Interleukin-2 based systemic and locoregional immunology

The major impact of recent clinical research with interleukin-2 (IL2) has been the demonstration that a strictly immunological manipulation can mediate the regression of established cancer in humans through the activation of cytotoxic lymphocytes and the release of secondary cytokines. Since 1985 a variety of clinical studies have been carried out in metastatic cancer patients with the use of interleukins, interferons, and Iymphokine activated killer cells. These studies have either employed a single agent approach or combined modality treatment also including hormonal and chemotherapy. Although the majority of human cancers are systemic diseases by nature, some tumor types are predilected to reside in one organ site or cavity. For example, metastatic colon cancer is often confined to the liver for prolonged periods of time. Ovarian cancer is usually restricted to the abdominal cavity, whereas mesothelioma mostly does not extend the pleural cavity until death. It is for these reasons that the clinical investigations described in this thesis are based on a systemic approach on the one hand and on a locoregional approach on the other hand in selected tumor types. The study treatments comprised single agent IL2 and combinations of IL2 and interferon (IFN)-a with or without chemotherapy. Regarding the systemic administration of IL2 based immunotherapy, we have chosen for a constant infusion schedule rather than intermittent bolus intravenous administration, based on available data in the literature of treatment equivalence and less toxicity accompanied with the continuous infusion method. For the locoregional treatment of liver metastases we have used a continuous arterial infusion method

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic malignant melanoma

The results of cytostatic therapy in metastatic melanoma are very disappointing. In phase II studies with high-dose cisplatin regimens, a remarkably high response rate was observed. In a phase I study with a short course of weekly cisplatin, combined with oral etoposide, we were able to reach, in most patients, a cisplatin dose intensity of 60 mg/m2/week. We performed a phase II study with this schedule in metastatic malignant melanoma. 15 consecutive patients were entered in the study. Treatment consisted of cisplatin 70 mg/m2 on days 1, 8, 15 and days 29, 36, 43 combined with oral etoposide 50 mg daily, days 1-15 and days 29-43. Patients with a response or stable disease continued treatment with oral etoposide 50 mg/m2 daily, days 1-21 every 4 weeks. All patients were evaluable for response and toxicity. The majority of the patients received six cycles of cisplatin with the planned cisplatin dose intensity of 60 mg/m2/week. A partial response was observed in 2 patients (13%; 95% confidence interval (CI) 2-44%) of, respectively, 22 and 12 weeks; stable disease was observed in 6 patients. Toxicity consisted mainly of alopecia and bone marrow suppression. 4 patients had tinnitus, one patient had neurotoxicity grade 1. The regimen studied has only limited activity in metastatic melanoma in spite of the high-dose intensity of cisplatin reached with this schedule

High-dose regimen of interleukin-2 and interferon-alpha in combination with lymphokine-activated killer cells in patients with metastatic renal cell cancer

Seventy-two patients with metastatic renal cell cancer were treated with the combination of high-dose interleukin-2 (IL2), interferon-alpha (IFNa), and lymphokine-ac