Original Article
An Acquired Chemotactic Defect in Neutrophils from Patients Receiving Interleukin-2 Immunotherapy
N Engl J Med 1990; 322:959-965April 5, 1990
- Abstract
- Abstract
Bacterial sepsis is a frequent complication in patients with cancer who are receiving high doses of interleukin-2. We evaluated the function of neutrophils from such patients to determine whether there was any abnormality in this form of host defense.
Before interleukin-2 therapy, neutrophils from 31 patients with metastatic cancer were normal in assays of random migration and chemotaxis. Superoxide production, phagocytosis, secretion of granule proteins, and bactericidal activity were also normal. Neutrophils from the patients near the end of the first course of interleukin-2 had severely impaired chemotaxis in response to a formylated peptide stimulus (mean [±SEM], 49.6±7.4 percent of base line; P<0.001). The defect in chemotaxis improved 5 to 10 days after patients completed the first course of interleukin-2 therapy but recurred toward the end of the second course of such therapy (35.3±6.9 percent of base line; P<0.001). The chemotactic response to a second stimulus (zymosan-activated serum) was also abnormal, but random migration, superoxide production, bactericidal activity, and the secretion of neutrophil granule constituents remained normal or increased throughout treatment with interleukin-2.
We conclude that patients who receive interleukin-2 immunotherapy acquire an acute, profound, and reversible defect in neutrophil chemotaxis that may contribute to the high morbidity resulting from bacterial infections in these patients. (N Engl J Med 1990; 322:959–65.)
Article Activity
- Article
INTERLEUKIN-2 is a 15,000-dalton protein that is produced and secreted by activated T lymphocytes and has profound effects on the immune response.1 , 2 One of these effects is the induction of lymphokine-activated killer cells that are able to lyse a broad spectrum of malignant cells in vitro.3 Because extensive studies in tumor-bearing animals and initial trials of high doses of interleukin-2 and lymphokine-activated killer cells in humans with metastatic cancer demonstrated marked tumor regression,4 5 6 7 a large-scale multi-institutional trial of such therapy was undertaken. These studies largely confirmed the observations that immunotherapy with interleukin-2 and lymphokine-activated killer cells can lead to tumor regression in patients with metastatic cancer.8 9 10
Patients who receive interleukin-2 have a wide array of toxic side effects.11 12 13 Among the most common are chills and fever, diarrhea, diffuse erythroderma, hyperbilirubinemia, anemia, thrombocytopenia, eosinophilia, and a capillary leak syndrome characterized by hypotension, edema, and renal insufficiency. In addition, bacteremia with nonopportunistic pathogens has been an unusually frequent complication of treatment with interleukin-2. Among 345 patients treated with a standardized regimen of interleukin-2 and lymphokine-activated killer cells at the institutions participating in the extramural interleukin-2 program sponsored by the National Institutes of Health, 88 (25.5 percent) had bacteremia (Aronson F, Weiss G, Margolin K, Dutcher J, Ito J: personal communication). The incidence of bacteremia ranged from 19.0 to 38.1 percent at the cooperating institutions. Since central venous catheters are used for vascular access during the course of treatment with interleukin-2 and because Staphylococcus aureus and S. epidermidis have been the most commonly isolated pathogens, vascular catheters have been implicated. At our institution, 20 of 107 courses of interleukin-2 were complicated by sepsis.14 Twelve of these episodes were documented to be catheter-related. For comparison, the incidence of sepsis is 4.3 percent in patients at this institution who receive total parenteral nutrition through an indwelling central venous catheter that remains in place for a length of time comparable to that in the interleukin-2—treated patients.15 At the five other participating institutions, the incidence of sepsis among patients without neutropenia who have central venous catheters for vascular access has been 5.1 percent. Because of the high incidence of staphylococcal infections in patients receiving interleukin-2 therapy, we suspected that neutrophil function might be impaired in these patients.
