Phase I trial of recombinant interleukin-2 followed by recombinant tumor necrosis factor in patients with metastatic cancer.

In this Phase I trial, the feasibility of sequential administration of continuous intravenous recombinant interleukin-2 (rIL-2) at 18 x 10(6) IU/m2/day for 6 days, followed by three daily bolus intravenous recombinant tumor necrosis factor (rTNF) infusions at doses escalating between 10 and 120 micrograms/m2/day, was investigated in 31 patients with metastatic malignancies. Prophylactic use of indomethacin prior to and during rTNF administration was found to significantly reduce toxicity. However, despite prophylactic indomethacin, a maximum tolerated dose of rTNF of 120 micrograms/m2 was reached. The limiting toxicity was hypotension. Predictable flu-like toxicities (i.e., fever/chills, hypotension, gastrointestinal toxicity, edema, malaise) were seen in most patients. These started during the rIL-2 infusion and continued during rTNF administration, particularly in the absence of indomethacin. Hematological, renal, and hepatic toxicities were not dose limiting. These toxicities were all reversible after treatment interruption. Pulmonary toxicity [i.e., anaphylactic-like reactions, bronchospasms, and adult respiratory distress syndrome (ARDS)] was seen in several patients immediately after rTNF infusions, irrespective of the rTNF dose or treatment cycle, and mainly in patients with extensive pulmonary metastases. The combined effect of treatment-related ARDS, lung metastases, and a Guillain-Barré syndrome led to the death of one patient. Two partial responses were seen in this study (i.e., breast and renal cancer). Based on these results, a Phase II trial of rIL-2 followed by rTNF has been initiated in metastatic breast cancer patients.

Recombinant interleukin-2 continuous infusion in ovarian cancer patients with minimal residual disease at second-look.

Recent reports suggest that recombinant interleukin-2 may be effective in the treatment of cancer patients with low tumor burden. Considering the poor long-term survival, 11 ovarian cancer patients with minimal residual disease at second-look have so far been selected for rIL-2 intravenous continuous infusion therapy: two induction courses (3 x 10(6) U/m2/day: 120 h + 108 h) followed by three maintenance courses (3 x 10(6) U/m2/day: 120 h) and third-look laparotomy. At present, three patients are still on treatment, three have completed it, and five have discontinued treatment. Sixty-seven per cent of the planned dose was administered in 49 cycles of which 42 (86%) required dose modifications due to hypotension (greater than or equal to grade III) and nephrotoxicity (greater than grade I). CNS and GI toxicity, allergies and fever, even though requiring dose modifications in a few cases, significantly affected patient compliance. The rebound lymphocytosis was clearly dose-related and a significant percentage increase after rIL-2 was detected only for IL-2 receptor positive cells. To date, four patients are evaluable for response after a median follow-up of 7 months, two progressed during the maintenance period, while one CR and one progression were detected in the two patients so far submitted to third-look laparotomy.

Continuous infusion of recombinant interleukin-2 with or without autologous lymphokine activated killer cells for the treatment of advanced renal cell carcinoma.

Data have been analysed for 327 patients with advanced renal cell carcinoma receiving a continuous infusion of recombinant interleukin 2 (rIL-2) alone (225 patients) or rIL-2 plus lymphokine activated killer (LAK) cells (102) on a normal oncology ward. Eligibility criteria were uniform across protocols, all patients having advanced progressive disease, but with an ambulatory performance status. The baseline characteristics of patients receiving rIL-2 alone did not differ significantly from those receiving LAK, with the exception that the LAK treated patients had a better performance status. Despite similar treatment intensity, toxicity was more severe in the patients receiving LAK. The addition of LAK did not lead to higher response rates or to prolonged response duration, progression-free survival or survival. This review confirms the activity of rIL-2 for the treatment of advanced renal cell carcinoma and demonstrates that the addition of LAK cells does not lead to increased efficacy.

Intravenous interleukin-2 just after high dose BCNU and autologous bone marrow transplantation. Report of a multicentric French pilot study.

