The use of biological agents in cancer therapy was first reported by Coley in 1891,who was able to achieve some striking responses with the use of bacterial cell filtrates. I This treatment, however, was accompanied by a high degree of toxicity,and with the advent of modem cancer surgery and radiotherapy, this line of investigation was discontinued. Although a number of nonspecific immune stimulants suchas Bacillus Calmette-Guérin (BCG) havebeen used in cancer therapy in the last fewdecades, alpha interferon is the first humancytokine to have been widely studied.

Interferon was first described by Isaacsand Lindenmann in 1957 as a biologicalsubstance that inhibits viral replication andis elaborated by virus-infected cells.2 Initially there was doubt about its existence;indeed, some scientists dubbed the discovery “¿�Imaginon.“¿�3As we now know, thepioneering work by Isaacs and Lindenmann was ultimately vindicated. By theearly l970s, the work of Cantell and theFinnish Red Cross Blood Bank providedsufficient quantities of crude alpha interferon obtained from buffy coat layers ofblood to conduct early clinical trials.

The earliest trials were by Strander et alin Sweden,4 using interferon for the adju

Dr. Goldstein is a Research Associate in theDepartment of Human Oncology at the University of Wisconsin in Madison, Wisconsin.Dr. Laszlo is Senior Vice President for Researchof the American Cancer Society in Atlanta,Georgia.

vant treatment of osteosarcoma. Such trialswere pursued in the United States withfunding by the National Cancer Institute in1975 and the American Cancer Society in1978. Problems of production, purity, andcost have since been resolved as the variousinterferon genes have been cloned and asrecombinant DNA technology has allowedproduction of high-quality material. Thishas led to trials across the spectrum of human cancers with a wide variety of interferon types and preparations, includingsome interferon produced from cultures oflymphoblastoid cells.

Although early interferon trials showedrespectable response rates comparable tothose achieved by chemotherapy, subsequent trials, usually with more purifiedpreparations, have not achieved the sameresults—either because of the eliminationof other as yet unidentified lymphokines orbecause of the use of stricter responsecriteria.

Interferons are glycoproteins that aresynthesized by a variety of cells in responseto viral infection, immune stimulation, andcertain chemical inducers. They appear toact in a paracrine capacity within the immune system, with a wide range of effectsthat mimic the diversity of the endocrinesystem. Although 20 interferons have nowbeen identified in humans, they can beclassified into three broad groups.5 Most ofthe subtypes belong to the alpha class, twosubtypes of beta (1 and 2) have been described, and there is only one gamma species. Alpha and beta interferons were both

258 CA-A CANCER JOURNAL FOR CLINICIANS

The Role of Interferon in CancerTherapy: A Current Perspective

David Goldstein, MDJohn Laszlo, MD

originally named according to their earlymethod of production (namely, leukocytederived alpha and fibroblast-derivedbeta),but in fact they appearto be synthesized byvirtually every cell in the body. Gammainterferon, however, is a lymphokine secreted solely by T cells.

There are marked homologies betweenhuman alpha and beta interferons: theirgenes cluster on chromosome 9,5 and theyshare a cell surface receptor encoded onchromosome 21. The gamma gene, by contrast, is on chromosome 12@and shows nohomology with other interferons. The receptor is found on chromosome 66 and appears to be different from that of alpha andbeta interferons.

Modesof ActionThe exact physiological roles of each of theinterferons remain unclear. In terms oftheir use in cancer therapy, however, theyhave been studied for both their direct (cytotoxic) and immune (stimulatory) effects.The predominant mechanism responsiblefor the documented anticancer activity hasnot been identified. This remainsan important area of investigation, since optimaldose scheduling may be very different depending on mechanism, and the mechanism(s), in turn, might vary for differentinterferons.

