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INTERLEUKIN-2: SUNRISE FOR IMMUNOTHERAPY?
308
would produce a distorted existence and mental invalidism". Armed with an insulin pen, a well-educated, highly motivated diabetic who is
physiological perfection
prepared to monitor blood glucose frequently good control without such unhappy results.
can
obtain
INTERLEUKIN-2: SUNRISE FOR IMMUNOTHERAPY? ATTEMPTS to activate the body’s own defences against have a long history-mainly of failure. However, the work of Dr Steven Rosenberg’s group at the National Cancer Institute (NCI) in Bethesda on the use of interleukin-2 (IL-2) may prove to be just as far reaching as that of the early chemotherapists. A conference at the Free University of Amsterdam last November summarised the current position on the therapeutic use of IL-2. IL-2 is a lymphokine produced by T-helper lymphocytes. It was originally known as T-cell growth in the of factor and discovered supernatants phytohaemagglutinin-stimulated lymphocyte cultures.2 It is produced by some T cell leukaemias and a gene from one of them (Jurkat) has been transfected into Escherichia coli to produce large quantities of recombinant IL-2 for therapeutic use.3 IL-2 not only supports the growth of T cells and permits their almost unlimited expansion in vitro, but also enhances tumour cell cytotoxicity by both T cells and natural killer (NK) cells. This effect, known as lymphokine-activated killer (LAK) activity, has stimulated therapeutic interest in the molecule. Nearly 3000 patients have been treated with IL-2 worldwide. Rosenberg’s group have amassed the greatest experience: these workers have treated 483 patients and seen impressive tumour regressions, particularly in metastatic melanoma and renal cell carcinoma. From animal studies Rosenberg has established that the response rate is related to the dose of IL-2, and that the reinfusion of LAK cells (mononuclear cells activated in 4-5 day culture with IL-2) greatly enhances the effect of the IL-2. At the meeting Rosenberg gave the results of a prospective randomised trial of LAK cells plus IL-2 versus IL-2 alone in 180 patients with metastatic renal cell carcinoma. Objective responses (> 50% shrinkage of measurable disease) were seen in 20% of patients treated with IL-2 alone compared with 30% in those treated additionally with LAK cells. Complete clinical remissions were seen only in the LAK group, in about a third of those responding. The complete responses have proved durable-in 1 patient for as long as four years-and even in patients with partial responses the disease has sometimes shown little inclination to relapse. These results were set in context by Prof Thiery Philip (Lyon), who reported his experience with 147 patients with metastatic renal cancer previously treated in centres in France with various therapies. Only 1 had an objective response, and the median survival was eight months. Like other researchers he had seen an objective response with IL-2 and LAK cells of approximately 20%. cancer
The benefit of increasing the dose of IL-2 was shown by Dr P. A. Paciucci (Mount Sinai, New York). He attempted to treat 32 patients with 100 megaunits/m21 day of IL-2 given by continuous infusion over twenty-eight days with twentyfour hours’ rest every seventh day. Only 8 patients were able to tolerate the full dose, but 6 of the 7 patients with melanoma who did so achieved objective responses. In general, higher response rates were seen in patients who received the larger doses. The side-effects of IL-2 have been well documented* and include fever; nausea, vomiting, and diarrhoea; erythroderma; hypotension; fluid retention; pulmonary interstitial oedema; confusion; and in rare cases cardiac arrhythmias. Although much has been made of their severity,s in fact they are less difficult to manage than those of cytotoxic drugs. Most side-effects cease within a few hours of stopping IL-2, and Rosenberg reported a treatment-related mortality of 19%, far less than that of bone marrow autografts and less than that of most surgery in patients with metastatic cancer. The second largest series of patients was reported by Dr W. H. West (Tennessee) who has treated 110 patients. Whereas Rosenberg gave IL-2 by intravenous bolus every eight hours, West used continuous intravenous infusions in an attempt to reduce side-effects. Although his response rates in melanoma and renal cancer were broadly in line with those of the NCI group, it remains to be established whether boluses or infusions produce fewer side-effects per patient response. The response of other
