Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326).

OBJECTIVE: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine. METHODS: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration. RESULTS: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias. CONCLUSIONS: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response.

Phase I study of toremifene in patients with advanced cancer.

A phase I multicenter evaluation of a novel antiestrogen, toremifene, was undertaken in postmenopausal women with various advanced difficult-to-treat malignancies. One hundred and seven women were treated at one of six dosage levels (10, 20, 40, 60, 200, or 400 mg/d orally) for at least 8 weeks. Weekly evaluations for toxicity were conducted. The most common side effects were nausea (31%), vomiting (12%), and hot flashes (29%). Five patients were removed from the study for possible adverse reactions: three patients experienced hypercalcemia; one experienced tremulousness, fatigue, and inability to think clearly; and one had vaginal bleeding. Twelve patients died while on study, 11 with disease progression and one with a pulmonary embolus. Sex hormone-binding globulin (SHBG) levels increased and there was a modest decline in serum antithrombin III levels. Four of 48 assessable patients had partial responses: three with breast cancer and one with endometrial cancer. Toremifene was generally well tolerated at the doses tested.

Prolonged interleukin-2 (IL-2) treatment can augment immune activation without enhancing antitumor activity in renal cell carcinoma.

Preliminary studies involving small numbers of patients have suggested that interleukin-2 (IL-2) administered by continuous infusion in repetitive weekly cycles using doses of 3 x 10(6) U/M2/day is immunologically active and can induce tumor responses in patients with renal cell carcinoma. This study was designed to examine both the immunological and clinical effects of prolonged infusion IL-2 given by repetitive weekly cycles; first at moderate doses for 4 weeks as an impatient followed by lower doses of IL-2 for up to 5 months. Prolonged IL-2 treatment was investigated because previous studies revealed that patients had a return to their baseline immune status within 4 weeks after completing IL-2 treatment. Twenty-five patients (including 18 with renal cell carcinoma) were treated with one of two regimens utilizing IL-2 as sole therapy. These regimens were designed to induce augmented and prolonged immune activation based upon in vitro and in vivo data. Though patients on both arms of the study demonstrated sustained lymphocytosis, increase in numbers of natural killer cells, and induction of lymphokine-activated killer activity with prolonged IL-2 administration, only 1 out of the 18 patients with renal cell carcinoma demonstrated a sustained partial antitumor response to therapy. Furthermore, several patients demonstrated profound immune activation, without any evidence of tumor regression. The lack of clinical responses in these patients showing marked activation of LAK cytotoxicity suggests that other variables must also influence the likelihood of antitumor effects for patients receiving IL-2 therapy.

The influence of autologous lymphokine-activated killer cell infusions on the toxicity and antitumor effect of repetitive cycles of interleukin-2.

Twenty patients with refractory malignancies were treated with a protocol evaluating the addition of ex vivo-activated autologous lymphokine-activated killer (LAK) cells to a clinically tolerable interleukin-2 (IL-2) regimen (four weekly cycles of human recombinant IL-2 at 3 x 10(6) U/m2/day by continuous infusion for 4 days/week). Sixteen patients completed their induction month of therapy, two had a partial response, six had stable disease, and eight had progressive disease. Four patients had clinical toxicity preventing completion of the induction month of therapy, and one of these patients died during therapy. Significant clinical toxicities included decreased performance status, weight gain, catheter-related thromboses, infectious complications, fever, hypotension, and dyspnea or hypoxemia requiring oxygen. Thus, the addition of LAK cell infusions to this IL-2 regimen did not cause a noticeable change in antitumor response rate but did not cause more severe toxicity.

Phase I study of the tolerance and pharmacokinetics of toremifene in patients with cancer.