At the cellular level, interferonappearsto act by gene activation (Fig. 1). This isassociated with decreased synthesis of anumberof proteins. as well as the synthesisof new proteins. In particular,fourenzymesystems are known to be induced that interfere with viral protein synthesis and arealso possibly involved in both antiproliferative and differentiating functions of various interferons. These include:

•¿�2' ,5' oligoadenylate synthetase—anenzyme family that catalyzes the synthesisof a family of oligonucleotides. the2'S‘¿�oligoadenylates.These oligonucleotides activate an endoribonuclease thatcatalyzes the cleavage of both viral andcellular RNA.7

•¿�A protein kinase that phosphorylatesproteins P1 and elongation initiation factor

EIF2a, which in turn inhibits the bindingof transferRNA to the ribosome. This inhibition is characterizedby discriminationbetween cellular and viral mRNA.8'9

•¿�A 2'S' phosphodiesterasethatcatalyzestransfer RNA degradation, thus further inhibiting protein synthesis, but also degrading 2'S' synthetase.8'9•¿�Indoleamine 2,3 dioxygenase, an en

zyme that degrades intracellular tryptophan.'°

These systems, which appear to inhibitviral replication, may also be involved inthe inhibition of tumor protein synthesisand probably contribute to the prolongationof the cell cycle and the increased percentage of cells in the GO phase observed withinterferon.5

Interferon also initiates the productionof a series of new proteins, the functions ofwhich are still unknown. Other cellularchanges occur in the cytoskeleton due toalterations in tubulin production. The cellmembrane is altered, as shown by increased expression of tumor-associatedantigens, human lymphocyte antigens(HLAs) class I and II, and beta-2 microglobulin in both tumor and normal cells.―

In some situations, interferon acts as adifferentiating agent, causing malignantclonogenic cells to differentiate and losethe capacity to divide. The decrease inexpression of the oncogene c-myc in Daudicells (a Burkitt's lymphoma cell line) afterinterferon treatment in vitro12has been proposed as a model for the mechanism bywhich interferon induces differentiation.

In addition to those effects, interferonsalter the immune system by stimulation ofa third arm of the immune system called“¿�naturalimmunity.―3 This includes thenatural killer (NK) cell, the killer cell, andthe lymphokine-activated killer (LAK)cell, all of which share some, but not all,of the characteristics of T cells and macrophages. These cells all show spontaneousdirect cytotoxic activity against a variety ofcultured and fresh tumor cells, and theircytotoxic activity, unlike that of T cells.does not require the expression of HLA.NK cell direct cytotoxicity and antibodydependent cellular cytotoxicity are modulated by the interferons. 14.15

VOL 38, NO 5 SEPTEMBER/OCTOBER1988 259

CytoskeletalChanges

Receptor

ENZYMEINDUCTION

Indolea 2'5'PhosphomineOligo diester

DioxyadenylateasegenaseSynthetase

ProteinKinase

)Receptor

1tRNA

Try @+KynProteinSynthesis

mRNA NewProteins

AlterationinMembraneStructure

TMHLAClassI and II

Induction

Inhibition

Fig.1. IntracellularEffectsofInterferons.(mRNA = messengerRNA,tRNA = transferRNA,TAA = tumor-associated antigen, HLA = histocompatibility complex, Try = tryptophan, Kyn =kynurenine) See text for details.

260 CA-ACANCERJOURNALFORCLINICIANS

Inhibition

Activation

Fig. 2. Proposed Immunomodulatory and Direct Antitumor Effects of Interferons and OtherCytokines.(TAA = tumor-associatedantigen,HLA = histocompatibilitycomplex,IFN = interferon,NK = naturalkiller,TNF= tumornecrosisfactor)

VOL. 38, NO.5 SEPTEMBER/OCTOBER1988 261

Other immune-augmenting activitiescommon to all the interferons includestimulation of HLA class I expression, activation of B cells, and augmentation ofother lymphokines such as interleukin-2(IL-2) and tumor necrosis factor (TNF).Gamma interferon appears to have a widervariety of immune-stimulatory effects thando alpha or beta interferons,'6 includingenhanced expression of class II antigensand Fc-fragment receptors and activationof macrophages in addition to the NK cellactivation common to all interferons (Fig.2). The optimum dose for immune stimulation is unclear, but in the case of alphainterferon, it does seem that lower dosesachieve higher NK activity.'7

Clinical Responses

A pattern appears to be emerging in theresponses seen with alpha interferons, inthat different dose levels are effective indifferent cancers, possibly because eitherantiproliferative or other mechanisms predominate. Virtually all of the clinical studies reviewed in this section used leukocyteand recombinant alpha preparations; bothbeta and gamma interferons are only juststarting Phase II trials. (We have publisheda detailed survey of the use of interferontherapy in all the cancers.―) All of theresponse rates mentioned here are definedas either “¿�complete―or “¿�partial.―A complete response (CR) means total disappearance of all cancer, and a partial response(PR) means greater than 50 percent shrinkage of all measurable tumor masses.

