COMBINATION THERAPY WITH INTERLEUKIN-2 AND ANTITUMOR MONOCLONAL-ANTIBODIES

PURPOSE Administration of recombinant interleukin-a (rIL-2) causes act ivation of natural killer (NK) cells, which express CD16, the Fc recep tor gamma III (Fc gamma III), and can mediate antibody-dependent cellu lar cytotoxicity (ADCC). In an effort to generate a more directed anti tumor response by rIL-2-activated NK cells, we have investigated combi nation therapy with rIL-2 plus the antitumor monoclonal antibody(mAb) 14.G2A and its molecular derivatives, which react strongly with the GD 2 ganglioside expressed on melanoma, neuroblastoma, and certain other tumors. PATIENTS AND METHODS The initial trial of this therapeutic str ategy involved 33 evaluable neuroblastoma patients who received rIL-2 by continuous intravenous infusion in combination with the murine 14.G 2A mAb. A follow-up phase I study was conducted in 24 evaluable adult melanoma patients with a mouse/human chimeric mAb (ch14.18), The ch14. 18 mAb has subsequently been investigated in combination with rIL-2 an d granulocyte-macrophage colony-stimulating factor in neuroblastoma pa tients following autologous bone marrow transplantation. Based on prec linical data, the administration of rIL-2 plus mAbs may be more effect ive in patients with minimal residual disease. An alternative strategy to induce ADCC has also been investigated because of the finding that many NK cells fail to express Fc gamma III. The IL-2-ch14.18 fusion p rotein has been tested in preclinical studies for its ability to induc e an effective antitumor response and is currently being evaluated for future clinical testing, RESULTS Based on in vitro assays, the serum of patients treated with rIL-2 plus either 14.G2A or ch14.18 mAbs demo nstrated sufficient levels of antibody and NK cell activity to mediate effective ADCC; however, many patients developed antibodies against t he administered murine and chimeric mAbs, leading to allergic complica tions. Concurrent administration of rIL-2 and ch14.18 resulted in a lo wer incidence of anti-ch14.18 antibodies. The IL-2-ch14.18 fusion prot ein has demonstrated dramatic antitumor effects in murine models. DISC USSION These studies have demonstrated the feasibility of concurrent a dministration of rIL-2 with the mouse/human chimeric ch14.18 mAb. Alth ough the early pilot studies were conducted in patients with bulky dis seminated disease, this approach may be more effective in patients wit h minimal residual disease. Further refinement of the reagents and pha se II and III trials will be necessary to evaulate fully the safety an d efficacy of this immunotherapeutic approach.