Effects of interferons in neoplastic diseases of man

Pharmac. Ther. Vol. 37, pp. 213 to 229, 1988

0163o7258/88 $0.00+0.50

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Copyright © 1988 Pergamon Press plc

Specialist Subject Editor: S. PESTKA

EFFECTS OF INTERFERONS IN NEOPLASTIC DISEASES OF MAN E. C. BORDEN Departments of Human Oncology and Medicine, University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792, U.S.A.

1. INTRODUCTION As modulators of host response and human proteins, interferons (IFNs) differ both physicochemically and biologically from other antitumor compounds currently in use (Borden and Ball, 1981; Borden, 1984b). Since initiation of trials with IFNs produced by recombinant DNA technology five years ago, an IFN has reached the market. A marked expansion in our understanding of interferons' effects on neoplastic diseases has also occurred over this interval. Clinical trials in cancer with IFNs, purified from buffy coat leukocytes, began first in 1970 (Strander et al., 1973). Expanded trials with buffy coat IFN-~ under American Cancer Society auspices began in 1979. Because of the limited amounts of naturally produced IFNs available, it was initially difficult to determine maximally tolerated dose, to treat patients for extended periods, or to conduct trials in large numbers of individuals. Production of bulk quantities of pure IFNs from prokaryotic cells for biological and clinical studies has resulted from recombinant DNA technology (Table 1). Clinical trials with IFN-a produced by recombinant DNA technology in E. coli began in 1981 (Fig. 1). These trials, with a single exception (Hawkins et al., 1984a), have employed IFN-~t2 (or IFN-~A), one of the major IFN-~ subtypes in IFN induced from buffy coats. Although IFN-fl and 7 produced by eukaryotic cells are glycosylated, biological differences from the unglycosylated molecules produced by prokaryotic cells have not yet been identified. TABLE 1. lnterferons Produced by the Pharmaceutical Industry in Clinical Use

Type

Producer

Subtype

Recombinant DNA derived

Burroughs-Wellcome

~tnj

-

Hoffmann-LaRoche

~A

+

Schering-Plough

~2b

+

Toray Rentschler Serano Triton/Cetus

J.P.v.37/2-D

fl~r

+

Genentech Biogen

+ +

Kyowa H a k k o / Ciba/Geigy

+

2 13

Characterization Virus-induced from Namalva cells; mixture of 8 subtypes Lysine at position 23 when compared to ~t2; deletion at position 44 when compared to other ~t subtypes Arginine at position 23; deletion at position 44 Fibroblast produced Fibroblast produced Fibroblast produced Serine at position 17 rather than cysteine Three extra amino acids at -NH2 terminus Three extra amino acids at - N H 2 terminus

Specific activity (units/mg protein) 108

2 x 108

2 x 108

2 x 10s 2 x 107 2 X 107 2 × 107

214

E.C. BORDEN m'

...... im__m LtJ "I'Q..

I 1980

a

I

1982

F

I

I

1984

1986

FIG. 1. Temporaldevelopmentof the introductioninto phases of clinicaltrials of interferon types. Cloning, purification, and formulation of IFN-fl and IFN-~: were more difficult problems. Clinical trials with these molecules began only in the latter part of 1983 (Fig. 1). With application of recombinant DNA technology to production of IFNs, it has become possible to conduct trials employing systematic, established approaches to drug development. Phase I trials to determine maximum tolerated dose and biologically optimum dose have been partially completed. Enough results have emerged from Phase II trials in patients with measurable metastatic disease with IFN-u to indicate that these molecules, given as single agents to patients with quantifiable disease, have clinically significant antitumor activity. This has made controlled Phase III studies a major objective for study of IFN-~ over the next several years. Such trials will evaluate in randomized design interferons as adjuncts to other treatment modalities--surgery, radiation and chemotherapy. The objective of this review will be to review succinctly therapeutic results of Phase I and II clinical trials. An effort will be made to identify some of the clinical parameters possibly influencing therapeutic outcome. Since the published data is more complete, emphasis will necessarily be on IFN-ct. IFNs are potent modifiers of biochemical and immunological responses. Identification in treated patients of those responses which are altered and correlate with therapeutic outcome will almost certainly lead to improved dose schedules. This has been a major focus of the interferon research program at the University of Wisconsin. We have recently reviewed various aspects of our studies of biological response modification in other sources (Borden et al., 1982a; Paulnock and Borden, 1985; Borden et al., 1986). 2. PHASE I TRIALS 2.1. SIDE-EFFECTS The side-effects of naturally produced, buffy-coat alpha interferons and purified etA or 0t2 have been similar (Gutterman et al., 1982). Fever, chills, myalgias, and headaches have occurred initially; acute symptoms have decreased with continued administration (Table 2). Fatigue, malaise, and anorexia have been common limiting toxicities when doses of TABLE2. Interferon-alpha Toxicities Initial Chronic injections administration Chills Fatigue Fever Anorexia Malaise Mild neutropenia Myalgias Transaminase elevations Mild neutropenia Diarrhea Less common: mental slowing,confusion, hair shedding, thrombocytopenia,nausea, vomiting