tumour types to IL-2 therapy is less encouraging. Several studies with combinations of IL-2 and either cytotoxic drugs or other biological response modifiers were reported but it is too early to assess the results. The most promising new application of IL-2 is with tumour infiltrating lymphocytes (TILs). If biopsy specimens of melanoma deposits are teased out, cell suspensions may be established in culture with IL-2. After a short period of culture, melanoma cells die and the culture is overgrown by T lymphocytes. This cell population may be expanded in long-term cultures with IL-2 so that about 1011 lymphocytes may be reinfused into the patient. Of 15 patients treated in this way by Rosenberg et al,6 objective responses were achieved in 9, including one complete remission. 2 of the patients who responded had previously shown no response to LAK therapy. In experimental systems TILs are up to a hundred times more potent than LAK cells. Whereas LAK cells are mainly activated NK cells, TILs appear to be activated cytotoxic T cells and so show greater specificity in their targets, and recirculate and home on tumour masses in a way that LAK cells do not. TILs may be obtained from other types of tumour but the methods are more complex. Immunotherapy has experienced many false dawns-the promises of tumour vaccination, interferon, and anriidiotypic antibodies have not been kept. Despite the difficulties of adapting IL-2 and LAK cells to the clinic, the outlook is bright.
Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985, 313: 1485-92 5. Moertel CG. On lymphokines, cytokines, and breakthroughs. N Engl J Med 1986, 256: 1341 6. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes in the immunotherapy of patients with metastatic melanoma N Engl J Med 1988; 319: 1676-80. 4.
Rosenberg SA, Terry W Passive immunotherapy of cancer in animals and man Adv Cancer Res 1977; 25: 323-88. 2. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 1976; 193: 1007-08. 3 Taniguchi T, Matsui H, Fujita T, et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature 1983; 302: 305-06. 1
Rosenberg SA,
would produce a distorted existence and mental invalidism". Armed with an insulin pen, a well-educated, highly motivated diabetic who is
physiological perfection
prepared to monitor blood glucose frequently good control without such unhappy results.
can
obtain
INTERLEUKIN-2: SUNRISE FOR IMMUNOTHERAPY? ATTEMPTS to activate the body’s own defences against have a long history-mainly of failure. However, the work of Dr Steven Rosenberg’s group at the National Cancer Institute (NCI) in Bethesda on the use of interleukin-2 (IL-2) may prove to be just as far reaching as that of the early chemotherapists. A conference at the Free University of Amsterdam last November summarised the current position on the therapeutic use of IL-2. IL-2 is a lymphokine produced by T-helper lymphocytes. It was originally known as T-cell growth in the of factor and discovered supernatants phytohaemagglutinin-stimulated lymphocyte cultures.2 It is produced by some T cell leukaemias and a gene from one of them (Jurkat) has been transfected into Escherichia coli to produce large quantities of recombinant IL-2 for therapeutic use.3 IL-2 not only supports the growth of T cells and permits their almost unlimited expansion in vitro, but also enhances tumour cell cytotoxicity by both T cells and natural killer (NK) cells. This effect, known as lymphokine-activated killer (LAK) activity, has stimulated therapeutic interest in the molecule. Nearly 3000 patients have been treated with IL-2 worldwide. Rosenberg’s group have amassed the greatest experience: these workers have treated 483 patients and seen impressive tumour regressions, particularly in metastatic melanoma and renal cell carcinoma. From animal studies Rosenberg has established that the response rate is related to the dose of IL-2, and that the reinfusion of LAK cells (mononuclear cells activated in 4-5 day culture with IL-2) greatly enhances the effect of the IL-2. At the meeting Rosenberg gave the results of a prospective randomised trial of LAK cells plus IL-2 versus IL-2 alone in 180 patients with metastatic renal cell carcinoma. Objective responses (> 50% shrinkage of measurable disease) were seen in 20% of