Adoptive immunotherapy with tumor-cytotoxic macrophages derived from recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) mobilized peripheral blood monocytes

Abstract

We examined the mobilization of blood monocytes (MO) with recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) with regard to the in vitro generation of MO-derived tumor-cytotoxic macrophages (MAC) for use in adoptive immunotherapy of cancer patients. Eleven patients with progressing metastatic cancer received interferon (IFN)-gamma activated tumor-cytotoxic MAC generated in vitro from autologous MO with and without pretreatment with rhuGM-CSF. RhuGM-CSF was administered subcutaneously at 10 micrograms/kg for 7 days. RhuGM-CSF treatment and adoptive cell transfer were well tolerated, and no toxicity greater than WHO II degrees occurred. Fever was the most common side effect and was seen in all patients during rhuGM-CSF treatment and during 9 of 22 MAC therapies. Bone pain was noted in 5 of 11 patients during rhuGM-CSF therapy. RhuGM-CSF treatment led to a continuous increase in the white blood cell counts and the number of MO within the leukapheresis products. The mean number of transfused MAC was 0.9 x 10(9) without rhuGM-CSF pretreatment and 1.9 x 10(9) after rhuGM-CSF administration. The maximum number of MAC that could be generated was 7.3 x 10(9), but after a dose escalation protocol only up to 2.7 x 10(9) MAC were transfused. Cytotoxicity against U937 cells increased during MO to MAC differentiation, but was decreased in both MO and MAC on treatment with rhuGM-CSF. This study proves the feasibility of reinfusing MAC generated in vitro from rhuGM-CSF mobilized MO.