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215

IFN-~t are administered repetitively (Table 2). Granulocytopenia occurs, but has not usually been dose limiting and has been rapidly reversible. Serum transaminase elevations have occasionally required cessation of IFN-ct. A more detailed review of the side-effects of IFN
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E.C. BORDEN

et al., 1980). Serum activity declined quickly, with the initial 0t distribution phase complete in 10 min and levels of 10 units or less with 3 hr. IFN-fl, administered as an infusion of 10 x 106 units over 6 hr, resulted in plateau levels of approximately 30-40 units (Hawkins et al., 1984b). High peak and lower sustained serum levels were best achieved by combined rapid bolus over 10 min and a continued infusion over 3 hr (Hawkins et al., 1984b). Although it is attractive to consider that the pharmacologic difference between nonglycosylated IFN-,t and glycosylated natural IFN-fl may result from the carbohydrate residues, this seems unlikely. Naturally produced, deglycosylated IFN-fl and recombinant DNA-derived, E.-coli-produced IFNfl, which lack carbohydrate residues, have been active in vitro (Mark et al., 1984). Furthermore, the IFN-fl utilized in the therapeutic studies in rhesus monkeys was derived from recombinant DNA (Schellekens et al., 1982). Finally, intramuscular injection of mice with natural human IFN-ct or IFN- B resulted in equivalent tissue levels in spleen and lungs (Billiau, 1981). Direct clinical comparison of natural and recombinant derived IFN-fl will thus be required to define the importance, if any, of the sugar residues in pharmacokinetic behavior of IFN-fl. Phase I trials with naturally derived IFN-y have identified further pharmacologic differences between interferons. Neither intramuscular injections nor rapid intravenous infusions resulted in sustained serum levels (Hawkins et al., 1985). Doses up to 50 x 106 units intravenously were rapidly cleared. Only with more prolonged infusion were measurable serum levels achieved (Gutterman et al., 1984; Kurzrock et al., 1986). Like IFN-/~, combined bolus and continuous infusion resulted in more sustained serum levels (Hawkins et al., 1985).

3. PHASE II STUDIES Phase II trials have defined effectiveness of pure IFN-g as single agents in several malignancies refractory to established therapies. Partial or occasionally complete responses in patients with disseminated or metastatic diseases of varied histogenic origin have been defined. Therapeutic effects with IFNs produced by recombinant DNA technology have been seen in some tumor types not evaluated in or responsive to IFN-ct derived from buffy coats (Krown et al., 1983a). In other instances, studies with natural IFNs have pointed to tumors for confirmation of results with the recombinant produced proteins (Quesada et al., 1984a). Interferon-g subtypes have not, in other cases, led to responses seen in trials with partially purified leukocyte interferon (Sherwin et al., 1983). 3.1. SOLIDTUMORS 3.1.1. Malignant M e l a n o m a Buffy coat IFN-~ administered intramuscularly was evaluated in metastatic melanoma in a cooperative trial of the American Cancer Society (Krown et al., 1984). Patients were randomly assigned to treatment with l, 3, or 9 x 106 units of interferon daily for 6 weeks. Of 44 evaluable patients, 1 patient at the lowest dose had an objective partial (>50%) regression of skin nodules. Thus, although some evidence for antitumor activity was observed at the doses and schedule used, this IFN-ct preparation was less effective than cytotoxic agents commonly used in the treatment of malignant melanoma. A trial of IFN-~t,~ at a daily intramuscular dose of 0.5 x 10 6 units/m2 was undertaken in 17 patients (Retsas et al., 1983). Two responses, one partial and one complete, occurred at this relatively low dose. Results with IFN-ctA and IFN-ct 2 suggest these molecules may have a therapeutic role in malignant melanoma. In a trial at Mayo Clinic (Creagan et al., 1984a), 31 patients, 15 of whom were performance status 2-3 or had received prior chemotherapy, were treated with IFN-ctA 50 x l 0 6 units/m Eintramuscularly 3 times per week for 12 weeks. Seven of these patients had regression of their disease (four partial responses, three complete responses) lasting from 3 to 11.2 months. Treatment with this dose and schedule resulted in > 80% of patients developing severe fatigue and deterioration in performance status (Creagan et al.,