Methods
Study Design
Patients were treated in the clinical study unit of the New England Medical Center and were participants either in a larger, six-center clinical trial of interleukin-2 and lymphokine-activated killer cells conducted by the National Cancer Institute Extramural Interleukin-2/Lymphokine-Activated Killer Cell Working Group or in institutional trials including high-dose interleukin-2. Thirteen patients had melanoma, 16 had renal-cell carcinoma, and 1 each had ovarian and pancreatic carcinoma. All 31 patients had metastatic disease; none were receiving concomitant chemotherapy. Four distinct treatment regimens were used, all involving the maximal tolerated doses of interleukin-2 either alone or in combination with lymphokine-activated killer cells, interferon alfa, or both. Neutrophil function was assessed in each of these 31 patients, all of whom completed treatment between January 1988 and July 1989. All treatment protocols were designed in cooperation with the National Cancer Institute and approved by the Food and Drug Administration and the human-investigation review committee at the New England Medical Center. Written informed consent was obtained from each patient.
Four patients were treated with interleukin-2 (Cetus, Emeryville, Calif.) and lymphokine-activated killer cells according to a protocol described by Rosenberg et al.,6 except that leukapheresis was performed on four days (days 8 through 11) instead of five days (days 8 through 12). Seven patients were treated according to a modified protocol in which interleukin-2 (Cetus) was administered by continuous intravenous infusion at a dose of 1 mg per square meter of body-surface area per day before leukapheresis (days 1 through 5) and at 1.25 mg per square meter per day during the administration of lymphokine-activated killer cells (days 11 through 16); leukapheresis was performed on days 7 through 10. Eleven additional patients received high-dose bolus infusions of interleukin-2 (Cetus) without lymphokine-activated killer cells; this group included seven patients assigned to a regimen in which the second course of interleukin-2 treatment was delayed until day 15. Finally, nine patients received interleukin-2 (Hoffmann—LaRoche, Nutley, N.J.) (4.5×106 U per square meter) together with interferon alfa (Hoffmann—LaRoche) (3×106 U per square meter) intravenously every eight hours on days 1 through 5 and 11 through 15; leukapheresis was performed on days 7 through 10, and lymphokine-activated killer cells were administered on days 11, 12, and 14. Nineteen of these patients also participated in a multi-institutional randomized, double-blind, placebo-controlled trial of antibiotic prophylaxis with the investigational quinolone temafloxacin (Abbott, North Chicago).
Blood for studies of neutrophil function was obtained five times: before treatment (day 1), near the end of the first course of interleukin-2 (day 4 or 5), immediately before the beginning of the second course (days 10 through 15), near the completion of the second course (day 15, 16, or 19), and approximately two weeks after the conclusion of treatment.
Isolation of Neutrophils
Venous blood treated with heparin (20 U of heparin per milliliter of blood) was obtained on the same day from patients and normal subjects (hospital personnel). Leukocyte preparations containing 95 to 98 percent neutrophils were isolated by Hypaque—Ficoll density-gradient centrifugation and dextran sedimentation as described elsewhere.16 Residual erythrocytes were lysed twice with hypotonic saline. The cells were suspended in Hanks' balanced salt solution.
Superoxide Assay
The production of superoxide by neutrophils was determined by measuring the capacity of cells to reduce ferricytochrome c to ferrocytochrome c.17 Neutrophils (1×106 or 5×106 cells per milliliter in Hanks' balanced salt solution, pH 7.2) were stimulated with 4-beta-phorbol 12-beta-myristate 13-alpha-acetate (PMA; Sigma Chemical, St. Louis) or N-formyl-1-methionyl-1-leucyl-1-phenylalanine (FMLP; Sigma) in the presence and absence of cytochalasin B (5 μg per milliliter; Sigma). Buffer was used as a negative control. At intervals during a 20-minute incubation at 37°C, the cell-free supernatants were assayed for superoxide production. The results were expressed as a percentage of superoxide production by the neutrophils from normal donors.
Degranulation
Neutrophils (5×106 cells per milliliter in Hanks' balanced salt solution, pH 7.2) were incubated with PMA or FMLP in the presence of cytochalasin B (5 μg per milliliter) or buffer. After a 20-minute incubation at 37°C, the cell-free supernatants as well as suspensions of cells lysed with 0.2 percent Triton X-100 (Fisher Scientific, Pittsburgh) were assayed for lysozyme, β-glucuronidase, and vitamin B12 binding protein according to previously described methods.17 , 18 Degranulation was expressed as the percentage of the granule protein released into the supernatants from the total cellular content of granule protein (lysates).
