rIL-2 Infusion Research Articles

IMCT-10A PHASE I DOSE ESCALATION STUDY TO TEST THE SAFETY OF INTRATUMORAL ADOPTIVE IMMUNE THERAPY WITH AlloCTL IN RECURRENT GLIOMA PATIENTS

In a Phase 1 dose escalation study we evaluated the safety, feasibility, toxicity, and survival of patients treated with allogeneic cytotoxic T lymphocytes and recombinant IL-2 (alloCTL, rIL-2) infusion administered to the resection cavity of patients with recurrent glioma (WHO grade III or IV). AlloCTL are generated when gamma-irradiated lymphoblasts from the brain tumor patient stimulate the proliferation of peripheral blood mononuclear cells (PBMC) isolated from an HLA-disparate healthy donor in ex vivo culture via one-way mixed lymphocyte reaction. Nine patients were treated on the protocol and received a range of 0.5-5 cycles of therapy. Patients and donors were mismatched at a minimum of 2 HLA A, B, DR loci. Infusates were at least 30% CD3+. Cytotoxicity of alloCTL against patient PBMC ranged from 21.0-84.4% at a 30:1 effector to target ratio. The ratio of CD4/CD8 T cells averaged 1.12 (range 0.14-2.95). In vitro restimulation of alloCTL with patient lymphoblasts allowed for quantitation of immune cell subset proliferation and production of IFN-γ. Adverse events were noted at all three dose levels tested, and were primarily limited to Grade 1-2. Grade 3-4 events were noted only at dose levels 2 and 3. One patient experienced a dose limiting toxicity characterized by Grade 3 fatigue, arthralgia, headache, and non-infectious meningitis. Patient serum samples were collected during the course of therapy to determine Th1/Th2 cytokine profiles using Luminex multiplex analysis. Tumor progression was evident in 8/9 patients resulting in removal from the clinical trial. Median overall survival from the time of inclusion into the study was 8.8 months (range- 3.6-35.7 months). Two patients are still alive at greater than 35.7 and 16.4 months. The results suggest that alloCTL infusion is safe, feasible, and may warrant further study based on the clinical results.

Phase I trial with recombinant interleukin-2 (rIL-2): immune activation by rIL-2 alone or following pretreatment with recombinant interferon-gamma

Alterations of immunological parameters were analysed in patients with advanced malignancies during a phase I trial with rIL-2. Five-day infusions of rIL-2 at doses from 1 x 10(6) to 24 x 10(6) biological response modifiers program (BRMP) U/m2 per day were given to 29 patients, with a minimum of three patients per dose. The dose of 24 x 10(6) U/m2 per day was the maximal tolerated dose (MTD). Immunological parameters were analyzed at days 0, 8 and 11 of the rIL-2 courses. Following a leucopenia during rIL-2 infusion, a lymphocytosis was found in all patients except one. The lymphocytosis peaked at day 8 and was detected at doses of rIL-2 as low as 1 x 10(6) U/m2 per day, reaching a plateau at a dose of 16 x 10(6) U/m2 per day. Although all lymphocyte subsets were increased in patients receiving rIL-2, some patients had predominant T cells (CD3+, NKH1(CD56)-), others had predominant natural killer (NK) cells (CD3-, NKH1 (CD56)+), and yet others showed a mixed profile. A strong induction of cells cytotoxic for K562 targets was found in all patients at days 8 and 11. Eighteen patients received, 1 month later, a second treatment in which infusion of rIL-2 was preceded by a course of 5 days infusion of 2 x 10(6) U/m2 per day recombinant interferon-gamma (rIFN-gamma). The infusion of rIFN-gamma prior to rIL-2 had no effect on the rIL-2-induced alterations of immunological parameters. Taken together, our results suggest that immune stimulation by rIL-2 occurs even at low doses and is maximal at a dose below the MTD; and that pretreatment with low-dose rIFN-gamma does not modify the immune stimulation by rIL-2.