Toremifene is a triphenylethylene derivative structurally and pharmacologically similar to tamoxifen. This Phase I trial assessed the safety, pharmacokinetics, anti-estrogenic, and estrogenic effects of toremifene at six dose levels (10, 20, 40, 60, 200, and 400 mg/day). The most common side-effects associated with therapy included gastrointestinal (nausea/vomiting 43%), anti-estrogenic (hot flashes 29%), and CNS (dizziness/vertigo 12%). Three patients with bone metastases from breast cancer developed hypercalcemia. At doses greater than or equal to 40 mg/day a decline in LH and FSH occurred which was not statistically significant. At all doses tested SHBG rose during therapy. A dose dependent estrogenic blockade was seen on the vaginal epithelium following challenge with transdermal estradiol. Steady-state concentrations of toremifene were reached within 4 weeks, and at doses greater than or equal to 60 mg/day ranged from 879-3445 ng/ml. The half-life was found to be 5 days, and at three weeks following discontinuation of treatment concentrations greater than 24 ng/ml were detected. The N-desmethyl and 4-hydroxy metabolites achieved steady state levels within 4 weeks and had half-lives of 6 and 5 days respectively. Partial responses were seen in 4 patients, 3 with breast cancer treated at 200 mg/day and 1 with endometrial cancer treated at 400 mg/day.

Depressed in vitro T cell responses concomitant with augmented interleukin-2 responses by lymphocytes from cancer patients following in vivo treatment with interleukin-2.

Peripheral blood lymphocytes obtained from cancer patients receiving interleukin-2 (IL-2) on two separate clinical protocols were evaluated for their in vitro responses to IL-2, alloantigens, and PHA. IL-2 in vivo induced enhanced in vitro proliferative responses to IL-2 and diminished in vitro proliferative responses to phytohemagglutinin (PHA) and alloantigens. Alloinduced cytotoxic T cell responses were also depressed following in vivo IL-2. We examined the kinetics of the in vitro proliferative response to PHA and IL-2 and found that while the response of lymphocytes primed in vivo with IL-2 to PHA was depressed at all times during the 2 week in vitro exposure, the response to IL-2 peaked earlier and higher than did the response to IL-2 by lymphocytes obtained prior to IL-2 therapy. These contrasting effects on antigen-induced T cell responses vs. IL-2 induced nonspecific proliferative and cytotoxic responses suggest the importance of dose and timing of IL-2 administration when used to enhance antigen-specific T cell responses or as an immune enhancing agent combined with vaccines.

Repetitive weekly cycles of interleukin 2: effect of outpatient treatment with a lower dose of interleukin 2 on non-major histocompatibility complex-restricted killer activity.

Fifteen patients with advanced malignancy who had failed conventional therapy were entered into a protocol consisting of 1 inpatient mo of repetitive weekly cycles of interleukin 2 (IL-2) at 3 x 10(6) units/m2/day by constant infusion for the first 4 days of each week. This was followed by IL-2 administered on an outpatient basis at the same schedule but at a dose of 1 x 10(6) units/m2/day for the next 1 to 6 mo. Nine patients had renal carcinoma, four had melanoma, and two had lymphoma. Thirteen patients completed the induction month, and ten patients completed greater than or equal to 1 mo of outpatient therapy. Only one patient had therapy discontinued because of toxicity due to IL-2. No major toxicities occurred during outpatient therapy. After 1 mo of IL-2 at 3 x 10(6) units/m2/day, profound changes similar to those previously documented were seen in peripheral blood lymphocyte (PBL) counts (4.7-fold increase), lymphokine-activated killer activity (16-fold increase), and the percentage of PBL with natural killer-associated markers including a 3.6-fold increase in the percentage of PBL expressing the Leu 19 (NKH-1) marker, a 3.7-fold increase in Leu 11 (FcIgGR), and a 3.0-fold increase in Leu 17 (OKT10). These indicators of IL-2 effect all remained elevated relative to the baseline at the end of 1 and 2 mo of outpatient therapy at the lower dose. However, lymphokine-activated killer activity and Leu 17 percentage were significantly reduced relative to the effect of the higher induction dose. PBL taken from patients while receiving maintenance therapy showed strong and rapid responses to IL-2 in vitro, confirming the in vivo effects of prolonged IL-2 treatment. Nevertheless, there were no complete or partial antitumor responses seen. This study demonstrates that an immunologically active dose of IL-2 can be given long term as outpatient therapy with tolerable toxicity and results in highly IL-2-responsive "primed" lymphokine-activated killer cells.

Altered tryptophan and neopterin metabolism in cancer patients treated with recombinant interleukin 2.

