Carlo Besana

INTERLEUKIN-2, INTERFERON-ALPHA AND INTERLEUKIN-2 PLUS INTERFERON-ALPHA IN RENAL CELL CARCINOMA. A RANDOMIZED PHASE II TRIAL

Background The purpose of the present study was to investigate the therapeutic effectiveness of interleukin-2 (IL-2) and interferon (IFN), either alone or in combination, in comparable groups of patients affected by advanced renal cell carcinoma (RCC). Patients and methods In order to limit selection biases, treatment was allocated on a random basis. Patients randomized to IL-2 alone were scheduled to receive eight rIL-2 24-hour i.v. infusion cycles, days 1 to 4, at a daily dose of 18 x 106 IU/m2 for a total of 25 weeks. Patients randomized to IFN alone were scheduled to receive rIFN-α at a daily dose of 6 x 106 IU/m2, days 1, 3 and 5, every week for a total of 52 weeks. Patients randomized to the combination of IFN and IL-2 were given the same drugs at the same daily doses for a total of 24 weeks. Drug dose was modified according to toxicity. Results Twenty-three percent (95% CI: ± 17.5) of patients treated with IL-2 alone showed an objective response to treatment (9% CR). The corresponding figures in patients treated with IFN alone or IFN plus IL-2 were 9% (95% CI: ± 11.9) and 9% (95% CI: ± 11.9), respectively. Complete responses were observed only in patients treated with IL-2. The median duration of response in the IL-2 arm was 18 months (range, 9.5-24). The duration of the two responses achieved by IFN alone was seven and nine, months, respectively. The corresponding figures in the two patients responding to the combination of IFN with IL-2 were 19 and 27 months, respectively. Total IL-2 dose appeared to be a major predictor of response. Only a minority of patients experienced grade 3-4 toxicity, the incidence being higher in those treated with IL-2 or IL-2 plus IFN. Conclusions Neither IFN nor IL-2 or the combination of the two appear to be very active in patients with advanced RCC, even when trial entry was restricted to patients with relatively indolent disease. This stresses the need for the development of new approaches.

Treatment of advanced renal cell cancer with sequential intravenous recombinant interleukin-2 and subcutaneous α-interferon

Starting from in vitro studies suggesting synergistic antitumour activity against renal cell cancer (RCC) of recombinant interleukin-2 (rIL-2) and alpha-interferon (IFN), a phase II trial was initiated to test the clinical activity of this combination. The two cytokines were administered sequentially, with the aim of reducing the risk of additive toxicity and enhancing the immunological reaction against the tumour. The original treatment schedule consisted of rIL-2 18 x 10(6) U/m2/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular injection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical response. 12 patients were treated according to this schedule; as some cardiovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m2/day). 17 out of 23 enrolled patients completed at least one cycle of treatment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an objective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 additional patients achieved stabilisation of disease; one of them reached CR after surgical extirpation of a lung mass. Sites of response included lung, nodes and bone. Duration of response is 12+ months for CR; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-dose rIL-2. Considering stable disease (SD) as responses, there seemed to be a higher chance of response for patients with smaller tumour burden (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular, was substantial; 9 patients experienced severe cardiotoxicity, consisting of major arrhythmias, myocardial ischaemia, reduction of ejection fraction measured with heart radionuclide scan, and were excluded from continuing treatment. Other rIL-2-related toxicities forcing exclusion from the study were severe thrombocytopenia (1 case), and generalised exfoliative dermatitis requiring steroids (1 case). Otherwise, treatment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment-related deaths were reported. The half-dose rIL-2 regimen was significantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.014), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and prothrombin time elongation (P = 0.038).(ABSTRACT TRUNCATED AT 400 WORDS)