Phagocytosis
Phagocytosis of opsonized bacterial particles was determined by measuring the uptake of 14C-labeled, heat-killed S. aureus as previously described.17 Phagocytosis was expressed as mean counts per minute (of duplicate determinations) per 107 neutrophils. The results were expressed as a percentage of phagocytosis by neutrophils from normal donors.
Bactericidal Assay
The ability of neutrophils to kill viable S. aureus strain 502a was measured at intervals according to methods described elsewhere,19 except that the ratio of bacteria to cells was 1:1.
Chemotaxis
The chemotaxis assay was carried out according to a modification21 of the method described by Metcalf et al.20 The bottom wells of blind well chambers were filled with 250 μl of 10−8 M FMLP, 10 percent zymosan-activated serum, or Hanks' balanced salt solution (pH 7.4), and the top wells were filled with 600 μl of Hanks' balanced salt solution containing 2 percent bovine serum albumin (Sigma) and 2.5×106 neutrophils per milliliter. The two wells were separated by a cellulose nitrate filter with 3–μm pores (type SM 11303, Sartorius, Westbury, N.Y.). The chambers were incubated at 37°C in humidified air with 5 percent carbon dioxide for 60 to 120 minutes. Triplicate filters were then removed, stained, and evaluated as described elsewhere.20 The chemotactic index was determined by calculating the percentage of stimulated migration above the random (unstimulated) migration. The results were expressed as a percentage of the chemotactic response to FMLP or zymosan-activated serum by the neutrophils from normal donors.
Statistical Analysis
Student's t-test was used for statistical evaluation of the findings.
Results
Clinical Characteristics
The clinical characteristics of the 31 patients are summarized in Table 1Table 1
Clinical Characteristics of 31 Patients Receiving Interleukin-2.. Seven patients had bacterial sepsis (four due to S. aureus, two to S. epidermidis, and one to Enterobacter cloacae and Escherichia coli) and received intravenous antibiotic therapy. One patient died of overwhelming sepsis. All seven patients also had desquamative skin rashes and surveillance cultures that were positive for staphylococcal species. No patient had marked neutropenia (<1.0×109 granulocytes per liter) during the study. Other toxic effects were similar to those described elsewhere for such therapy.13 Superoxide Production
The effect of interleukin-2 therapy on spontaneous and stimulated production of Superoxide by neutrophils is shown in Figure 1Figure 1
Effect of Interleukin-2 Therapy on Spontaneous and Stimulated Production of Superoxide by Neutrophils (Panel A) and the Kinetics of Superoxide Production by Neutrophils from Patients and Normal Subjects at the Indicated Times after Stimulation with the Phorbol Ester PMA (Panel B).. This response was not decreased at any time during the therapy. As shown in Figure 1A, there was an increase in FMLP-induced production of Superoxide by neutrophils near the end of the second course of interleukin-2 (day 4 or 5) and in spontaneous production approximately two weeks after the end of treatment (P<0.02). The mean (±SEM) spontaneous production of superoxide by normal cells was 6.3±1.2, 9.4±2.6, 11.9±2.3, 11.4±3.5, and 7.5±1.3 nmol of cytochrome c reduced per 5×106 neutrophils per 20 minutes before treatment (day 1), near the end of the first course (day 4 or 5), immediately before the second course (days 10 through 15), near the end of the second course (day 15, 16, or 19), and approximately two weeks after treatment ended, respectively. Superoxide production by normal cells after stimulation with PMA (5 μg per milliliter) was 57.5±3.5, 50.1±2.9, 46.6±2.2, 46.6±3.6, and 52.9±5.3 nmol of cytochrome c reduced per 5×106 neutrophils per 20 minutes, respectively. FMLP-stimulated production of Superoxide by normal cells was 27.6±5.8, 40.9±7.1, 40.4±7.7, 26.0±9.1, and 30.0±10.3 nmol of cytochrome c reduced per 5×106 neutrophils per 20 minutes, respectively. The kinetics of Superoxide production by neutrophils from the normal subjects and those collected from the patients before and near the end of the first course of interleukin-2 (day 4 or 5) are shown in Figure 1B. Both the rate and the total amount of Superoxide produced by a lower concentration of neutrophils (1 × 106 per milliliter) stimulated with PMA (10 ng per milliliter) were normal. There were also no differences between the normal donors and patients in the spontaneous production of Superoxide or in the rate of Superoxide generation by neutrophils stimulated by FMLP in the presence or absence of cytochalasin B.Degranulation