Immune stimulation or interferon administration induces indoleamine 2,3-dioxygenase and GTP cyclohydrolase activity in humans, resulting, respectively, in tryptophan degradation to kynurenine and in neopterin production. To determine if similar effects result from interleukin 2 (IL-2) administration, plasma tryptophan and urinary kynurenine and neopterin were measured in patients undergoing a phase 1 toxicity trial of recombinant IL-2 given by daily bolus or continuous i.v. administration for 7 days at doses of 1 x 10(5) to 1 x 10(7) units/m2/day. Significant dose-dependent decreases in plasma tryptophan levels and corresponding increases in urinary kynurenine and neopterin were observed. These metabolic effects of IL-2 are probably mediated by induction of gamma-interferon production, although elevated levels of gamma-interferon were not found in the sera of these patients. In view of the indispensable role of tryptophan in synthesis of protein, niacin, and serotonin, we suggest that some of the toxic side effects may be the result of this loss of tryptophan. Since these metabolic changes were detected at relatively low doses of IL-2, these assays provide a highly sensitive means for monitoring in vivo metabolic responses to IL-2 therapy.

"Eight-drugs-in-one-day" chemotherapy administered before and after radiotherapy to adult patients with malignant gliomas.

Thirty-one adult patients with malignant glioma (23 with glioblastoma multiforme, six with anaplastic astrocytoma, and two with brainstem glioma) were treated with up to ten cycles of "eight-drugs-in-one-day" chemotherapy (methylprednisolone 300 mg/m2, vincristine 1.5 mg/m2 [maximum of 2 mg/cycle], CCNU 75 mg/m2, procarbazine 75 mg/m2, hydroxyurea 3000 mg/m2, cisplatin 90 mg/m2, cytosine arabinoside 300 mg/m2, and imidazole carboxamide 150 mg/m2). Chemotherapy was planned as two cycles before and eight cycles after 60 Gy of involved brain irradiation. A total of 117 cycles of chemotherapy was administered. There was one treatment-related death. Myelosuppression was the most frequent toxic effect (leucopenia was less than 1000/mm3 in 9% of cycles and 1000-2500/mm3 in 25%; thrombocytopenia was less than 100,000/mm3 in 33% of cycles). Sixteen patients developed infections requiring treatment, two of which were life-threatening. Five patients suffered ototoxicity. Nausea and vomiting were observed in 35% of patients. A reversible rise in creatinine was observed in five patients. One patient developed a severe motor neuropathy, and three patients developed mild peripheral neuropathies. Three patients had episodes of atrial fibrillation. One new bundle branch block with supraventricular tachycardia was observed in a patient with pulmonary embolus. Five patients developed thrombophlebitis, three of whom had pulmonary emboli. Two patients suffered strokes in areas anatomically separate from their tumor. Eleven patients declined to continue therapy after receiving an average of three cycles. Two had complete, and five had partial responses. The median survival time was 47 weeks. The responses and survival times observed are comparable to less toxic treatment protocols for adults with malignant gliomas.

The role of interleukin-2 in cancer therapy.

Despite the abundance of evidence from murine models suggesting a powerful immunological approach to the treatment of cancer, the available data on clinical response have not been as dramatic. The use of interleukin-2 (IL-2) either alone or in combination with lymphokine activated killer (LAK) cells clearly is therapeutic for some patients, albeit a minority. It does not appear from the available evidence that the regimens tested show major differences in antitumour activity, although there is a sense that higher doses may be slightly more effective. Nor is it clear that the addition of LAK cells significantly or sufficiently enhances clinical responses to warrant their widespread use. It must therefore be concluded that other patient and tumour related factors must have an undefined role in the ability to attain meaningful responses. Immunological response to IL-2 and tumour burden are factors which can be examined given the available clinical data. While animal studies have shown that antitumor effects are related to the dose and number of LAK cells given, this is not as clear in patient studies. Some reports have suggested a correlation between clinical response and the in vivo induction of LAK activity or the magnitude of the rebound lymphocytosis. Clinical trials at the University of Wisconsin have shown striking increases in both the number of peripheral blood lymphocytes and LAK induction in patients who showed no clinical response. This in vivo LAK induction, as expected, is not the sole determinant in achieving a measurable response. Whether it is a necessary biological response needed to achieve antitumour effects remains uncertain. The role of tumour burden in response to IL-2 remains elusive. In many trials, including our own, patients with bulky disease have responded to therapy that was ineffective in other patients with what appeared to be a minimal tumour burden. Despite the disappointment that initial expectations have not quite been met, something extremely important has occurred in the treatment of cancer. For the first time, the controlled activation of a patient's endogenous immune system has been shown to have some promise as an antitumour treatment. Clearly, if the response rates reported to date are the best attainable its role will be limited. This remains doubtful as investigators are actively exploring combinations of IL-2 with other biologicals, cytokines, monoclonal antibodies and chemotherapeutic agents. Preclinical data suggest enhanced antitumour effects will be mediated by these combinations. While the magic bullet has not yet been found, there has been a major step forward since IL-2 was first described.

