Clinical effects and toxicity of interleukin-2 in patients with cancer

Abstract

Interleukin-2 (IL-2) is a 15,000 dalton glycoprotein produced naturally by human T-cells during an immune response. IL-2 has been demonstrated to have substantial activity alone or in combination with the adoptive transfer of lymphokine-activated killer cells in murine tumor models. IL-2 derived from both natural (Jurkat human T-cell tumor) and recombinant (Escherichia coli) sources has been studied in Phase I protocols designed to evaluate toxicity in patients with a variety of solid tumors and to ascertain improvement in clinical parameters and immunologic status. A total of 16 patients (7 with acquired immune deficiency syndrome [AIDS] and 9 with non-AIDS malignancies) were treated with Jurkat derived IL-2. The total maximum dose (1.3 X 10(5) U/kg) was limited only by supply of this reagent. A total of 25 patients have been treated with recombinant IL-2 (RIL-2) alone. Dose-limiting toxicity manifested by marked malaise and weight gain was achieved with doses of RIL-2 of 10(6) U/kg as a single bolus or 3000 U/kg/hr. IL-2 could be administered intraperitoneally with similar toxicity. Minimal renal or hepatic toxicity was demonstrated. Hematologic toxicity was limited to mild anemia (25/25), thrombocytopenia (10/25), and marked reversible eosinophilia (15/25). Pronounced weight gain greater than 2 kg (16/25) occurred in most patients, primarily those who received cumulative doses of greater than 1-3 X 10(5) U/kg of IL-2. The weight gain amounted to as much as 10% to 20% of the pretreatment weight over 3 weeks of treatment and limited our ability to give higher doses. Two partial responses (greater than 50% decrease in cross sectional diameters) were seen in two patients with melanoma metastatic to the lung.

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

“…Lymphodepletion is known to enhance the efficacy of adoptively transferred CD8 T cells but renders the host more susceptible to infections. In addition, IL-2 treatment is known to cause severe dose-limiting toxicities in patients [11]. It is therefore important to determine whether CD8 T cells with a less differentiated phenotype are also more efficient in anti-tumor or anti-viral activity in adoptive transfer models without lymphodepletion, vaccination or cytokine treatment.…”

Interleukin 2-induced increase of vascular permeability without decrease of the intravascular albumin pool

“…The anti-tumour activities of IL-2 are dose and schedule related, as shown in various clinical studies (Rosenberg et al, 1989) and in experimental animals (Rosenberg et al, 1985). However, high-dose IL-2 regimens are limited by substantial toxicity, in particular pulmonary and systemic oedema, decreased systemic resistance, increased cardiac output, hypotension and oliguria mimicking a septic shock-like condition (Lotze et al, 1986;Parkinson, 1988).…”

Thyroid dysfunction can predict response to immunotherapy with interleukin-2 and interferon-2α

“…Documented response rates in renal cell carcinoma and malignant melanoma in patients treated with IL-2, or with combinations of IL-2 and one of the above agents, range from 20-40% Rosenberg et al, 1989). Treatment with IL-2 is associated with a well-documented range of side-effects (Lotze et al, 1986b;Parkinson, 1988;Lotze et al, 1986a Statistical analysis Differences in survival between groups were analysed using a log-rank test. Further statistical analysis of these data was complicated by the fact that patients failing to respond to treatment were withdrawn after two treatment cycles, while those patients responded to treatment continued on study.…”