The effect of interleukin-2 therapy on the secretion of neutrophil granule constituents in response to FMLP (5×10–7 M) before treatment and after the first course of interleukin-2 is shown in Figure 2Figure 2
Effect of Interleukin-2 Therapy on the Secretion of the Granule Proteins Lysozyme, β-Glucuronidase, and Vitamin B12–Binding Protein by Neutrophils Stimulated by the Chemotactic Peptide FMLP plus Cytochalasin B.. There were no significant differenees in neutrophil secretion between the patients and normal subjects. The total cellular content of all three granule-associated proteins was normal. The secretion of lysozyme by neutrophils from patients in response to FMLP (plus cytochalasin B) was also normal in cells isolated before and after the second course of interleukin-2 (n = 5; data not shown).Phagocytosis of S. aureus
The effect of interleukin-2 therapy on the uptake of 14C-labeled, heat-killed S. aureus by neutrophils is shown in Figure 3Figure 3
Effect of Interleukin-2 Therapy on Phagocytosis of 14C-Labeled S. aureus by Neutrophils.. Phagocytosis was normal at all times during the study (n = 5).Bactericidal Activity
Neutrophils from normal subjects and from patients before treatment and after their first course of interleukin-2 were tested for their ability to kill S. aureus (Fig. 4Figure 4
Effect of Interleukin-2 Therapy on the Bactericidal Activity of Neutrophils.). All three groups of neutrophils were able to kill approximately 90 percent of the bacteria after a 90-minute incubation. The kinetics of the bactericidal activity were similar for the neutrophils from the normal subjects and patients before and after interleukin-2 therapy.Chemotaxis
Figure 5Figure 5
Effect of Interleukin-2 Therapy on the Chemotactic Response of Neutrophils to the Chemotactic Peptide FMLP(10–8 M). shows the effect of interleukin-2 therapy on the chemotactic response of neutrophils to FMLP in all 31 patients. Random migration was normal throughout the course of therapy. The mean distance of random migration of the neutrophils from the normal subjects was 69±3 μm (range, 66 to 72), as compared with 62±3 μm (range, 58 to 71) for the neutrophils from the patients. However, migration in response to FMLP was markedly inhibited near the end of both the first (49.6±7.4 percent of normal) and the second (35.3±6.9 percent of normal) course of interleukin-2 (P<0.001 for both). FMLP stimulated the neutrophils obtained from patients near the end of the first course of treatment (day 4 or 5) and the second course (day 15, 16, or 19) to migrate 73±3 μm and 66±5 μm, respectively, whereas it stimulated the neutrophils obtained from normal subjects at the same times to migrate 126±4 μm and 117±4 μm, respectively. Among the neutrophils from patients, there was no significant difference between migration toward a buffer stimulus (i.e., random migration) and toward the chemotactic peptide. The chemotactic defect was not observed in four patients near the end of the first course (day 4 or 5) of interleukin-2. In three of the four patients who had normal migration of neutrophils after the first course of interleukin-2, neutrophil chemotaxis was markedly abnormal near the end of the second course (45.7±4.6 percent of normal). The chemotactic response of neutrophils to FMLP returned to normal during the rest phase before the second course of interleukin-2. Neutrophils from one patient migrated normally near the end of both the first and second courses. When studied approximately two weeks after the completion of the interleukin-2 therapy (post-treatment), the chemotactic response was variable. In 6 of the 15 patients tested, the chemotactic response to FMLP was ≤70 percent of the normal response (range, 11 to 70 percent). In the other nine patients, the response was normal or enhanced (106 to 213 percent of normal). Overall, the post-treatment differences were not statistically significant.The migration of neutrophils in response to a second stimulus, zymosan-activated serum, was evaluated in eight patients before and after the administration of interleukin-2. Neutrophils from each of these patients also failed to migrate in response to zymosan-activated serum (P<0.001; Fig. 6Figure 6