patients treated with IL-2 alone compared with 30% in those treated additionally with LAK cells. Complete clinical remissions were seen only in the LAK group, in about a third of those responding. The complete responses have proved durable-in 1 patient for as long as four years-and even in patients with partial responses the disease has sometimes shown little inclination to relapse. These results were set in context by Prof Thiery Philip (Lyon), who reported his experience with 147 patients with metastatic renal cancer previously treated in centres in France with various therapies. Only 1 had an objective response, and the median survival was eight months. Like other researchers he had seen an objective response with IL-2 and LAK cells of approximately 20%. cancer
The benefit of increasing the dose of IL-2 was shown by Dr P. A. Paciucci (Mount Sinai, New York). He attempted to treat 32 patients with 100 megaunits/m21 day of IL-2 given by continuous infusion over twenty-eight days with twentyfour hours’ rest every seventh day. Only 8 patients were able to tolerate the full dose, but 6 of the 7 patients with melanoma who did so achieved objective responses. In general, higher response rates were seen in patients who received the larger doses. The side-effects of IL-2 have been well documented* and include fever; nausea, vomiting, and diarrhoea; erythroderma; hypotension; fluid retention; pulmonary interstitial oedema; confusion; and in rare cases cardiac arrhythmias. Although much has been made of their severity,s in fact they are less difficult to manage than those of cytotoxic drugs. Most side-effects cease within a few hours of stopping IL-2, and Rosenberg reported a treatment-related mortality of 19%, far less than that of bone marrow autografts and less than that of most surgery in patients with metastatic cancer. The second largest series of patients was reported by Dr W. H. West (Tennessee) who has treated 110 patients. Whereas Rosenberg gave IL-2 by intravenous bolus every eight hours, West used continuous intravenous infusions in an attempt to reduce side-effects. Although his response rates in melanoma and renal cancer were broadly in line with those of the NCI group, it remains to be established whether boluses or infusions produce fewer side-effects per patient response. The response of other
tumour types to IL-2 therapy is less encouraging. Several studies with combinations of IL-2 and either cytotoxic drugs or other biological response modifiers were reported but it is too early to assess the results. The most promising new application of IL-2 is with tumour infiltrating lymphocytes (TILs). If biopsy specimens of melanoma deposits are teased out, cell suspensions may be established in culture with IL-2. After a short period of culture, melanoma cells die and the culture is overgrown by T lymphocytes. This cell population may be expanded in long-term cultures with IL-2 so that about 1011 lymphocytes may be reinfused into the patient. Of 15 patients treated in this way by Rosenberg et al,6 objective responses were achieved in 9, including one complete remission. 2 of the patients who responded had previously shown no response to LAK therapy. In experimental systems TILs are up to a hundred times more potent than LAK cells. Whereas LAK cells are mainly activated NK cells, TILs appear to be activated cytotoxic T cells and so show greater specificity in their targets, and recirculate and home on tumour masses in a way that LAK cells do not. TILs may be obtained from other types of tumour but the methods are more complex. Immunotherapy has experienced many false dawns-the promises of tumour vaccination, interferon, and anriidiotypic antibodies have not been kept. Despite the difficulties of adapting IL-2 and LAK cells to the clinic, the outlook is bright.
Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985, 313: 1485-92 5. Moertel CG. On lymphokines, cytokines, and breakthroughs. N Engl J Med 1986, 256: 1341 6. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes in the immunotherapy of patients with metastatic melanoma N Engl J Med 1988; 319: 1676-80. 4.
Rosenberg SA, Terry W Passive immunotherapy of cancer in animals and man Adv Cancer Res 1977; 25: 323-88. 2. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 1976; 193: 1007-08. 3 Taniguchi T, Matsui H, Fujita T, et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature 1983; 302: 305-06. 1
Rosenberg SA,