A new approach to generating antitumor effectors for adoptive immunotherapy using human adherent lymphokine-activated...

Lymphocytes from human peripheral blood incubated with interleukin-2 (IL2) develop lymphokine-activated killer (LAK) activity with the ability to kill a wide variety of tumor cells in a non-major histocompatibility complex-restricted manner. Adoptive immunotherapy with LAK cells and IL2 has been reported to lead to a regression of solid tumors in some patients with advanced malignancies. Aiming to improve the effectiveness of clinical adoptive immunotherapy, we developed a procedure for selective enrichment from human blood mononuclear cells (MNC) of IL2-activated antitumor effector cells. These cells, termed adherent LAK (A-LAK) cells because of their characteristic property of adherence to plastic, demonstrated both higher proliferative potential and greater antitumor cytotoxicity than unseparated MNC. Human A-LAK cells represented only 1 to 4% of IL2-activated MNC at 24 h but expanded from 130- to 1100-fold in 20 days. They comprised a population highly enriched in CD3-Leu19+ effector cells with antitumor activity against fresh human solid tumor cells and established cell lines. A-LAK cells retained antitumor activity for up to 14 days when cultured in the presence of IL2. They also mediated antibody-dependent cytotoxicity. Large-scale generation of A-LAK cells from the blood of patients with cancer proved feasible and should yield populations that are effective in vivo at lower doses than those required with unseparated LAK cells. This offers the potential for improving the antitumor effects, reducing the toxicity, and facilitating the administration of adoptive immunotherapy in humans. A Phase I/II clinical trial utilizing A-LAK cells and IL2 in patients with melanoma and renal cell carcinoma is now in progress.