Effect of Interleukin-2 Therapy on the Chemotactic Response of Neutrophils to 10 Percent Zymosan-Activated Serum.). Although random migration of neutrophils was normal in these patients, zymosan-activated serum stimulated migration of 68±5 μm, as compared with 116±10 μm for normal cells.Discussion
This study demonstrates that neutrophils from patients undergoing high-dose interleukin-2 therapy with or without lymphokine-activated killer cells acquired a profound chemotactic defect. The defect was present during the first course of treatment with interleukin-2, was reversed one week after the completion of the interleukin-2 infusion, and recurred during the second phase of the treatment protocol, which included the infusion of lymphokine-activated killer cells in 20 of the 31 patients. This defect was evident in patients receiving high-dose interleukin-2 from two manufacturers, by either intermittent or continuous intravenous infusion, with or without lymphokine-activated killer cells and interferon alfa, and with or without prophylactic administration of a quinolone antibiotic. In some patients, impairment of neutrophil chemotaxis persisted for at least two weeks after the end of the treatment. Unlike chemotaxis, random migration, superoxide production, phagocytosis, bactericidal activity, and secretion of granule constituents were normal or increased in neutrophils from these same patients.
The pressing clinical question arising from this study is how the acquired chemotactic defect relates to the high incidence of bacterial sepsis in patients receiving interleukin-2 therapy. None of the patients treated with interleukin-2 had a history of sepsis, and neutrophil function was normal in all patients on entry into the study. The infections in patients treated with interleukin-2 typically coincided with the occurrence of the neutrophil defect and were not associated with neutropenia. In general, the organism most likely to cause infections in patients with marked defects in neutrophil function is S. aureus. As in patients with chronic granulomatous disease whose neutrophils have an abnormal respiratory burst, S. aureus is the most frequent pathogen isolated from patients with Chédiak—Higashi syndrome,22 hyperimmunoglobulinemia E (Job) syndrome,23 neutrophil actin dysfunction,24 and adhesive glycoprotein deficiency25; all these diseases are associated with profound chemotactic defects. The organisms causing sepsis in the patients treated with interleukin-2 at this institution were S. aureus (65 percent), S. epidermidis (25 percent), and E. coli (10 percent).14 S. aureus was also isolated from the vast majority of patients with bacteremia at the five other institutions participating in the trial of interleukin-2 treatment (Aronson F, Weiss G, Margolin K, Dutcher J, Ito J: personal communication). Thus, in these patients whose other neutrophil functions were normal, there was not only a temporal relation between the development of a chemotactic defect and sepsis in patients treated with interleukin-2, but also a concordance between the organisms isolated from these patients and the organism cultured from patients with other diseases associated with clinically important chemotactic defects.
Murphy et al. recently reported a high frequency of nonopportunistic bacterial infections in patients with the acquired immunodeficiency syndrome (AIDS) who received interleukin-2.26 A similar cohort of patients with AIDS receiving interferon gamma did not have bacterial infections. Seventeen of 52 patients given interleukin-2 had a total of 20 bacterial infections, whereas no infections occurred in 22 patients given interferon gamma. S. aureus was the etiologic agent in 5 of the 12 episodes of bacteremia. These investigators speculated that a defect in phagocyte function might account for the predisposition to bacterial infection in patients with AIDS who receive interleukin-2, but this conjecture was not tested.