Eight-drugs-in-one-day chemotherapy in postirradiated adult patients with malignant gliomas.

Fifteen patients, 12 with glioblastoma multiforme and 3 with anaplastic astrocytoma, were treated with "eight-drugs-in-one-day" chemotherapy [methylprednisolone 300 mg/m2, vincristine 1.5 mg/m2 (maximum of 2 mg/cycle), CCNU 75 mg/m2, procarbazine 75 mg/m2, hydroxyurea 3,000 mg/m2, cisplatin 90 mg/m2, cytosine arabinoside 300 mg/m2, and imidazole carboxamide 150 mg/m2]. All patients had prior brain irradiation but none had previous chemotherapy. The population included 10 patients with progressive disease after irradiation and 5 who presented within 2 months of completing radiation. Patients received an average of 5 monthly cycles of chemotherapy. Three patients achieved a complete and 2 a partial response (CR + PRrate was 33%). The median survival time was 46 weeks. Myelosuppression was the dose-limiting toxicity. Leucocyte counts between 2.0-4.5 x 10(3)/mm3 were observed in 40% of patients, between 1.0- less than 2.0 x 10(3)/mm3 in 33%, and less than 1.0 x 10(3)/mm3 in 7%. Platelet counts between 50-130 x 10(3)/mm3 were observed in 27% of patients, and less than 50 x 10(3)/mm3 in 33%. Six patients suffered infections, 4 had reversible renal toxicity, 2 developed paresthesias, and one a debilitating myopathy related to treatment with dexamethasone. Ototoxicity was seen in 3 patients. Two patients developed pulmonary emboli. Nine patients had nausea and vomiting, in one case associated with Candida esophagitis. One long-term survivor developed necrosis of the corpus callosum and dementia. Four patients discontinued treatment after an average of 3.5 cycles because of toxicity. Although extremely toxic, this regimen has modest activity in previously irradiated adult patients with malignant glioma.

The cellular immunotherapy of cancer: current and potential uses of interleukin-2.

The potential for immune-mediated destruction of neoplasms was suggested nearly one century ago. Despite this, no "magic bullet" has yet been identified. Nevertheless, the physiology of cell-mediated immune reactions has been well characterized in molecular, cellular, and clinical studies of allograft and microbial immunity. Extensive studies performed in laboratory animal models have documented the in vitro and in vivo destruction of various neoplastic tissues by immune cells. This destruction can be directed against autologous, syngeneic, or allogeneic tumors in several systems with varying degrees of "tumor specificity". Two approaches exist towards utilizing these immune reaction in vivo. The first involves providing the tumor bearer with immunostimulatory agents, either specific or nonspecific, designed to activate and amplify the destructive potential of the individual's endogenous immune cells able to recognize and destroy autologous tumor. The second approach provides immune cells with antitumor capacity to a tumor-bearing individual, these cells having been activated exogenously. A number of successful regimens involving these two approaches, and combinations of them, have been delineated in animal tumor models. These experimental studies lay a strong foundation for initiating clinical trials of these concepts for patients with cancer. This review summarizes the diverse experimental studies in animals leading to clinical trials, presents recent data from ongoing clinical trials directly testing the potential for cellular immunotherapy, and then presents some of the major challenges facing further development and application of this potential therapeutic approach.

Phase 1 clinical trial of recombinant interleukin-2: a comparison of bolus and continuous intravenous infusion.