The best responses have occurred in thehematologic malignancies, most notablyhairy cell leukemia, but also the nodularlymphomas, cutaneous T-cell lymphoma,and chronic myeloid leukemia. For hairycell leukemia, a rare form of leukemiacharacterized by pancytopenia and splenomegaly, the reported total response rateshave been up to 100 percent; this includespartial responses, defined as greater than90 percent disappearance of hairy cells andincrease in all hematologic parameters inthe peripheral blood, and complete responses, defined as the clearing of all leukemic cells from the bone marrow (Table

1). Response to treatment is characterizedby reduction in the need for blood andplatelet transfusions and relief from intercurrent infections. Hairy cell leukemia maybe unique in that very low doses are apparently equally effective.'8

Patients with lymphoma, however, appear to respond better to high-dose therapy,and response rates of greater than 50 percent have been reported.―The highest response rates are in the nodular group,whereas the high-grade lymphomas havefew responders (although several trialshave reported responses at higher dose levels).―In addition to these low-grade lymphomas, T-cell lymphomas can be quitesensitive to interferon therapy. “¿�@Themarked difference in dose rates suggeststhat either a differentiating effect or an immune mechanism (such as NK stimulation)is likely to be important to hairy cell leukemia, rather than a direct antiproliferativeeffect as in the lymphomas. The recentdiscovery of the effects of beta 2 interferonon B-cell differentiation202' and the evidence that increased NK activity occursafter the disappearance of hairy cells22tendto favor the former hypothesis. It is of interest that the slow-growing nodular typeof lymphoma shows the best response,which suggests that the antiproliferative effect of interferon is most important in thosetumors with a smaller growth fraction.

Chronic myeloid leukemia has alsobeen shown to be highly responsive to interferon therapy.23 A response rate in excess of 80 percent has been reported, withthe best responses in patients diagnosedwithin 12 months. Although this disease ishighly responsive to a number of agents inthe chronic phase and interferon has notbeen shown to prolong survival, it is intriguing that in some patients with a complete response, the Philadelphia chromosome has completely disappeared.

For multiple myeloma (Table 2), theinitial report by Mellstedt of responses tointerferon therapy in four of four patients(two CR, two PR) led to 12 other trials,which yielded an overall median responserate of 19 percent.―In particular, two recent randomized trials have compared interferon with chemotherapy as primary

262 CA-A CANCERJOURNALFORCLINICIANS

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VOL. 38, NO 5 SEPTEMBER/OCTOBER1988 265

therapy. The first compared leukocyte interferon with a melphalan-prednisone combination and showed interferon to be inferior, both in terms of response rate (14versus 44 percent) and duration of response(23 versus 35 months).24 The second trialcompared recombinant interferon alpha(rlFNa) with the combination of vincristine, melphalan, cyclophosphamide, andprednisone (VMCP). Interferon againshowed an inferior response rate (14 versus57 percent) and duration (3.2 versus 7.6months). 25

This is in contrast to data with rIFNashowing a much higher response rate (50percent, seven of 15 patients) in previouslyuntreated patients compared with that forthose with previous treatment (15 percent,two of 17 patients).26 The discrepancy inthese results may be explained by tumormass, since it appears that most of the responses in the latter trial were in patientswith small tumors. Another interestingphenomenon appears to be that myelomaof the IgA subclass is the most likely torespond.24 Several trials of combinationtherapy with cytotoxics have been reported; there was no significant improvement by combining interferon with prednisone.27 A more encouraging result ofcombining rIFNa with melphalan-prednisone in untreated patients (response rate of75 percent, median duration of more than10 months)2t suggests that further exploration of its use in combination is indicated,as is its use as a second- or third-line agentfor relapsing patients.

Interestingly, the leukemias—bothacute and chronic and even chronic lymphatic leukemia—have shown very low response rates, which is surprising given thepositive results with hairy cell leukemiaand nodular lymphoma.

