by human monocytes.

Antibody-dependent cellular cytotoxicity (ADCC) is exerted by immune cells expressing surface Fcγ receptors (FcγRs) against cells coated with antibody, such as virus-infected or transformed cells. CD16, the FcγRIIIA, is essential for ADCC by NK cells, and is also expressed by a subset of human blood monocytes. We found that human CD16- expressing monocytes have a broad spectrum of ADCC capacities and can kill cancer cell lines, primary leukemic cells and hepatitis B virus-infected cells in the presence of specific antibodies. Engagement of CD16 on monocytes by antibody bound to target cells activated ß2-integrins and induced TNFα secretion. In turn, this induced TNFR expression on the target cells, making them susceptible to TNFα-mediated cell death. Treatment with TLR agonists, DAMPs or cytokines, such as IFNγ, further enhanced ADCC. Monocytes lacking CD16 did not exert ADCC but acquired this property after CD16 expression was induced by either cytokine stimulation or transient transfection. Notably, CD16+ monocytes from patients with leukemia also exerted potent ADCC. Hence, CD16+ monocytes are important effectors of ADCC, suggesting further developments of this property in the context of cellular therapies for cancer and infectious diseases.

Clinical scale expansion of cytokine-induced killer cells is feasible from healthy donors and patients with acute and chronic myeloid leukemia at various stages of therapy.

OBJECTIVE: In our clinical studies involving cytokine-induced killer (CIK) cells for patients with hematological malignancies, starting cells came from a heterogeneous group of patients and donors. Here we study the feasibility of expansion and analyzed the characteristics of the end product from starting cells derived from different sources and at different disease states. MATERIALS AND METHODS: Seventy-five clinical scale cultures were grown from 28 patients and 20 donors in Good Manufacturing Practices facilities under CIK condition. RESULTS: CIK cells could be successfully expanded from healthy donors, patients with acute myeloid leukemia recovering from chemotherapy, untreated patients with acute myeloid leukemia or myelodysplastic syndrome with circulating leukemic blasts, and patients with chronic myeloid leukemia on imatinib. Furthermore, CIK cells of donor origin could be expanded from leukapheresis product collected from patients who relapsed post-allogeneic transplantation, thereby offering a useful method of obtaining activated donor cells in patients for whom further donor cells were unavailable. Interestingly, CIK cells cultured from patients with untreated acute myeloid leukemia and myelodysplastic syndrome had a significantly higher proportion of CD3(+)CD56(+) subset and higher fold expansion of CD3(+) cells as compared to other groups of patients or healthy donors. Multivariate analysis showed that fresh starting cells expanded better than frozen-thawed cells, while prior exposure to granulocyte colony-stimulating factor or imatinib before harvesting did not adversely affect CIK cell expansion. CONCLUSIONS: Clinical scale expansion of CIK cells is feasible from both healthy donors and leukemia patients at various stages of treatment. This robust system allows clinical translation using CIK cells as immunotherapy in various clinical settings.