This multicentric pilot study was conducted in order to evaluate the feasibility of early interleukin-2 (IL2) after high dose chemotherapy requiring autologous bone marrow transplantation (ABMT). BCNU at 800 mg/m2 was followed, 3 days later, by the reinjection of the bone marrow cells. At day 4, IL2 at 18 x 10(6) i.u./m2/day was given as a continuous infusion during a minimum of 6 days (first phase of study) or for 6 more days after 1 day break (second phase of the study). Twenty patients were included. Toxicity was not negligible, with one toxic death, but IL2 therapy does not damage the haematological recovery of most patients. However, a 6-day IL2 treatment period only appears tolerable. In 18 evaluable patients, three responses were observed: one complete response (CR) of short duration in a non-Hodgkin's lymphoma, one CR (24 months +) and one partial response (PR) (6 months) in two patients with metastatic gastric adenocarcinoma. This study confirms that IL2, restricted to a 6-day treatment period, is feasible immediately after high-dose chemotherapy requiring ABMT without haematological problem in most patients. The response rate was unexpected for a pilot study and this combined therapy obviously requires further study.

Recombinant interleukin-2 (rIL-2) after autologous bone marrow transplantation (BMT): a pilot study in 19 patients.

In vivo use of rIL-2 autologous BMT may be the means of reproducing a kind of "adoptive immunotherapy" from grafted cells after allogeneic BMT. This approach may enhance the spontaneous generation of cytotoxic T-cells and NK cells which are presumably involved in this immunotherapy. Potential risks of such an approach would be to increase the usual toxicity of rIL-2 and to jeopardize the hemopoietic reconstitution. To determine the feasibility of this approach we have treated 19 poor prognosis patients with a succession of autologous BMT followed 78 +/- 12 days later by a continuous infusion of rIL-2. Eighteen million international units (IU) per m2 per day of Proleukine (CETUS, Amsterdam, The Netherlands) were administrated over 6 or 12 days. No patient died of the procedure. Clinical toxicity related to rIL-2 was not increased. Hemopoietic toxicity, significant both for platelets and granulocytes, was transient. Immune stimulation was dramatic for lymphocytes and subpopulations (CD3+ and NK cells) and for cytolytic functions (NK and LAK activity). This trial establishes the feasibility of administration of high doses of rIL-2, 2 months after autologous BMT. In this setting a 6 day period of continuous infusion of 18 million per m2 per day of Proleukine appears to be a regularly tolerable dosage conducting to a major immune activation and invites further studies to determine the clinical impact of such an approach.

Interleukin-2 induces chemotactic deficiency in patients with onco hematologic malignancies and autologous bone marrow transplantation.

Unusual gram positive bacteremia has been reported in non granulopenic patients receiving recombinant human interleukin-2 (IL-2) suggesting a beneficial effect of anti gram positive prophylaxis in such patients. We report here studies on granulocyte functions examined during the course of high dose IL-2 therapy (16 to 24 million IU/m2/days for 11 to 18 days) administered during a period of 35 days in 14 patients including 4 solid tumors, 5 chronic myeloid leukemias, 4 recipients of autologous bone marrow transplant (ABMT) and 1 recipient of syngeneic bone marrow transplant. Neutrophils functions were studied before IL-2 administration (d 0), after the first cycle (d 8) and after the third cycle (d 36). Nylon fiber adherence, superoxide production, random migration, phagocytosis, nitroblue tetrazolium reduction, lysozyme and elastase release were not impaired significantly throughout therapy. However N-Formyl-Methionyl-Leucyl-Phenylalanine (FMLP) stimulated chemotaxis of granulocytes, normal before therapy, was significantly impaired as early at d 8 and severely inhibited at d 36 (p less than 0.001). Three septicemia, one corynebacteria parvum septicemia and two gram-negative septicemia despite normal neutrophil counts and oxacillin or Penicillin G plus Pefloxacin prophylaxis, occurred among the 14 patients studied. Although neutrophil functions were not more depressed in transplanted patients than in the other non transplanted patients, special attention should be paid to such patients in whom delayed immune reconstitution could increase the risk of sepsis.

