This trial was designed to explore the immunomodulatory effects of poly ICLC in combination with IL-2, and to determine a dose combination with maximal immune augmentation consistent with tolerable toxicity. Poly ICLC is one of a family of polyribonucleotides originally studied in humans for the interferon-inducing and antiproliferative activities previously observed in animal studies. Poly ICLC is a prototypical biological response modifier which has such potent and reproducible immune and antitumor effects in animal models that it is routinely used as the positive control agent against which new immunomodulators and cytokines are compared. In prior clinical studies, no optimal immunomodulatory dose was determined and most studies have concentrated on determining maximum tolerated doses and doses which were capable of inducing interferon. In fact, no evidence has been seen for consistent antitumor effects at maximally tolerated doses. Experimental animal data, however, suggest that the maximum tolerated dose is neither the optimal biologic dose nor the optimal immunotherapeutic dose, both of which are considerably lower than the MTD. In this study, poly ICLC doses below the MTD are explored to evaluate immunomodulatory effects and search for antitumor activity. Poly ICLC is given initially alone and subsequently in combination with IL-2. The IL-2 regimen employs twice weekly administration by 24-hour continuous infusion using a (moderate) dose of 3 million units/m2 which has previously been shown to generate circulating endogenous LAK activity and to be well tolerated for long periods of outpatient administration. Patients first receive poly ICLC intramuscularly as a single agent for one month. In subsequent 1-month cycles, poly ICLC is given IM b.i.w., together with IL-2 twice weekly. Cohorts of patients receive fixed poly ICLC doses below the known MTD to search for an optimum immunomodulatory dose.