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1984a). A lower dose (12 x 106 units/m 2) was utilized in a subsequent trial on the same schedule (Creagan et al., 1984b). Although fewer complete responses occurred, the results were statistically indistinguishable (6 of 30 responses) from the higher dose trial. Doses in the same range of IFN-~n also resulted in complete responses (Goldberg et al., 1985). Sixteen patients were entered on a trial using IFN-~ 2 at a dose of 10 x 106 units/m: subcutaneously 3 times a week for a minimum of 3 months (Spiegel et al., 1985). In 12 evaluable patients, 1 complete regression occurred in local disease. Two patients (lung and skin metastases) had objective partial response. This trial has been extended to include additional patients; overall 11 of 64 responses occurred (Robinson et al., 1984). IFN-~2 produced two responses in six evaluable patients treated intravenously 5 days per week for 4 weeks at doses of 10, 30, 50 and 100 x 10 6 units (Kirkwood and Ernstoff, 1985). A cyclic schedule was used in 29 patients, treated at doses of 30 x 106 units/m2 (Hawkins et al., 1984c). Dose modification was required in only four patients. One complete response in subcutaneous nodules was observed after 17 cycles (51 weeks) of treatment. Two other patients achieved partial response after 4 and 11 cycles of treatment. All three responses were durable (42+, 52+, and 57+ weeks) (Hawkins et al., 1984c). Thus, in sum, in these trials with recombinant IFN-~A or IFN-~2, an objective response frequency of 18% has been observed in 160 patients. This level of activity is equivalent to that of the best chemotherapeutic agents, imidazole carboximide and nitrosoureas, in this disease. 3.1.2. R e n a l Cell Carcinoma Buffy coat IFN-~ was used in studies conducted at M. D. Anderson Hospital and by the American Cancer Society (Quesada et al., 1983; Kirkwood et al., 1985). Treatment in the M. D. Anderson trial consisted of 3 million units intramuscularly daily (Quesada et al., 1983). Of 38 patients treated, 10 had objective partial responses which lasted for 2 - 9 + months. In addition, nine other patients had reduction in tumor masses which were < 50%, or which occurred while disease was progressing at another site. In the second trial, 27 patients were randomly assigned to receive treatment at doses of 1 or 10 x 10 6 units intramuscularly daily (Kirkwood et al., 1985). Patients failing to respond to the lower dose after 1 month were then treated with the higher interferon dose. Of the 27 patients, 1 had a complete response and 2 had partial responses. IFN-~A was assessed in a trial in which patients received doses of either 2 or 20 x 106 units/m: administered daily (Kirkwood et al., 1985; Quesada et al., 1985b). No objective responses occurred at the low dose (Quesada et al., 1985b). At the higher dose, 4 of 15 responded. Subsequently, 26 additional patients were treated at 20 x 106 units/m: with 8 of 26 responses (Quesada et al., 1985a). Median duration of response was 3 months. Dose reduction was required in more than half the patients (Quesada et al., 1985a). In 19 evaluable patients treated with IFN-~A 50 x 10 6 units/m s intramuscularly 3 times a week, two partial responses occurred (Krown et al., 1983b). Responses were seen in lung, soft tissue, and liver, lasting from 20 to 32 weeks. At this dose and schedule, dose reduction for fatigue and anorexia was required in 11 of the 19 patients (Krown et al., 1983b). Because of toxicity observed in the previous trials, IFN-~A was evaluated in a schedule of gradual dose escalation fom 3 to 36 x 106 units intramuscularly over a 10-day period (Krown, 1985). Patients were maintained at 36 x 106 units daily for 9 weeks after which responding and stable patients continued on a thrice-weekly schedule. In 62 evaluable patients, 7 partial responses were observed. By gradually increasing the dose, the acute toxicity of high fever and chills was avoided, with only 6 patients developing fever >38.5°C. However, dose reduction for granulocytopenia, fatigue, and anorexia to 18 x 106 units was required in many patients. In a trial of IFN-~n, used with escalating dose, 5 of 30 evaluable patients responded (Trump et al.,1987). These 10-day cycles, given every 3 weeks, were limited by granulocytopenia rather than by chills or fever. Chemotherapy has not proved to have a significant role in controlling progression of metastatic renal carcinoma. Thus, although response rates have remained < 50%, these results have been encouraging in a disease which has not generally been responsive to

