Distinct Clinical and Laboratory Activity of Two Recombinant Interleukin-2 Preparations (original) (raw)
Related papers
Cancer Research, 1987
The availability of recombinant human interleukin 2 (rl I IL 2) has resulted in its clinical utilization both as a single agent and in combination with lymphokine-activated killer cells. In this report, we discuss the effects of rH IL 2, administered by various routes, on effector cell function, pharmacokinetics and bioavailability, and therapeutic activity. Studies of the pharmacokinetics of in vitro natural killer (NK) cell augmentation by rH IL 2 revealed that a short exposure to high levels of rH IL 2 can augment NK cell activity; however, a prolonged exposure (>12 h) was required to augment NK cell activity at lower doses of rH IL 2. These observations suggested that chronic administration of rH IL 2 might improve immunomodulatory and therapeutic activity. This hy pothesis was supported by the results of studies in which we treated experimental and spontaneous metastasis, which revealed that the daily i.p. administration of rH IL 2 resulted in significantly greater therapeutic activity than administration three times/week. The therapeutic protocol for daily i.p. administration had a biphasic dosage optimum, such that low dose therapeutic activity was observed at approximately 100-1000 units/animal in the treatment of experimental métastasesor 10 to 100 units/animal in the treatment of spontaneous métastases. There was a second dosage optimum at > 100,000 units/animal rH IL 2 delivered i.p. on a daily basis. Intermediate doses had no significant therapeutic activ ity. Additional studies revealed that low dose therapeutic activity was not observed in nude mice. In contrast, therapeutic activity was observed in nude mice at high doses of rH IL 2 suggesting that low dose activity was associated with a T-cell-mediated effect, whereas high dose activity may have been mediated by NK or lymphokine-activated killer-like cells. This observation was in agreement with the dose response for T-cell adjuvant activity supporting the hypothesis that low dose therapeutic activity was T-cell associated, because adjuvant activity was observed when rH IL 2 was given daily at approximately 100 units/animal for 3 days, and higher doses had no activity or had a suppressive effect. Because we were concerned about the pharmacological aspects of rH IL 2 treatment, we also examined its therapeutic properties after continuous administration i.p. by osmotic pumps. Under these conditions, therapeutic activity was observed after administration of 600 units/h, whereas lower or higher doses did not have significant therapeutic activity.
Cancer Research
The availability of recombinant human interleukin 2 (rl I IL 2) has resulted in its clinical utilization both as a single agent and in combination with lymphokine-activated killer cells. In this report, we discuss the effects of rH IL 2, administered by various routes, on effector cell function, pharmacokinetics and bioavailability, and therapeutic activity. Studies of the pharmacokinetics of in vitro natural killer (NK) cell augmentation by rH IL 2 revealed that a short exposure to high levels of rH IL 2 can augment NK cell activity; however, a prolonged exposure (>12 h) was required to augment NK cell activity at lower doses of rH IL 2. These observations suggested that chronic administration of rH IL 2 might improve immunomodulatory and therapeutic activity. This hy pothesis was supported by the results of studies in which we treated experimental and spontaneous metastasis, which revealed that the daily i.p. administration of rH IL 2 resulted in significantly greater therapeutic activity than administration three times/week. The therapeutic protocol for daily i.p. administration had a biphasic dosage optimum, such that low dose therapeutic activity was observed at approximately 100-1000 units/animal in the treatment of experimental métastasesor 10 to 100 units/animal in the treatment of spontaneous métastases. There was a second dosage optimum at > 100,000 units/animal rH IL 2 delivered i.p. on a daily basis. Intermediate doses had no significant therapeutic activ ity. Additional studies revealed that low dose therapeutic activity was not observed in nude mice. In contrast, therapeutic activity was observed in nude mice at high doses of rH IL 2 suggesting that low dose activity was associated with a T-cell-mediated effect, whereas high dose activity may have been mediated by NK or lymphokine-activated killer-like cells. This observation was in agreement with the dose response for T-cell adjuvant activity supporting the hypothesis that low dose therapeutic activity was T-cell associated, because adjuvant activity was observed when rH IL 2 was given daily at approximately 100 units/animal for 3 days, and higher doses had no activity or had a suppressive effect. Because we were concerned about the pharmacological aspects of rH IL 2 treatment, we also examined its therapeutic properties after continuous administration i.p. by osmotic pumps. Under these conditions, therapeutic activity was observed after administration of 600 units/h, whereas lower or higher doses did not have significant therapeutic activity.
Efficacy and antitumor activity of a mutant type of interleukin 2
Scientific Reports
Interleukin-2 (IL-2) is an important cytokine in survival, expansion, function of CD8+ T cells and natural killer cells in immunotherapy of melanoma and renal cell carcinomas. Its severe toxicity following binding to its high affinity IL-2 receptor alpha (IL-2Rα) has restricted its application in cancer patients. In the present study, we investigated the antitumor efficacy and cytotoxicity of a mutated human IL-2 previously designed by selective amino acid substitutions, and its reduced affinity towards high-affinity IL-2Rα (CD25) was approved compared to the wild type IL-2 (wtIL-2). Furthermore, their ability to induce PBMC cell proliferation, and interferon-gamma secretion was compared. The mutant IL-2 also represented higher antitumor activity and more efficient cytotoxicity than wild type hIL-2. The developed mutant IL-2 can be an alternative tool in IL-2 associated immunotherapy of various cancers.
Cancer research, 1988
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 I...
Cancer research, 1988
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...