Local immunotherapy of recurrent glioblastoma multiforme by intracerebral perfusion of interleukin-2 and LAK cells.

A non randomized pilot study has been undertaken to evaluate the feasibility of local immunotherapy (IT) of recurrent glioblastoma multiforme (GM) by continuous intracerebral perfusion of recombinant interleukin-2 (rIL-2, Eurocetus) with and without lymphokine activated killer (LAK) cells. At time of surgical removal of the tumor, a catheter was implanted in the cavity left by tumor debulking allowing continuous perfusion of rIL-2. Five patients received 18 x 10(6) IU/day or rIL-2 for five days. At days 1, 3, and 5 after surgery, rIL-2 perfusion was briefly interrupted for the injection of LAK cells. Eight other patients received rIL-2 alone, either 24 x 10(6) IU/day (five patients) or 54 x 10(6) IU/day (three patients). Capillary leak syndrome, which is the main side effect of systemic infusion of rIL-2, was never observed, but local immunotherapy induced fever, confusion, and cerebral edema in all patients. Despite local IT, tumor progression was diagnosed by CT scan 4 to 12 weeks after the treatment.

Does Aeromonas salmonicida affect the immune system of carp, Cyprinus carpio L.?

Aeromonas salmonicida is a significant bacterial pathogen of cyprinid and salmonid fishes causing the systemic disease furunculosis. Several observations led us to believe that A. salmonicida was able to evade or suppress the immune system of the fish: injection of whole bacteria or surface antigens was unsuccessful at protecting fish against lethal challenges; memory did not develop in survivors of sublethal infections; diseased fish often carried other opportunistic bacterial pathogens in addition to A. salmonicida, and serum protein and particularly immunoglobulin significantly decreased during A. salmonicida infections. We tested the ability of fish sublethally infected with virulent and avirulent A. salmonicida to mount a humoral immune response to sheep erythrocytes and found fewer plaque forming cells in the pronephros and lower serum anti-SRBC antibodies in infected fish as compared to controls. We also monitored the cellular immune response of diseased fish by skin allograft rejection and found an enhancement of the response that increased as the disease progressed. However, the extend of inflammation was reduced in infected fish as compared to non-infected animals. At this moment these preliminary observations are difficult to explain. Our future research will focus more specifically on cell populations that may be affected by A. salmonicida.

Hematologic and immunologic effects of the systemic administration of recombinant interleukin-2 after autologous bone marrow transplantation.

T cells from allogeneic bone marrow grafts are responsible for a graft versus leukemia effect. Use of recombinant Interleukin-2 (rIL-2) after autologous bone marrow transplantation (BMT) may enhance immune function and hopefully reproduce the allogeneic reaction. We report here the hematologic and immunologic changes observed in the first 10 patients of a phase 1 trial studying the infusion of IL-2 after autologous BMT. All patients had high-risk malignancies and received 6 days of a constant infusion of IL-2 (Eurocetus, Amsterdam, The Netherlands) at dose of 3 x 10(6) Cetus Units/m2/d, 79 +/- 12 days after autologous BMT. Clinical toxicities involving cutaneous, cholestatic, gastrointestinal, and hemodynamic effects occurred during IL-2 treatment but reversed in all cases. Completion of treatment was 91% of the scheduled dose of IL-2. Hematologic toxicity was moderate and transient with no graft failure. Increases in eosinophil and lymphocyte counts were significant (P less than .05). Stimulation of the immune system was intense and prolonged, manifested by increase numbers of CD3+, CD3+DR+, CD3+ CD25+ lymphocytes, and natural killer (NK) cells (all P less than .01), and increase of Lymphokine-activated killers (LAK) and NK activities (P less than .01 and P less than .05). This study establishes the feasibility of a 6-day administration of rIL-2 after autologous BMT leading to a major immune activation 2.5 months after BMT.