218

E.C. BOROEN

other forms of systemic therapy. In Phase I trials with naturally produced IFN-fl (Abdi et al., 1986) and IFN-fl~r (Rinehart et al., 1986), objective responses have been observed. It remains to be determined whether a dose and schedule of IFN-fl can be identified which will result in a higher frequency of response. 3.1.3. Breast Carcinoma

Preclinical animal model systems have suggested the antitumor potential for treatment of patients with breast carcinoma (Borden and Balkwill, 1984). Two independent trials with buffy coat IFN-~t were conducted, initially at M. D. Anderson Hospital (Gutterman et al., 1980) and subsequently in a multi-institutional trial by the American Cancer Society (Borden et al., 1982b). A combined analysis has been undertaken of the 40 evaluable patients entered into both studies (Borden et al., 1983). There were 11 objective partial responses (50% or greater reduction in the product of the diameter of the measurable tumor) in the two trials. Responses were noted at both visceral and soft tissue sites including lymph nodes, chest wall, pleura, biopsy-confirmed bladder involvement, primary breast involvement and pulmonary involvement. The median duration of response in the American Cancer Society trial of interferon was 91 days with a range of 14-176 days. In the M. D. Anderson trial, where a maintenance period of interferon was given, the median duration of response was 196 days, with a range of 56-756 days. Although partial responses occurred in breast cancer in Phase I trials with IFN-aA (Horning et al., 1982; Sherwin et al., 1982), in Phase II trials with recombinant IFN-0t little antitumor effect occurred. Objective responses occurred in 3 out of 15 patients treated with IFN-atA at doses of 20 x 1 0 6 units/m z intramuscularly daily or 50 x 1 0 6 units/m 2 intramuscularly 3 times weekly (Nethersell et al., 1984). All patients treated had advanced breast cancer and had failed conventional treatment. However, in another trial, IFN-ct A demonstrated no activity in 17 patients with advanced refractory metastatic breast cancer (Sherwin et al., 1983). All patients treated on this trial had failed at least one standard combination chemotherapy regimen, and frequently also hormonal therapy. Unacceptable fatigue necessitated 50% dose reductions in all patients within the first month of treatment and further dose reduction to 10% dose level in nine patients. In the third trial, 14 patients with advanced breast cancer were treated with IFN-ct2 50 x 1 0 6 units/m2 intravenously for 5 days over 2-3 weeks (Muss et al., 1984). No objective responses occurred in 12 evaluable patients. The negative results seen in these studies with recombinant IFN-0tA and ~2 are in contrast to the preclinical data and the activity seen with naturally produced IFN-ct in metastatic breast cancer trials. Whether the differences between buffy coat IFN-~ and IFN-0tA or ~t2 in these trials result from interferon preparation, dose, schedule, or patient characteristics will require continued evaluation. Naturally produced I F N - f l injected locally or systematically has also resulted in regression (Quesada et al., 1982; Pouillart et al., 1982). Additional Phase II trials in minimally treated, good performance status patients will be required to determine activity of IFN-fl or IFN-y in this disease. 3.1.4. Colorectal Carcinoma Trials in patients with metastatic colorectal carcinoma with IFN-0~ derived from leukocytes have utilized doses of 3 million units intramuscularly. Of 14 patients treated daily, two had objective partial responses and a third had a minor response (Gutterman and Quesada, 1983). Of 18 patients treated 5 times per week, all patients had progressive disease during the period of administration (Figlin et al., 1983). Fifteen patients with advanced adenocarcinoma of the colon were treated with recombinant produced IFN-~h (Sighals et al., 1984). Nine of these patients had not received prior chemotherapy. Patients were treated with a dose of 50 x 106 units/m2 administered as an intravenous infusion for 5 consecutive days every 2-3 weeks. Granulocytopenia and transaminase elevations led to a decrease in the starting dose to 30 x 1 0 6 units/m2. Of eight