頭部血管肉腫の１例

Angiosarcoma of the scalp is a relatively rare skin malignant disorder. We experienced a case of angiosarcoma. A 74-year-old woman admitted our hospital with a tumor which had appeared 1 month before on her right frontal scalp. Three months ago she got injures for two times on the scalp where exact same place the tumor appeared. She was diagnosed as angiosarcoma by typical clinical and histopathological features. She was intensively treated with rIL-2 and surgical operation. Intra-arterial infusion of rIL-2 was carried out before the operation. After the operation she was treated with intra-venous infusion of rIL-2. At the time of beginning the treatment, diameter of the tumor was 5cm and decreased to 3cm just before the operation. We estimated the IL-2 therapy benefitable for decreasing the tumor-size. No recurence is observed until now. [Skin Cancer (Japan) 2000; 15 : 276-279]

Neutrophil activation, vascular leak toxicity, and cytolysis during interleukin-2 infusion in human cancer

Background . Recombinant interleukin-2 (rIL-2) therapy for advanced malignancy is usually associated with a vascular leak syndrome (VLS) similar to that seen in severe sepsis. We investigated the possibility that the IL-2-induced VLS may be associated with the presence of circulating activated polymorphonuclear (PMN) leukocytes as occurs in sepsis syndrome. Methods . Estimation of phenotypic (CD11B/CD18) and functional (H 2O 2, HOCl) up-regulation of circulating neutrophil activity was made by fluorescence-activated cell sorter analysis and ultraviolet spectrophotometry. Associated systemic cytokine enhancement tumor necrosis factor-α by enzyme-linked immunosorbent assay for bioactivity and parallel estimation of clinical evidence of vascular leak syndrome were also studied in human subjects with advanced cancer receiving therapeutic doses of rIL-2. Results . The present studies confirm previous reports that tumor necrosis factor-α is released into the circulation during infusional therapy with rIL-2. In addition, we have found that this is accompanied by both phenotypic (up-regulation of CD11b/CD18 adhesion receptor expression) and functional (hydrogen peroxide and hypochlorous acid production) evidence of potent PMN activation. Furthermore, patients showing disease response to treatment have significantly greater production of PMN oxidants. Conclusions . These data suggest that the VLS seen during rIL-2 infusion in human beings may be attributable to PMN mechanisms similar to those invoked during severe sepsis. Consequently, this study may provide further insights into the mechanism of rIL-2's therapeutic action in advanced malignant disease.

The Use of a Sequential High Dose Recombinant Interleukin 2 Regimen After Autologous Bone Marrow Transplantation Does Not Improve the Disease Free Survival of Patients with Acute Leukemia Transplanted in First Complete Remission

We report the outcome of 50 consecutive patients with CR1 acute leukemia (AML = 22; ALL = 28) treated with autologous BMT, after cyclophosphamide and TBI, followed with a sequential high dose rIL2 regimen. rIL-2 (RU 49637 from Roussel-Uclaf, Romainville, France) was started after hematological reconstitution an average of 72 ± 22 days post transplant. The schedule consisted of a continuous infusion over 5 cycles (Cycle 1: 5 days starting on day 1; cycle 2-5: 2 days starting on day 15, 29, 43 and 57). Patients were treated at 4 different dosages (12 (N = 40), 16 (N = 3), 20 (N = 2), 24 (N = 5) × 106 IU/m2/day). Toxicities were mainly related to capillary leak syndrome and thrombocytopenia. Patients received an average of 122 ± 49 106 IU/m2Two patients with AML died from toxicity. rIL-2 infusion was associated with very a high level of immune stimu-lation of both T-cells (P > 0.05) and natural killer (NK) cells (P > 0.05) and associated cytolytic functions (P > 0.05). With a minimal and median follow-up of 21 and 46 months, 3 year leukemia free survival is 41 ± 6% overall, 39 ± 10% and 43 ± 8% for AML and ALL respectively. Relapse probabilities at 3 years are 59 ± 11% for AML and 57 + 8% for ALL. We conclude that this short infusion of rIL-2 over 2 months, resulting in an increased immune stimulation, is not associated with a better leukemic control for patients with acute leukemia transplanted early after reaching first complete remission.

Immunopharmacology and cytokine production of a low-dose schedule of intraperitoneally administered human recombinant interleukin-2 in patients with advanced epithelial ovarian carcinoma.