In contrast to these highly responsivehematologic malignancies, the other tumors appear to fall into two groups. First isan intermediate group in which moderateresponses to a variety of interferon regimens have been seen. In Kaposi's sarcoma(Table 3), some trials have reported highresponse rates.2933 ln general, these havebeen in patients with less severe immunedeficiency—that is, their T4 levels were

still reasonably high and they had a lowerincidence of opportunistic infections. Theresponse rate is much lower in patients withdepleted T4 cells and a high rate of opportunistic infections. These factors appear todetermine outcome, and interferon doesnot make a long-term impact on the disease, with response durations of less thansix months even in the groups with highresponse rates. The current median response rate for all trials of Kaposi's sarcoma is 34 percent, with a median suvivaltime of only about 26 weeks. No one hasyet shown that interferon therapy increasesthe survival of these patients.

Similarly, in renal cancer (Table 4), theinitially high response rates have not beensustained in further studies, and the overallmedian response rate is 15 percent.@@Longterm survival and delayed responses, however, have been seen.34'35 Several trialssuggest that responses tend to occur in softtissue metastases, particularly after removal of tumor bulk.36'3t High-dose treatment does not appear to improve this response rate,37'3t nor has combination withvinblastine ,@ but cumulative myelosuppression can be dose-limiting.

In malignant melanoma (Table 5),more than 400 patients have now beentreated, and the overall median response is18 percent. Complete response rates havebeen seen at higher doses.40'4' It has beensuggested that these higher doses cause lesssystemic toxicity if given intravenously.This is probably because intramusculartherapy results in sustained serum levels ofinterferon for a longer period of time thandoes intravenous therapy.4° Melanoma isalso a disease where a number of delayedresponses have been noted. The use of interferon in combination with dacarbazine(one of the few active chemotherapy agentsin melanoma) has shown encouragingresponse rates without substantially increased toxicity, but reports are too preliminary to form an opinion about improvement over single-agent therapy ,42,43

In summary then, although responsesin these tumors do occur, they are modest.Nevertheless, the number of complete responses appears higher, as does the duration of responses. Since current chemo

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VOL.38,NO. 5 SEPTEMBER/OCTOBER 1988 267

therapy has little to offer in these diseases,further optimization of route, dose, andschedule of interferon as a single agent, inaddition to studies in combination withother agents, would appear likely to yieldfurther improvements.

The more common tumors show littleresponse to interferon. Breast cancer is acase in point. Two early trials@'45showedresponses of 35 and 22 percent, respectively. Since then, numerous trials havebeen conducted. A review of a selectionfrom the 17 trials done to date shows themedian response rate to be effectivelyzero.―A similar result was found for bothlow- and high-dose interferon therapy incolon cancer, as well as for several othertumors, particularly lung cancer, whereadequate numbers of patients have beenstudied.― An exception appears to be themalignant carcinoid tumors. Almost half ofthe patients studied have shown markeddecreases in tumor-related markers such as5 hydroxyindolacetic acid (5 HIAA) aftertreatment, with dramatic decreases insymptoms, and a small proportion (twoCR, two PR) also showed objective tumorregressions for prolonged periods (medianof 34 months).@ Similar results have alsobeen reported recently in other malignantendocrine pancreatic tumors.47

Local therapy remains a relatively littleexplored but promising area. High response rates for intralesional therapy ofskin lesions—both primary and secondary—already suggest that interferon maybe useful for palliation in these conditions.― In glioma, intrathecal interferonhas shown much higher responses than theintravenous route, and may prove to be amajor form of therapy.― Interferon alsoshows promise in localized cervical cancer,although it is clearly not recommended asan alternative to surgery.48

Equal in significance to interferon's impact on cancer has been its effect on twovery troublesome benign neoplasms. Recurrent laryngeal papillomas can prove fatal in the small number of adolescents whosuffer from them. Interferon trials haveshown excellent responses, with a medianresponse rate of 68 percent for all trials;some patients require long-term mainte

nance therapy to prevent recurrence. Condylomata acuminata, a distressing genitalcondition, has also shown a very gratifyingresponse to low-dose@ and theFood and Drug Administration has recentlyapproved the use of interferon for this condition.