We have examined the ability of in vivo treatment of mice with recombinant interleukin 2 (rIL-2) to affect natural immunity measured against tumor (YAC-1) or virally infected (herpes simplex type 1) target cells. rIL-2 treatment leads to significant increases in natural killer/ lymphocyte-activated killer (NK/LAK) function and spleen cells re covered. This effect is dose dependent and strain related. The latter parameter correlated with the pretreatment NK activity level of the strain. The rIL-2 induced NK/LAK augmentation is also kinetic-ally restricted as treatment must have occurred within 48-72 h of assay to be effective. The rIL-2 therapy effectively enhances both antitumor and antiviral NK/LAK activity and results in a noticeable increase in asialo-CMi-positive cells in the spleens of treated mice as well as a significant increase in IL-2 receptor expression as monitored by either cytometry or radioligand binding. In vivo treatment of mice with an antibody directed to the ASGiMideterminant effectively reduces the rIL-2 augmentation of both antitumor and antiviral activity even though this treatment does not affect the pretreatment level of antiviral activity. Various natural and induced immunodeficiency states (immunotherapy, irradiation, immunosuppressive drugs, cytoreductive drugs) have been examined for the ability of in vivo treatment with rIL-2 to enhance NK/LAK activity. In vivo rIL-2 administration is differentially effective in enhancing NK/LAK activity in these situations. Notably, in these induced immunodeficiency states, although NK/LAK activity is commonly enhanced, the number of spleen cells recovered often is only marginally affected. Thus, as expected, a limiting aspect in this use of a natural immunomodulator is the number of potentially responsive cells present in the immunodeficiency condition. In addition, correlations between rIL-2 effect, several of the immunode ficiency states, and vascular leak syndrome are briefly discussed.
Cancer Immunology Immunotherapy, 1990
The in vivo administration of repetitive weekly cycles of interleukin-2 (IL-2) to patients with cancer enhances the ability of freshly obtained peripheral blood lymphocytes (PBL) to lyse both the natural-killer(NK)-susceptible K562 and the NK-resistant Daudi targets. Lysis of both targets is significantly augmented by inclusion of IL-2 in the medium during the cytotoxicity assay. This boost is much greater for cells obtained following the in vivo IL-2 therapy than for cells obtained prior to the initiation of therapy or for cells from healthy control donors. In addition to direct lytic activity, the PBL obtained following in vivo IL-2 show a rapid increase in lymphokine-activated killer (LAK) activity with more prolonged in vitro IL-2 exposure, indicating that LAK effectors primed in vivo respond with "secondary-like" kinetics to subsequent IL-2 in vitro. Lymphocytes from healthy control individuals, cultured in IL-2 untier conditions attempting to simulate the in vivo IL-2 exposure, function similarly to PBL obtained from patients following IL-2, in that low-level LAK activity was significantly boosted by inclusion of IL-2 during the cytotoxic assay and the cells also responded with secondary-like kinetics to subsequent IL-2 in vitro. The augmentation of the LAK effect was also dependent on the dose of IL-2 added during the 4-h »lCr-release cytotoxicity assay, with higher doses of IL-2 having a more pronounced effect. While continuous infusion of IL-2 induces a greater cytotoxic potential per milliliter of blood obtained from patients, the peak serum IL-2 levels attained are greater with bolus IL-2 infusions. These pharmacokinetic results, together with the IL-2 dose dependence of LAK activity generated in vivo shown in this report, suggest that a combination of treatment with bolus IL-2 infusions superimposed on continuous IL-2 infusion may transiently expose IL-2 dependent LAK cells, activated in vivo, to higher concentrations of IL-2, facilitating their in vivo cytotoxic potential.
Effects of human recombinant interleukin 2 on in vitro tumor cytotoxicity in dogs
American journal of veterinary research, 1991
In these studies, the effects of recombinant human interleukin 2 (rHuiL-2) were examined on in vitro tumor cytotoxicity by canine blood lymphocytes obtained from peripheral vessels through use of a chromium release microcytotoxicity assay. Cytotoxic activity by lymphokineactivated killer cells was significantly increased, compared with that by untreated lymphocytes in a dose-dependent manner. The maximal effect was attained with 300,000 IU of rHuiL-2/ml. Lymphokine-activated killing also was dependent on the duration of incubation with rHuiL-2. After 1 day of rHuiL-2 incubation, cytotoxicity was significantly increased, compared with that of untreated lymphocytes. Of the 3 times examined, cytotoxicity peaked after 3 days of rHuiL-2 incubation. High levels of cytotoxic activity were still present at 7 days of incubation. Numbers of granular lymphocytes increased over the times examined. These results demonstrate functional and morphologic changes in canine peripheral blood lymphocytes obtained from peripheral vessels after incubation with rHuiL-2 in a dose-and time-dependent manner. Cell-mediated cytotoxicity is associated with the occurrence and progression of cancer in several species.1"5 Natural killer (NK) cell activity, a type of cellular cytotoxicity, is reduced in people and dogs with lymphoma.6"10 This cytotoxic activity by human, murine, and porcine lymphocytes may be enhanced by interleukin 2 (iL-2).11"13 Treatment of people with hemolymphatic malignancies has recently involved attempts to activate killer cell activity in vitro and in vivo with recombinant IL-2.14"19 The proliferative effects of recombinant human interleukin-2 (rHuiL-2) on blood lymphocytes obtained from peripheral vessels (PEL) from dogs have been examined.20 To further investigate the effects in dogs, studies were conducted to determine the in vitro cytotoxic effects of IL-2 on canine PEL. Previous studies of this nature have been limited.21 Large granular lymphocytes (LGL) have been associ