The toxicologic, biologic, and clinical effects of recombinant interleukin-2 (IL-2) were tested in 25 patients with cancer. Escalating doses from 10(3) to 10(7) U/m2 per day were given by either daily bolus injection (BI) or continuous infusion (CI) for 7 consecutive days. Dose-limiting toxicities included a decline in performance status, systolic hypotension, and fever, which reversed promptly with discontinuation of therapy. The maximum tolerated dose of IL-2 by BI for 7 days was 3 X 10(6) U/m2 per day and for CI was 10(6) U/m2 per day. Significant changes in the number, phenotype, and function of circulating peripheral blood lymphocytes occurred at doses greater than or equal to 10(6) U/m2 per day by both administration schedules. With the initiation of therapy, a decline in the number of circulating peripheral blood lymphocytes (PBL) was seen in patients treated by either BI or CI. Additionally, the in vitro cytotoxic activity of these PBL against K562 was markedly decreased. Within 24 h of completing BI or CI, a rebound increase in the number of circulating PBL was seen. The phenotype of the circulating PBL after completion of treatment showed a significant (p greater than or equal to 0.05) increase in the numbers of OKT-3+, OKT-8+, OKT-10+, OK-Ia+, OKM1+, and OKT-11+ for patients treated by CI. Those patients treated by BI had a significant increase in Ia+ and OKT10+ cells. At IL-2 doses greater than or equal to 10(5) U/m2 per day, the PBL obtained following treatment with rIL-2 demonstrated in vitro cytotoxic capacity against K562 target cells that was significantly enhanced over pretreatment levels. This study demonstrates that IL-2 can be given by CI or BI in a non-ICU setting with acceptable dose-dependent toxicity. Upon completion of treatment an increase in the number of activated cells could be detected. Although no clinical responses occurred, the generation of endogenous activated PBL capable of enhanced cytotoxicity is encouraging. Future studies will explore the use of multiple courses of treatment with IL-2 to determine if therapeutic efficacy can be accomplished.

Repetitive weekly cycles of interleukin-2. II. Clinical and immunologic effects of dose, schedule, and addition of indomethacin.

Clinical trials with high doses of interleukin 2 (IL-2) have shown antitumor responses, but many of the patients have experienced severe and occasionally life-threatening toxic effects. Preclinical studies indicate that modifications in IL-2 dose, route, and schedule can influence both immune activation and antitumor effects. This study evaluated the clinical tolerance to and immunologic modifications induced by four repetitive weekly cycles of IL-2, with two dose levels (1 X 10(6) and 3 X 10(6) U/m2 per day) of IL-2 and three different daily administration schedules [bolus, continuous, or combined (bolus and continuous)], with and without indomethacin treatment. Patients in all treatment groups experienced acceptable, non-life-threatening toxic effects and immune system stimulation characterized by rebound lymphocytosis with increased numbers of natural killer and lymphokine-activated killer cells and enhanced direct cytolytic function. These immune changes were significantly enhanced by the repetition of IL-2 cycles beyond the first week of therapy. At an IL-2 dose of 3 X 10(6) U/m2 per day, bolus IL-2 was less immunostimulatory than continuous-infusion IL-2. The combined regimen (with half of each daily dose given as a bolus and half as a 24-hr infusion) was as stimulatory as continuous-infusion IL-2 and also induced antitumor effects. Finally, the addition of indomethacin to this regimen did not significantly modify in vitro or in vivo immune response parameters but appeared to worsen the systemic toxic effects of renal dysfunction and capillary leakage. These results suggest that continuous or combined infusion of IL-2 at 3 X 10(6) U/m2 per day on this schedule should be considered for further testing in phase II trials or in combination with other therapeutic modalities.

Clinical and immunological effects of recombinant interleukin 2 given by repetitive weekly cycles to patients with cancer.

Eleven patients received four consecutive weekly cycles of human recombinant interleukin 2 (IL-2) by continuous infusion for 4 days/week. Two dose levels were tested, 1 and 3 X 10(6) units/m2/day. Toxicities experienced by most patients included fever, rigors, fatigue, anemia, eosinophilia, and liver function abnormalities. All side effects from treatment reversed and no severe or life-threatening problems occurred. A marked lymphocytosis was seen following the 4 weeks of therapy. Fresh lymphocytes obtained during this lymphocytosis mediated enhanced destruction in vitro of a natural killer cell-resistant tumor cell line (Daudi). The increase in the absolute number of circulating lymphocytes and their enhanced ability to mediate direct lysis of Daudi targets resulted in a greater than 100-fold mean increase in cytotoxic potential by the end of IL-2 treatment. One patient, with renal carcinoma, who was treated at 3 X 10(6) units/m2/day experienced a sustained measurable response with greater than 50% regression of pulmonary and hepatic metastases. Five patients were retreated with a second course of IL-2, lasting 4 weeks. This therapy was well tolerated in four of these five patients, with similar immunological changes occurring. No further antitumor responses were seen in these patients. Thus, a relatively well tolerated immunotherapy regimen using IL-2 can induce dramatic increases in lymphocyte number and augment their in vitro antitumor reactivity.