Phase II studies with the newer recombinant compounds, beta and gamma interferons, have only begun. The Phase I trialswith recombinant interferon beta (rIFNI3wr)suggest that it can be tolerated at muchhigher doses than can alpha interferon.495'Since most in vitro work suggests that theantiproliferative effects of interferon exhibit a linear dose response, rIFN13@,,1mayprove more successful than alpha interferon in Phase II trials of solid tumors.Early Phase II trials in renal and coloncancer, however, have not demonstrated ahigher response rate.5254

Phase I studies with recombinant interferon gamma (rIFN'y)5557have shown sideeffects similar to those of alpha interferon,but with the added dose-limiting toxicity ofhypotension. In addition, a marked increase in triglyceride levels has been seenin some patients.58 Several Phase II trialsin renal carcinoma59'60and sarcoma6' havefailed to show useful antitumor activity. Incontrast, two trials in melanoma haveshown activity, although less than that seenwith alpha interferon.62'63Some of the preclinical data, which showed that gammainterferon had greater antiproliferative effects than did alpha interferon, was donewith impure preparations that may havecontained other cytokines, particularlyTNF.M The antiproliferative role of gammainterferon is more likely to be in combination with other cytokines. Synergy hasbeen demonstrated both in vitro and in vivofor gamma interferon and a number of cytokines, including both alpha and beta interferons, TNF, and IL-2. This synergy iscurrently being explored in a number ofclinical trials. Phase I studies of gammawith alpha65 and beta@ interferons havebeen reported, and Phase II studies in melanoma and renal carcinoma are nearingcompletion. Phase I trials with TNF arealso approaching completion.

The potent effects of gamma interferon

268 CA-A CANCERJOURNALFORCLINICIANS

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Reference Type (MU/M2) (Evaluable) (%)

Retsas HuIFN(Ly) 2,5 im qd 17 0/1(5)et al8t

Krownet aI@HuIFN(Le)1,3,9 rnqd45(44)1/0(3)Hersey

et aI91rlFNa2a15,30,50 rntiw20(18)2/0(11)Creagan

etaI@1rlFNc@2a +

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rn tiw+

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30310/8(23)

1/5(20)2/5(23)Kirkwood

etaI40rlFNa2b3—100im qd

x7 for 4 weeks10-100ivqd x6for6 weeks29

160/2(15) 3/0(19)

Dorval rlFNa2b 10sc 22 2/4(27)et alt2 tiw

Legha93 rlFNa2a 36 im qd 35(31) 0/3(10)18 rn tiw 31 0/2(7)

Reviewof Median= 1511Major PublishedTrials to Date11

im = intramuscularlyiv = intravenouslysc = subcutaneouslyqd = every daytiw = three times a weekqid = four times a dayCR = complete responsePR = partial responseMU= 1 x lO6lU

Key: HuIFN(Ly) = Human lymphoblastoid interferonHuIFN(Le) = Human leukocyte interferonrIFN = Recombinant interferon

a2a = Roferon-A/Rochea2b = Intron A/Schering

VOL 38,NO 5 SEPTEMBER/OCTOBER 1988 269

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TH@-:E-, ‘¿�-@@ @LPH ANIERFERONHighly

Respons,veTumorsHairy

CellLeukemiaMycosisFungoidesNodularPoorlyDifferentiatedLymphomaChronicMyeloidLeukemia(Papillomas:Laryngeal,Vaginal)Moderately

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on the immune system described earlier,however, may well make its anticancer rolefundamentally different from that of type Iinterferons. Gamma interferon may havean important adjuvant therapy potential forboth monoclonal antibodies and adoptiveimmunotherapy, since it may render targetcells more susceptible by increasing theexpression of HLAs and tumor antigens―and augment effector cells for both directand antibody-directed cytotoxicity.67

Interest in combining interferons withchemotherapy to increase their therapeuticpotential was spurred by in vitro work suggesting synergism with several antimitoticagents,68'69 including cyclophosphamide,doxorubicin, and vincristine. Also, sinceinterferon delays entry into the S phase.7°it could prove useful as a synchronizingagent prior to phase-specific chemotherapy. Unfortunately, the early Phase I trialsin which treatment has been essentiallyconcurrent have shown synergism in termsof toxicity but not in tumor response. Mosttrials have noted reductions in chemotherapy doses because of cumulative hemato

logic toxicity (Table 6) and, in the case ofvinblastine, increased neurotoxicity39 andhyponatremia.7' It is still very early in thedevelopment of such combinations@ itseems clear, however, that because of theunique cellular effects of interferon, itshould not be treated as yet another form ofcytotoxic agent to be added in simple combination. Interferon's toxicities, such ashematologic suppression. are readily reversible and not cumulative. Interferonthus lends itself to novel approaches, suchas sequential therapy at the nadir of eachchemotherapy cycle to synchronize cellsbefore the next course of cytotoxics. Asimilar situation would appear to be true inthe even more preliminary studies of interferon and radiotherapy.72