We determined in the peritoneal cavity (p.c.) of epithelial ovarian carcinoma patients during a 4-day treatment cycle of low-dose recombinant human interleukin-2 (rIL-2): (a) pharmacokinetics of IL-2, (b) endogenous cytokine production, and (c) numbers and percentages of peritoneal exudate lymphocytes. We administered 6 x 10(5) IU/m2 of rIL-2 (0.03 mg/m2 Proleukin rIL-2) intraperitoneally (i.p.) over 30 min on each of 4 days. One and one-half liters of D5 0.25 NS was injected i.p. before each rIL-2 infusion. Multiple peritoneal fluid samples were obtained from each of four patients on day 1 and day 4 for detection of IL-2, endogenous cytokines, and soluble IL-2 receptor (IL-2R-alpha). IL-2 concentrations in the peritoneal fluid were determined by bioassay and interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-10, transforming growth factor (TGF)-beta 2, and sIL-2R-alpha by enzyme-linked immunosorbent assay. Numbers of cells per microliter and lymphocyte subpopulation percentages after staining with a panel of monoclonal antibodies were determined on day 1, day 4, and subsequent off-treatment days. IL-2 disappearance in the p.c. was well described by a pharmacokinetic model having constant-rate infusion and biexponential disposition. About 90% of the IL-2 disappearance occurred during the beta-phase, during which IL-2 concentrations were sustained at approximately 10-30 ng/ml (day 1 and day 4) and the median t1/2 beta was 21.5 and 9.2 h on days 1 and 4, respectively. In four of four patients, p.c. production of IL-10 was observed on day 1 and day 4 (maximum 387 pg/ml). Maximum levels of IFN-gamma and sIL-2R-alpha were observed on day 4. (IFN-gamma 217 pg/ml; sIL2-R-alpha: 3486 U/ml). No increases in TNF-alpha or TGF-beta 2 were observed. Large increases in p.c. CD3+, CD4+, CD8+, CD16+, and CD56+ cells were observed. We conclude that biologically active levels of IL-2 are generated in p.c. fluids after i.p. administration of rIL-2 at 0.03 mg/m2.

Adhesion molecule expression and leucocyte trafficking following immunotherapy with recombinant interleukin-2.

The relevant anti-tumour mechanisms of recombinant interleukin-2 (rIL-2) in vivo are unclear but an influx of T-lymphocytes and macrophages has been noted in regressing lesions. One of the dose limiting toxicities of rIL-2 is the development of a capillary leak syndrome attributed to widespread endothelial activation. Changes in expression of endothelial and leucocyte-associated adhesion molecules were assessed in tumour and uninvolved skin in patients with metastatic breast cancer receiving rIL-2. Increased expression of intracellular adhesion molecule-1, its leucocyte-associated ligand, leucocyte function associated molecule-1, vascular cell adhesion molecule and its ligand, very late after activation antigen-4 as well as members of the selectin family of adhesion molecules, were noted in uninvolved skin following rIL-2. Expression of these adhesion molecules was noted in tumour stroma before rIL-2 but little change was observed following rIL-2 infusion. An influx of monocytes and T-lymphocytes (expressing the IL-2 receptor and of the memory subtype) and a lower number of neutrophils was noted in uninvolved skin following rIL-2. Although monocytes and T-lymphocytes were present in tumour stroma before rIL-2 no changes were observed following infusion. The changes noted in the dermis contrast with those seen at tumour sites and may partly explain the low therapeutic index of rIL-2.

Interleukin-2—Induced renal dysfunction in cancer patients is reversed by low-dose dopamine infusion

Recombinant interleukin-2 (rIL-2) is widely used in patients with advanced cancer to enhance killer cell functions. However, the main drawback of rIL-2 therapy is the frequent development of oliguric acute renal failure (ARF), presumably due to a vascular leak syndrome. The aim of this study was to evaluate the effect of low-dose dopamine infusion on this form of ARF. Nine patients with metastatic renal cancer and previous unilateral nephrectomy were treated with a continuous intravenous infusion of rIL-2 (3 × 10 6 Cetus units/m 2/d) for 5 days (study A). After 1 week, all the patients repeated the same cycle, but with the addition of a continuous intravenous infusion of dopamine (2 μg/min/kg body weight) that was started at the third day of treatment (study B). During study A, all patients showed a progressive (up to 34%) decrease of creatinine clearance. After rIL-2 withdrawal, these alterations persisted and were associated with a reduction in urinary output, sodium urinary excretion, and plasma protein. In study B, dopamine administration after renal function impairment (‡glomerular filtration rate = −44%) led to a prompt improvement of creatinine clearance. Creatinine clearance showed a further significant enhancement after the withdrawal of both drugs, reaching a value within the baseline range on the third day of follow-up. Similarly, the decline in urinary output and sodium excretion during rIL-2 was promptly counteracted by dopamine; in addition, after withdrawal of rIL-2 and dopamine, plasma protein levels were normalized. In conclusion, our data suggest that rIL-2-induced ARF in cancer patients is due to renal hypoperfusion mainly caused by a reduction in oncotic pressure. Importantly, intravenous infusion of dopamine at low dosage is effective in reversing this form of renal impairment; such a therapeutic approach, while reducing recovery time, avoids dose reduction or discontinuation of rIL-2 treatment.

