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R24 is a monoclonal antibody that recognizes the disialoganglioside GD3 expressed on the surface of malignant melanoma cells. Once bound, it can mediate destruction of these cells through both complement-mediated lysis and antibody-dependent cellular cytotoxicity. Agents such as interleukin 2 (IL-2), which can augment effector cell function and promote destruction of antibody-coated tumor cells, might produce improved antitumor responses when combined with R24. In this series, we evaluated the combination of R24 and IL-2 in a Phase 1b study in patients with metastatic melanoma. Twenty-eight patients with metastatic melanoma were entered into the protocol at two institutions. Patients received 8 weeks of IL-2 by continuous i.v. infusion at a dose (4.5 x 10(5) Amgen units/m2/day) designed to selectively expand natural killer (NK) cells. In weeks 5 and 6, patients received R24 for a total of four doses. Twenty-four h after each R24 infusion, patients received a 2-h bolus dose of IL-2 to help promote activity of NK effectors against antibody-coated melanoma targets. Additional IL-2 boluses were administered in weeks 7 and 8. Doses were escalated through two bolus doses of R24 (5 or 15 mg/m2) and two bolus doses of IL-2 (2.5 or 5.0 x 10(5) units/m2). Although one patient experienced severe capillary leak syndrome during IL-2, therapy was otherwise well tolerated. At the higher dose level of R24, two of four patients experienced transient but severe abdominal and chest discomfort, necessitating dose reduction. One patient with ocular melanoma and liver metastases had a partial response. Two additional patients had minor responses. A dramatic increase in NK cell number was noted as a result of treatment, as was augmentation of cytolytic activity against cultured NK-sensitive targets. Antibody-dependent cellular cytotoxicity against cultured melanoma cells in the presence of exogenous R24 or in the presence of serum obtained from patients following R24 infusion also increased during treatment. Our experience indicates that R24 and low-dose IL-2 can be safely combined in patients with metastatic melanoma and that this combination can promote destruction of cultured melanoma cells. The clinical activity of this combination against ocular melanoma may merit further investigation.

Interleukin 2 (IL-2) administered at low doses for prolonged periods can markedly expand the number of CD56(+) natural killer (NK) cells in patients with metastatic cancer. The cytotoxic capacity of NK cells obtained from patients receiving IL-2 in vivo can be dramatically augmented by additional exposure to IL-2 in vitro. These observations formed the basis of a clinical trial in which patients with metastatic cancer were treated with low-dose continuous daily infusions of IL-2 to increase the number of their NK cells in conjunction with intermittent boluses of additional IL-2 to stimulate this expanded pool of cytotoxic cells. Twenty-three patients were registered to receive IL-2 at 4.5 x 10(5) units/m2/day for 8 weeks by continuous i.v. infusion. After 4 weeks of "priming" with low-dose continuous infusion IL-2, cohorts of three to five patients received 5 weekly 2-h boluses of IL-2 at doses ranging from 2.5 x 10(5) units/m2 to 1.0 x 10(6) units/m2. Low-dose continuous infusion IL-2 was usually well tolerated; 2-h bolus infusions of IL-2 were often associated with high fevers and constitutional symptoms that resolved after several hours. Low-dose continuous infusion IL-2 resulted in the progressive expansion of circulating CD56(+)CD3(-) NK cells. In contrast, each bolus infusion of IL-2 resulted in an immediate dramatic decrease in both the number of NK cells and activated T lymphocytes with recovery noted within 24 h. Bolus doses of IL-2 as low as 2.5 x 10(5) units/m2 were capable of producing these effects. Cytolytic activity against NK-sensitive and -resistant targets correlated with the presence of circulating activated NK cells. Our results demonstrate that NK cells expanded by low-dose continuous infusions of IL-2 can be further activated in vivo by exposure to very low doses of IL-2 as a 2-h i.v. bolus. This capacity to manipulate human NK cells in vivo through varying the dose and schedule of IL-2 administration may help in defining the therapeutic potential of these cytotoxic effectors in the treatment of both neoplastic and infectious diseases.