The mechanism for the induction of a chemotactic defect in the neutrophils of patients treated with interleukin-2 cannot be established from the available data. Despite the fact that neutrophils do not express high-affinity receptors for interleukin-2, as determined by binding of antibodies to the Tac peptide,27 Kowanko and Ferrante have reported inhibition of random and chemotactic migration after in vitro incubation of neutrophils with either purified T-cell—derived or recombinant interleukin-2.28 Interleukin-2 also appeared to stimulate the respiratory burst and the release of lysosomal enzymes. Although we did observe a defect in neutrophil chemotaxis in our patients undergoing treatment with interleukin-2, we did not observe a decrease in random migration or a stimulation of Superoxide production or granule-protein secretion when interleukin-2 was given in vivo, as has been reported in vitro. Moreover, the chemotactic response to FMLP of normal neutrophils after in vitro incubation with recombinant interleukin-2 (at concentrations that included the serum levels in patients treated with interleukin-2, 0.1 to 1000 U per milliliter) was completely normal (data not shown).
Tumor necrosis factor29 and interferon gamma30 are consistently detected in the plasma of recipients of interleukin-2. These secondary cytokines are believed to be responsible for many of the toxic manifestations of interleukin-2 therapy.11 Moreover, tumor necrosis factor can produce defective neutrophil chemotaxis in vitro and therefore may be responsible for the neutrophil deficit associated with interleukin-2 therapy.31 Tumor necrosis factor stimulates the expression of leukocyte adhesion molecules by cultured endothelial cells,32 and these molecules are also expressed in vivo after interleukin-2 therapy.33 This could deplete from the circulation neutrophils that express receptors for these adhesion molecules and are capable of normal chemotaxis. The contribution of other cytokines inducible by interleukin-2 to the chemotactic defect observed in patients treated with interleukin-2 is less clear. Although granulocytemacrophage colony-stimulating factor may be generated in response to interleukin-2 and may be responsible for the eosinophilia noted in our patients, this cytokine is known to inhibit the random migration of neutrophils34 and enhances the expression of FMLP receptors and the chemotactic response to this peptide.35 These findings suggest that granulocytemacrophage colony-stimulating factor is not the mediator of the impairment in granulocyte function associated with interleukin-2.
The concomitant administration of dexamethasone markedly reduces the side effects of interleukin-2 therapy, possibly through the inhibition of secondary cytokines such as tumor necrosis factor. None of 18 patients treated at the New England Medical Center with interleukin-2 plus dexamethasone have had bacterial infections. Neutrophil chemotaxis was measured in three of these patients and found to be only slightly decreased (Mier JW, et al.: unpublished data). This result suggests that the neutrophil defect may be due either to a steroid-sensitive direct effect of interleukin-2 or to a cytokine inducible by interleukin-2 (e.g., tumor necrosis factor) whose synthesis, release, or interaction with neutrophils is blocked by steroids.
If this intrinsic neutrophil defect is responsible for the high incidence of sepsis in patients receiving interleukin-2, then prophylactic antibiotics directed principally against S. aureus and S. epidermidis may be of benefit. We are conducting a randomized, double-blind, placebo-controlled trial of prophylactic antibiotics in conjunction with the ongoing extramural trials of interleukin-2. It is hoped that the routine inclusion of antibiotics in the high-dose interleukin-2 regimens may prevent what is clearly one of the most serious consequences of such treatment.
Supported in part by a grant (AI-16732), a General Clinical Research Center grant (CRR-00088), and a contract (RO1-CM-73706) from the National Institutes of Health.
We are indebted to Ms. Carol McClarey for assistance with the preparation of the manuscript, to the medical house staff and clinical study unit nurses for caring for these patients, to Ms. Jody Gould, R.N., and Ms. Kerry O'Brien, R.N., for coordinating patient care, and to Ms. Karen Mazzotta, R.N., Mr. James Phillips, and Mr. William Andrews for data collection.
Source Information
From the Divisions of Geographic Medicine and Infectious Diseases (M.S.K., R.N.) and Hematology—Oncology (J.W.M., M.B.A.), Department of Medicine, New England Medical Center and Tufts University School of Medicine, Boston. Address reprint requests to Dr. Klempner at the New England Medical Center, 750 Washington St., Box 236, Boston, MA 02111.
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