TUFTS Management Fellow Interns at NIEHS

Interferon-alpha (IFN-a) and interleukin-2 (IL-2) are cytokines with a variety of immune effects that suggest they might be useful anticancer agents. Indeed, antitumor responses to IFN-a or IL-2 have been documented in various types of experimental and human malignancies, especially renal-cell carcinoma and malignant melanoma. Published clinical trials of IFN-alpha and IL-2 in these cancers have reported response rates in the order of 20% (for a review see Foon, 1989). IL-2 therapy is generally administered by i.v. bolus or continuous infusion at doses of 18 million IU m2 day or higher. Because of the severity of adverse reactions, these high-dose i.v. regimens require continous monitoring or even the admission of patients to intensive-care units (Rosenberg et al., 1988a; Lee R.E. et al., 1989). Some preclinical data have documented that the combination of IFN-a and IL-2 produces a better antitumour activity with respect to the single agent (Cameron et al., 1988; ligo et al., 1988; Rosenberg et al., 1988b). The mechanism of this synergism is unknown. One hypothesis is that IFN-a up-regulates the expression of MHC class I and class II antigens (Faltynek & Oppenheim, 1988; Goldstein et al., 1989) and that the response to IL-2 treatment appears to be strictly related to the expression of these antigens (Atzpodien et al., 1990a). Based on these data some investigators have conducted clinical trials using reduced doses of IL-2 in combination with IFN (Rosenberg et al., 1989). Recent studies (Lee K.H. et al., 1989; Atzpodien et al., 1990b; Pichert et al., 1991) have confirmed that cytokine combination regimens with IL-2 doses in the range of 3 to 9 million IU m2 day and IFN-a are associated with manageable toxicity and are at least as effective as more toxic high-dose IL-2 regimens. Here we describe a regimen consisting of weekly sequential administration of i.m. IFN-a and varying IL-2 doses. Our primary aim was to verify if IL-2 doses lower than those used so far are still able to induce immunologic effects. Twelve patients with histologically confirmed cancer refractory to standard therapy or for which no effective standard therapy is available were included in the study (Table I). All patients had clinically measurable disease, no chemo/ hormonal/radio or immunotherapy within 4 weeks prior to study entry, no evidence of brain metastasis. The protocol