Recombinant interleukin-2 treatment before and after autologous stem cell transplantation in hematologic malignancies: clinical and immunologic effects.

Autologous bone marrow transplantation (ABMT) for hematologic malignancies is associated with a high relapse rate. Interleukin-2 (IL-2) administration is a therapy that may prevent relapse if used when the tumor burden is minimal. In this study we administered recombinant IL-2 (rIL-2) therapy to 12 patients affected by hematologic malignancies either before or after autologous stem cell transplantation (ASCT). rIL-2 was given by a 6 day continuous intravenous infusion with escalating doses, up to 18 x 10(6)/m2/day, depending on patient tolerance. The functional immune responses of the patients were assessed as natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities and in vitro interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis. During rIL-2 treatment, the expected side effects occurred; only 3 patients, who showed severe cardiovascular toxicity, required suspension of the treatment. All toxicities reversed after the end of the therapy. Immunologic monitoring was carried out the day before starting rIL-2 infusion and then repeated on days 3, 7, and 14 after rIL-2 was discontinued. Following every rIL-2 course, a pronounced increase in CD3+, CD8+, CD56+ cells was found, with a peak value on day 3. The NK and LAK activities showed a significant increase on day 3 (p < 0.001) over pretherapy values; the increase lasted until day 14, although the difference at later time points was not significant. Before transplant the synthesis of both IFN-gamma and TNF-alpha decreased following rIL-2 therapy, whereas higher levels of these lymphokines were found after posttransplant rIL-2 courses.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant Interleukin-2 Infusions and Decreased IgG2 Subclass Concentrations

The administration of low doses of recombinant interleukin-2 (rIL-2) in vivo to patients with malignant neoplasms has been demonstrated to selectively increase the number of circulating natural killer (NK) cells in these patients. Recent evidence from SCID mouse models suggests that IgG subclass levels can be influenced by the presence and activity of NK cells. Therefore, we sought to examine the effect of rIL-2 infusions on human serum IgG subclass concentrations. We determined serum IgG subclass concentrations in 27 cancer patients receiving low-dose rIL-2 by daily continuous intravenous infusion. Eleven of these patients had active, metastatic, nonhematologic tumors; 16 patients had received IL-2 when they were in a minimal residual disease state after autologous or allogeneic bone marrow transplantation. Samples obtained before beginning IL-2 therapy and 8 to 10 weeks into therapy were tested. Treatment with IL-2 resulted in an increase in the percentage of CD56+ NK cells from 18% to 54% (P = .0001). A significant decrease in geometric mean IgG2 concentration from 2,017 micrograms/mL to 1,655 micrograms/mL was noted over this time interval (P = .03). Furthermore, the geometric mean IgG2 concentration after treatment was significantly lower than that of healthy controls (P = .026). In contrast, no significant changes in serum IgG1, IgG3, or IgG4 were noted during r-IL2 infusions. Our data suggest that rIL-2 treatment selectively decreases serum IgG2 concentrations. We speculate that increased NK cells mediate downregulation of human serum IgG2.

Adoptive CD8+ T-cell immunotherapy of AIDS patients with Kaposi's sarcoma.

This article reviews published and original findings from two clinical trials of adoptive CD8+ T-cell immunotherapy of patients with acquired immunodeficiency syndrome (AIDS) and Kaposi's sarcoma (KS). In the first trial, AIDS patients with either KS or oral hairy leukoplakia (OHL) received five rounds of reinfusions of 10(8)-10(10) ex vivo expanded and activated autologous CD8+ T cells. Recombinant interleukin-2 (rIL-2) was coadministered only with the fifth and final infusion. Improvement, and in some cases, resolution of OHL, KS, and candidiasis was observed with no side effects. The observation that clinical improvement of KS was more pronounced when reinfusion of CD8+ T cells was followed by rIL-2 infusion led to a second clinical trial designed to examine the effect of repeated infusions of autologous CD8+ T cells with concomitant rIL-2 administration in the treatment of AIDS-related KS. Improvement of KS status was observed in four out of the eight patients studied (three partial and one complete response). The CD8+ T-cell immunotherapy protocol also provided the opportunity to comparatively study CD8+ T-cell-associated genetic programs. Baseline expression patterns of soluble and surface immune markers by CD8+ T cells from AIDS patients and uninfected controls were predominantly of the type 1 type and differed mainly at a quantitative or kinetic level. Deficiencies in immune mediator expression by CD8+ T cells from AIDS patients tended to dissipate with progression through the protocol. Findings are discussed in the context of current knowledge and therapeutic implications of CD8+ T-cell function in AIDS and neoplasia.

