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physiological perfection would produce a distortedexistence and mental invalidism". Armed with an insulin

pen, a well-educated, highly motivated diabetic who is

prepared to monitor blood glucose frequently can obtaingood control without such unhappy results.

INTERLEUKIN-2: SUNRISE FORIMMUNOTHERAPY?

ATTEMPTS to activate the body’s own defences againstcancer have a long history-mainly of failure. However, thework of Dr Steven Rosenberg’s group at the NationalCancer Institute (NCI) in Bethesda on the use ofinterleukin-2 (IL-2) may prove to be just as far reaching asthat of the early chemotherapists. A conference at the FreeUniversity of Amsterdam last November summarised thecurrent position on the therapeutic use of IL-2.

IL-2 is a lymphokine produced by T-helperlymphocytes. It was originally known as T-cell growthfactor and discovered in the supernatants of

phytohaemagglutinin-stimulated lymphocyte cultures.2 Itis produced by some T cell leukaemias and a gene from oneof them (Jurkat) has been transfected into Escherichia coli toproduce large quantities of recombinant IL-2 for

therapeutic use.3 IL-2 not only supports the growth of Tcells and permits their almost unlimited expansion in vitro,but also enhances tumour cell cytotoxicity by both T cellsand natural killer (NK) cells. This effect, known as

lymphokine-activated killer (LAK) activity, has stimulatedtherapeutic interest in the molecule.

Nearly 3000 patients have been treated with IL-2worldwide. Rosenberg’s group have amassed the greatestexperience: these workers have treated 483 patients and seenimpressive tumour regressions, particularly in metastaticmelanoma and renal cell carcinoma. From animal studies

Rosenberg has established that the response rate is related tothe 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 meetingRosenberg gave the results of a prospective randomised trialof LAK cells plus IL-2 versus IL-2 alone in 180 patientswith 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% inthose treated additionally with LAK cells. Complete clinicalremissions were seen only in the LAK group, in about athird of those responding. The complete responses haveproved durable-in 1 patient for as long as four years-andeven in patients with partial responses the disease hassometimes shown little inclination to relapse. These resultswere set in context by Prof Thiery Philip (Lyon), whoreported his experience with 147 patients with metastaticrenal cancer previously treated in centres in France withvarious therapies. Only 1 had an objective response, and themedian survival was eight months. Like other researchers hehad seen an objective response with IL-2 and LAK cells ofapproximately 20%.

1 Rosenberg SA, Terry W Passive immunotherapy of cancer in animals and man AdvCancer Res 1977; 25: 323-88.

2. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes fromnormal human bone marrows. Science 1976; 193: 1007-08.

3 Taniguchi T, Matsui H, Fujita T, et al. Structure and expression of a cloned cDNA forhuman interleukin-2. Nature 1983; 302: 305-06.

The benefit of increasing the dose of IL-2 was shown byDr P. A. Paciucci (Mount Sinai, New York). He attemptedto treat 32 patients with 100 megaunits/m21 day of IL-2 givenby continuous infusion over twenty-eight days with twenty-four hours’ rest every seventh day. Only 8 patients were ableto tolerate the full dose, but 6 of the 7 patients withmelanoma who did so achieved objective responses. Ingeneral, higher response rates were seen in patients whoreceived the larger doses.The side-effects of IL-2 have been well documented* and

include fever; nausea, vomiting, and diarrhoea;erythroderma; hypotension; fluid retention; pulmonaryinterstitial oedema; confusion; and in rare cases cardiacarrhythmias. Although much has been made of theirseverity,s in fact they are less difficult to manage than thoseof cytotoxic drugs. Most side-effects cease within a fewhours of stopping IL-2, and Rosenberg reported a

treatment-related mortality of 19%, far less than that ofbone marrow autografts and less than that of most surgery inpatients 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 everyeight hours, West used continuous intravenous infusions inan attempt to reduce side-effects. Although his responserates in melanoma and renal cancer were broadly in line withthose of the NCI group, it remains to be established whetherboluses or infusions produce fewer side-effects per patientresponse.The response of other tumour types to IL-2 therapy is

less encouraging. Several studies with combinations of IL-2and either cytotoxic drugs or other biological response modi-fiers were reported but it is too early to assess the results.The most promising new application of IL-2 is with tumourinfiltrating lymphocytes (TILs). If biopsy specimens ofmelanoma deposits are teased out, cell suspensions may beestablished in culture with IL-2. After a short period ofculture, melanoma cells die and the culture is overgrown byT lymphocytes. This cell population may be expanded inlong-term cultures with IL-2 so that about 1011 lymphocytesmay be reinfused into the patient. Of 15 patients treated inthis way by Rosenberg et al,6 objective responses wereachieved in 9, including one complete remission. 2 of thepatients who responded had previously shown no responseto LAK therapy.

In experimental systems TILs are up to a hundred timesmore potent than LAK cells. Whereas LAK cells are mainlyactivated NK cells, TILs appear to be activated cytotoxic Tcells and so show greater specificity in their targets, andrecirculate and home on tumour masses in a way that LAKcells do not. TILs may be obtained from other types oftumour but the methods are more complex.Immunotherapy has experienced many false dawns-the

promises of tumour vaccination, interferon, and anri-

idiotypic antibodies have not been kept. Despite thedifficulties of adapting IL-2 and LAK cells to the clinic, theoutlook is bright.

4. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemicadministration of autologous lymphokine-activated killer cells and recombinantinterleukin-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-infiltratinglymphocytes in the immunotherapy of patients with metastatic melanoma N Engl JMed 1988; 319: 1676-80.