Role of Interleukin-2 in Regulating Lymphocyte Activation and Recirculation

TO UNDERSTAND better the immunological reactions primed by interleukin-2 (IL-2) in cancer patients we have investigated the biological effects of systemic rIL-2 on the circulating lymphocytes of cancer patients [ 1, 21. We report here immunological tests, either functional or phenotypic, in 8 patients with advanced renal cell carcinoma treated with rIL-2 (18 x lo6 U/m*/day) by continuous intravenous administration for 5 consecutive days. Heparinised blood samples were drawn immediately before starting the first treatment cycle, 24 and 96 h after starting the rIL-2 infusion, and 2 days after the end of the infusion (168 h). Mononuclear cells were obtained by centrifugation over Ficoll gradient and resuspended in RPM1 1640 medium (Biochrom, Berlin, FRG). Phenotypic analysis was performed in a direct, doubie-staining, immunofluorescence assay. During lymphopenia, induced by the IL-2 administration, we observed a progressive decrease in the percentage of theCD3+CD4+ T-lymphocytes, while theCD3+CD8+ subset did not change significantly. Small CD4+ and CDS+ T cells are extracted by high endothelial venules with different efficiency (higher for the CD4+ than for the CD8+ subset) {3] and the rIL-2 infusion seems to emphasise this difference. The hypothesis that the decrease of the CD4+ T cells might be due to increased extravasation, is also sustained by concomitant reduced proliferation of the patients’ peripheral blood mononuclear cells (PBMC) cultured for 3 days with different concentrations of phytohaemaglutinin (PI-IA) or concavalin A (ConA) (Sigma Chemical Co, St. Louis, Missouri). On stopping the rIL-2 infusion, when a rebound lymphocytosis is observed, the percentage of the CD4+ T-lymphocytes, and the capacity of

INTRAPLEURAL ADMINISTRATION OF INTERLEUKIN-2 AND LAK CELLS IN LOCALLY ADVANCED NON-SMALL-CELL LUNG CANCER. A CASE REPORT

Aims and background The systemic administration of recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells is ineffective in non-small-cell lung cancer (NSCLC). However, there is some evidence that their intrapleural administration could be effective, since it increases the concentrations of the cytokine and the effector cells in the tumor area, thereby obtaining greater antitumor activity. Study design We report the case of a patient affected by a locally advanced lung adenocarcinoma with pleural effusion (T4 NO MO – stage 1Mb) treated with repetitive courses consisting of a priming continuous i.v. infusion (48 h) of rIL-2 (18 MIU/m2/day) intraplural administration of LAK cells (3 – 9 × 109/day), in a single daily bolus, for 3 consecutive days and concomitant administration of rlL-2 (1.8-7.2 × 106 IU/day), for 5 days. Results We observed early disappearance of neoplastic cells in the pleural effusion, progressive decrease until disappearance of the pleural effusion, cavitation of the primary lesion during the treatment, and its stabilization for 9 months until progression. Radiologic changes were accompanied by a marked eosinophilia (up to 50 × 109/L), and the intrapleural route of administration of rIL-2 induced a relevant increase in eosinophil count in peripheral blood. Immunologic changes in lymphocyte subpopulation phenotypes were also observed. The performance status of the patient improved, and she was still alive and eupnoic 25 months from the diagnosis and 23 months from the start of treatment. Conclusions This case suggests a therapeutic role for intrapleural rIL-2, and we believe that the relationship among intrapleural administration of rIL-2 and LAK cells, the development of peripheral eosinophilia, and clinical response should be further investigated.

Intensive chemotherapy with recombinant-human granulocyte-macrophage colony stimulating factor (r-hu-gm-csf) for small cell lung cancer (sclc): a pilot study

Systemic chemotherapy is the treatment of choice for patients with small cell lung cancer (sclc), Myelosuppression is the limiting toxicity related to most comnbination regimens in sclc, inducing substantial morbidity, frequent dose reductions, and delay in administrating subsequent cycles. Vp-16, Ifosfamide and Carboplatin are all highly active as single agents against sclc, with a ramge of objective response between 60 % and 75 %, A combination of these 3 drugs (with concurrent chest radiotherapy) showed impressive activity) > 90 % objective response rate) in a previous report by another group (Smith, 1990), at the cost of a 100 % incidence of grade III-IV neutropenia, with 7 % therapyrelated deaths and dose reductions required for 72 % of patients. The association of recombinant human granolocyte-macrophage colony stimulating factor (r-hu-gm-csf) to a chemotherapy regimen consisting of Carboplatin and Vp-16 could allow higher doses of cytotoxic drugs to be given, possibly resulting in much higher complete response rates, even in extended disease (Morstyn, 1989). Basing on these data, we designed a pilot study on the association of r-hu-gm-csf to intensive chemotherapy.