Independent expression of p55 and p75 interleukin-2 receptors (IL-2R) during intravenous or subcutaneous administration of recombinant interleukin-2 (rIL-2) by T-lymphocytes and natural killer cells.

The effects of immunotherapy with recombinant interleukin-2 (rIL-2) on peripheral blood lymphocytes have been a matter of debate. In this study the authors addressed the issue of the biologic effects of two different schedules of rIL-2 administration (i.e., continuous intravenous infusion versus subcutaneous injection) on the expression of the p55 and p75 chains of interleukin-2 receptor (IL-2R). Sixteen patients were studied: 6 patients with a previous diagnosis of acute leukemia entered the study at least +60 days (+63(-)+144 days) after autologous bone marrow transplantation and were treated with continuous rIL-2 infusion; 10 patients with advanced metastatic renal cancer were treated with subcutaneous rIL-2 therapy. In both groups of patients, therapy consisted of two cycles of 5-day rIL-2, and immunologic evaluation was performed two days after completion of the second cycle. Intravenous treatment was associated with a marked increase in CD56+ natural killer (NK) cells expressing the p75 but lacking the p55 IL-2R; however, the absolute number of CD3+ lymphocytes was unchanged, and they showed a low or absent expression of the p55 and negativity for the p75 IL-2R. After subcutaneous rIL-2 therapy, a slight increase in the percentage of NK cells expressing only the p75 IL-2R was shown. CD3+ lymphocytes still retained the p75 IL-2R negative phenotype, however, with a significant increase (> 15%) in p55 IL-2R expression. The absolute number of CD3+ lymphocytes was also significantly increased. Functional tests on the purified CD3+ population indicate that these cells exhibited low values of cytotoxic and proliferative activities in vitro. The authors' data point out that subcutaneous administration of rIL-2 during a 2-week period is associated with a marked increase in T-cells that bear the low affinity p55 IL-2R. These findings could be relevant considering the independent role of lymphokine modulation mediated by the p55 and p75 IL-2R on T- and NK cells.

Prolonged continuous infusion of low-dose rIL-2

Prolonged continuous infusion of low-dose rIL-2

Phase II study of intermittent continuous infusion of low-dose recombinant interleukin-2 in advanced melanoma and renal cell cancer

Previously we described the immunological and clinical effects of prolonged continuous infusion of low dose rIL-2. In this phase II study we explored the therapeutic efficacy of intermittent continuous infusion of low dose rIL-2. We selected 15 patients with advanced melanoma and 8 patients with renal cell cancer in good clinical condition, with low tumour burden and no previous systemic treatment. A treatment cycle consisted of infusion of 1.8 x 10(6) IU/m2/24 hrs rIL-2 for 3 weeks on an out-patient basis followed by a 3-week rest. A maximum of four cycles were given. A total of 35 cycles were given. Treatment was well tolerated. Transient hyperthyroidism occurred in 8 patients. No objective responses were noted. We noted a high incidence of central nervous system involvement occurring shortly after treatment. Intermittent continuous infusion of low dose rIL-2 in advanced melanoma and renal cell cancer is well tolerated but the initial therapeutic results are not promising.

ｒＩＬ‐２治療を試みたａｎｇｉｏｓａｒｃｏｍａの２例

Case 1, a 49-year-old woman, presented with a blackish nodule, 25×15 in diameter, on her left arm. Because of her history of mastectmy and axillary lymph node dessection for the breast cancer 14 years before, the tumor was considered as Stewart-Treves syndorome. The tumor was surgically excised, and also treated with an intralesional injection of recombinant interleukin 2 (rIL-2) after and before the excision for totally 4 weeks. After 2 months of discharge, she died because of metastasis on adrenal gland. The rIL-2 therapy was not succesfull for this case.Case 2, a 82-year-old woman, presented with a red-violet macular lesion with several nodules on the hairly scalp, which was diagnosed as angiosarcoma of the scalp of the erdery. The tumor was treated with an intralesional injection and an intravenous infusion of rIL-2 combining with radiation therapy. After the treatment for a month, the tumor was significantly reduced. And it was surgically excised. There was no evidence of local recurrence or metastasis for 7months after the excision. The combination therapy of rIL-2, radiation and surgical excision was very effective for the case.Taken together, we concluded that rIL-2 therapy might be effective for the angiosarcoma of the scalp of the erdery, however, not effective for the Stewart-Treves syndorome.