An entirely different role of interferon,and one for which low rather than highdoses are preferred. is to speed up the recovery of immunological competence following the suppressive effects of chemotherapy, thus potentially decreasing theincidence of recurrence. ‘¿�@It seems obviousfrom the early combination trials that more

CA-A CANCERJOURNALFORCLINICIANS272

in vitro and animal model exploration ofsuch novel approaches is urgently neededto help design more effective and less toxiccombination therapies.

Toxicity

Contrary to initial expectations, interferonhas not proven to be an innocuous treatment, despite its being a natural substance.The toxicities appear to be dose-related,with all patients developing fever and chillsat doses above I x 106 lU (MU)/M2, oftenrequiring acetaminophen and sometimeseven mependine hydrochloride (Demerol)for control. Patients also develop constitutional symptoms reminiscent of influenza,such as myalgia, anorexia, lassitude, anddepression, which often require dose reduction because of their severity.74 Othertoxicities include myelosuppression, nausea, and vomiting; increased hepatic enzyme levels may occur but are rarely doselimiting.75 At higher doses of interferon,neurotoxicity is frequently encountered, asmanifested by personality changes, confusion, loss of attention, disorientation, andparanoid ideation. Diffuse electroencephalographic slowing has been documentedfor rIFNa76 and more recently in Phase Istudies of gamma interferon.

Recently evidence has been presentedabout the incidence and effects of the development of antibodies to interferon.76aIn a study of 51 patients with hairy cellleukemia, neutralizing antibody was detected in 16 patients, six of whom developed some degree of clinical resistance. Ofinterest, there was no difference in toxicityin those patients with antibody. Furthermore, these antibodies had restricted specificity and did not neutralize naturally produced interferon alpha, suggesting thatsubstitution of an alternative interferoncould reinduce a response.

It should be noted that in an earlierreview of more than 617 patients who received intramuscular interferon alfa-2a fora variety of cancers, 25% were reported tohave neutralizing antibody, but no difference in response rate or survival wasdetected. 76b

Summary

Recombinant interferon alpha has nowbeen established as having a distinct if narrow role when used as a single agent incancer therapy. The responses to singleagent therapy can be grouped as shown inTable 7. Interferon is likely to be the treatment of choice for hairy cell leukemia andpossibly also for symptomatic nodular lymphoma. Interferon is very useful in treatingpapillomas and condylomas, and its role asa local agent will probably expand.

The list of responding cancers for alphainterferon or other subtypes as a singleagent is unlikely to expand greatly over thenext few years. Nevertheless, in both melanoma and renal carcinoma, meaningful responses do occur. It is important to beaware of the possibility of both delayed andincreasing extent of response with durationof treatment: adequate trials of interferonmay therefore require longer periods oftreatment than does conventional chemotherapy. Furthermore, because prior failureto respond to chemotherapy does not predict response to interferon, its use as asecond-line agent should also be considered.

The future of such biological agents,however, clearly lies in combination withother agents as the “¿�fourtharm―of cancertherapy.77 The challenge is to define whatthe role of that fourth arm will be.

There seems to be a clear choice withthe interferons. They can be used at pharmacological doses, in which case their antiproliferative effect is likely to be due toinduction of certain enzymes that result ina cytostatic effect in susceptible cancers, ofwhich there are a limited but therapeutically important number.

Alternatively, the interferons can beused at physiological doses, which aremore likely to cause immunological andcell membrane effects such as NK-cellstimulation, as well as Fc-receptor andtumor-antigen expression. Thus, combination with cytotoxic agents may well requirehigh doses, whereas combination withother biological agents, such as monoclonal antibodies or LAK cells, may bemost effective at much lower doses.

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maximize their usefulness in therapy andavoid the trap of thinking of them as purelycytotoxic agents.

Over the next few years it will be important to establish the optimal biologicaldoses of the interferons, so that we can

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