The in vitro function of lymphocytes from 25 cancer patients receiving four to seven consecutive days of recombinant IL-2.

Twenty-five cancer patients received human recombinant interleukin-2 (IL-2) for 4 to 7 consecutive days in a Phase I trial. IL-2 was administered either as a daily intravenous bolus infusion (lasting 15 min), or as a continuous infusion lasting 24 h each day. Prior studies have demonstrated that in vivo administration of IL-2 at high doses is associated with changes in the phenotype of circulating peripheral blood lymphocytes (PBL) (determined with monoclonal antibodies), and the induction of augmented in vitro natural killer activity (NK) by PBL obtained following in vivo IL-2. We have noted that fresh lymphocytes obtained after 4-7 consecutive days of IL-2 (greater than or equal to 10(6) U/m2/day) show an augmented ability to kill NK-sensitive and -insensitive target cells (K562 and Daudi targets, respectively), especially when tested with IL-2 present during the 4-h 51Cr release assay. We have further analyzed lymphocytes in a battery of in vitro proliferative and cytotoxic assays. We present here the summary of this quantitative analysis of their responses in both antigen-specific and -nonspecific immune responses. Striking in vitro changes were observed in the proliferative response to IL-2 and in cytotoxicity stimulated by (or requiring) in vitro IL-2. Proliferative responses to antigens and to mitogens were not as dramatically altered following in vivo IL-2, nor were allospecific or allo-activated cytotoxic interactions. These studies indicate that the most striking changes in lymphocyte function measured in vitro following in vivo IL-2 are seen in those functions requiring IL-2.

In vivo induction of the lymphokine-activated killer phenomenon: interleukin 2-dependent human non-major histocompatibility complex-restricted cytotoxicity generated in vivo during administration of human recombinant interleukin 2.

The availability of purified human recombinant interleukin 2 (IL-2) has enabled clinical trials to test its in vivo effects. We report here the immunological effects of 7 consecutive days of IL-2 treatment given to 25 patients with cancer in a clinical Phase I study. Peripheral blood lymphocytes obtained from patients following therapy with IL-2 had enhanced proliferative responses to IL-2 and enhanced direct cytotoxic activity on K562 target cells. This lytic activity was further augmented by the addition of IL-2 during the 51Cr release assay. Fresh peripheral blood lymphocytes from some patients who had just completed treatment at the higher IL-2 dose levels were able to kill both the natural killer-resistant Daudi cell line and fresh tumor cells while pretreatment samples and peripheral blood lymphocytes from healthy controls were not. This lytic activity was best detected when IL-2 was present in the in vitro effector assay. These results demonstrate that the administration of IL-2 to patients with cancer induces a population of effector cells able to directly destroy natural killer-resistant target cells, when assayed in the presence of IL-2.

Repetitive weekly cycles of recombinant human interleukin-2: responses of renal carcinoma with acceptable toxicity.

A phase I trial of repetitive weekly cycles of human recombinant interleukin-2 (IL-2) was performed in 23 patients with metastatic carcinoma. Patients received 4 days of IL-2 each week, followed by 3 days of observation, for 4 consecutive weeks. IL-2 was administered iv at 1.0 or 3.0 X 10(6) U/m2/day by one of three schedules involving continuous or bolus infusions. All treatment was carried out in a general hospital ward without intensive care unit monitoring or support. Seventeen patients had metastatic renal cell carcinoma; three of these demonstrated measurable (greater than 50% shrinkage) partial responses. This study demonstrates that IL-2 given alone without lymphokine-activated killer cells in this manner can induce antitumor effects with acceptable toxicity.