Immunotherapy with intralesional and systemic interleukin-2 of patients with non-small-cell lung cancer.

Eight patients affected by non-small-cell lung cancer were treated with intralesional and systemic recombinant IL-2 (rIL-2) injection with the aim of activating both tumour-infiltrating lymphocytes and circulating cytotoxic or killer cells. The schedule of treatment was as follows: a daily fine-needle transparietal intralesional rIL-2 injection (1 x 10(5) Cetus units) from day 1 to day 5 and systemic rIL-2 infusion (1 x 10(5) Cetus units kg-1 day-1) from day 6 to day 10. One to four cycles of treatment were received by each patient. Clinical and immunological evaluations were performed (a) before treatment, (b) following the intralesional rIL-2 administration, (c) 1 h after the beginning of rIL-2 infusion and (d) at the end of the systemic rIL-2 infusion. No complete remission was achieved, two patients showed a partial remission, three resulted in stable disease and three patients progressed. Natural killer and lymphokine-activated killer cell activity dramatically decreased 1 h after the beginning of rIL-2 infusion and increased at the end of treatment. A progressive increase of circulating CD8+ and HLA class II+ T cells as well as of CD8+ T cell clones, most of which displayed NK activity, was recorded following rIL-2 infusion. Present data indicate that (a) the local administration of rIL-2 coupled with systemic rIL-2 infusion may be suggested as an alternative approach for the immunotherapy of lung cancer, (b) rIL-2 induces different immunological modifications according to the route and the time of its administration and (c) rIL-2 administration increases the amount of circulating immune cells with potential antitumour activity.

Low-dose dopamine induces early recovery of recombinant interleukin-2—Impaired renal function

Recombinant interleukin-2 (rIL-2) can produce impairment of renal function with hypotension, fluid retention, elevated blood urea nitrogen, oliguria and low fractional sodium excretion; these side-effects are a common cause of reduction or interruption of rIL-2 infusion. The aim of this study was to investigate the control and treatment of renal toxicity induced by rIL-2 therapy. Here we show that dopamine, at a low dose of 2 micrograms/kg/min, completely prevented renal toxicity induced by rIL-2. While continuing rIL-2 therapy, 24-h continuous infusion of low-dose dopamine produced a rapid normalisation of urine output and a significant decrease in serum creatinine levels and body weight (P < 0.01), with an early and complete recovery of the rIL-2--impaired renal function: mean recovery time of renal function in patients treated with dopamine was significantly lower (P < 0.05) than in nontreated patients (4.8 days vs. 10 days, respectively).

Interleukin 2 therapy in cancer: identification of responders.

C-reactive protein (CRP) levels in serum were measured in fifteen patients with metastatic colorectal carcinoma, prior to and during treatment with a continuous intravenous infusion of rIL.2. Patients were subsequently classified as responders or non-responders to this therapy. Baseline serum CRP levels, prior to treatment, were significantly lower in the responders (range < 2-8 mg l-1) when compared with the non-responders (range 7.5-116 mg l-1), P = 0.004. Furthermore, the responding patients demonstrated significantly and grossly elevated CRP stimulation indices (SI) compared with non-responders at different time intervals during the rIL2 infusion. At the cessation of rIL2 therapy, the CRP stimulation index was 31.3 +/- 9.3 in the responders, and only 1.6 +/- 0.3 in the non-responders (means +/- s.e.m, P = 0.014). These findings suggest that it is possible to predict those cancer patients who are most likely to respond to and benefit from rIL2 therapy, either prior to the commencement of or during the first course of rIL2.

THE TREATMENT OF COLORECTAL HEPATIC METASTASES BY CONTINUOUS LOCAL INFUSION OF INTERLEUKIN-2

Patients with hepatic metastases from colorectal cancer appear to be resistant to most forms of therapy. Recent reports suggest synergism between systemically administered recombinant interleukin-2 (rIL-2) and 5-fluorouracil (5-FU) with responses documented in the treatment of advanced colonic tumours albeit with significant toxicity. Local continuous infusion of rIL-2 into selected sites may reduce toxicity and increase efficacy. We have assessed the feasibility of continuously infusing rIL-2 into the region of a hepatic metastasis in 3 patients via a catheter placed within the liver under ultrasound guidance in a regimen including systemic rIL-2 and 5FU.

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.