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219

patients considered evaluable, none responded. Twenty one patients with advanced colorectal carcinoma were treated with IFN-ctA (Neefe et al., 1984); none had received prior chemotherapy for advanced disease. IFN-ctA was administered intramuscularly 3 times per week at a dose of 50 x 10 6 units/m2. Dose reduction was required in 13 of 20 patients. Eighteen patients were evaluable for disease response. Seventeen developed progressive disease within 3 months or less. One patient had complete resolution of pulmonary nodules on chest X-ray and a 50% decrease in the size of hepatic nodules on liver scan. The pulmonary nodules reappeared after the fourth month of treatment. A similar trial (Eggermont et al., 1985) evaluated 20 patients with advanced colorectal carcinoma. Patients received a dose of 20 x 106 unit/m 2 of IFN-~A either twice weekly for 12 weeks or for 8 consecutive days every 3 weeks. During the third month of treatment, one patient treated twice weekly had a near complete regression of a liver metastasis. Carcino-embryonic antigen in the serum decreased and liver function tests returned to normal. This response lasted for 3 months. No other patient responded. These results suggest that IFN-~ has little practical therapeutic potential in colorectal carcinoma. It is, however, interesting that in four of five trials, objective regressions were observed. With increased understanding of the mechanism of resistance in vivo, IFN might prove useful in treatment of this disease.

3.1.5. L u n g Cancer Trials of buffy coat alpha-interferon have been conducted in patients with nonsmall cell (most with adenocarcinoma) lung cancer (Krown et al., 1982; Sarna et al., 1983). Fifty six evaluable patients previously treated with cytotoxic chemotherapy were treated at a dose of 3-10 x 106 units intramuscularly daily; one had a partial response lasting 9 weeks, and four others had minor or mixed responses (Krown et al., 1982; Sarna et al., 1983). Thus, using these low doses of buffy coat leukocyte IFN, a true response rate of < 15% can be predicted in previously treated patients with nonsmall cell lung cancer. A Phase II trial with IFN-~ 2 at hih dose (50 x 106 units intramuscularly 3 times per week) also did not result in response in 12 previously untreated patients (Grunberg et al., 1985).

3.1.6. Kaposi's Sarcoma

IFN-0tA or IFN-0t 2 has been assessed in patients with Kaposi's sarcoma in the setting of acquired immunodeficiency syndrome (AIDS). The efficacy of IFN-ctA was evaluated in sequential trials at the same institution using a high (36-54 x 106 units) or low (3 x 106 units) dose given intramuscularly daily for the first 28 days and thrice weekly thereafter (Krown et al., 1983a; Real et al., 1986). Patients with no response at the low dose had the dose escalated to 36 x 10 6 units in a stepwise manner. Toxicity was minimal at the low dose while 9 of 34 high-dose patients required dose reduction. In 34 evaluable high-dose patients, 8 complete responses and 5 partial responses were observed. Responses occurred in the skin, nodes and gastrointestinal tract with a mean duration of 13 months. In 36 evaluable low-dose patients, only 1 had a partial response. After dose escalation, 3 complete responses and 2 partial responses occurred in 33 patients. Twenty patients were treated with IFN-~t2 on a randomized trial of either 1 x 106 units/m2 by subcutaneous injection or 50 x 106 units/m2 by intravenous injection. Treatment was given for 5 consecutive days on alternate weeks (Groopman et al., 1984). Partial responses occurred in four of nine patients treated at the high dose and in one of nine at the low dose. In both trials, the rate of opportunistic infection was less after IFN-~t administration to responding patients. No decrease in infection frequency could, however, be identified in the groups overall (Krown et al., 1983a; Groopman et al., 1984). In both series, the higher dose seemed more efficacious than the lower in inducing regression of the neoplastic disease.

220

E.C. BORDEN

3.1.7. Ovarian Carcinoma

The antiproliferative potency of five IFNs was assessed in 22 ovarian tumors (Willson et

ai., 1984a). Fourteen (64%) were sensitive to at least one IFN. In a Phase I/II trial of IFN-cq, only one patient responded (Willson et al., 1984b). Another study which utilized rIFN-~tA intramuscularly in 15 patients with recurrent or persistent ovarian cancer demonstrated no antitumor effect (Niloff et al., 1985). However, 6 of 14 patients who received escalating doses of intraperitoneal IFN-ct~ at 5-50 x 106 units weekly responded (Burek et al., 1985). Three complete responses and two partial responses were documented by repeat laparotomy (Burek et al., 1985). One patient who did not undergo laparotomy also responded with complete resolution of ascites. Surgically documented response was more frequent in patients with tumor < 5 mm (5 of 7) than > 5 mm (0 of 4). Although serum IFN was measurable as soon as 4 and up to 48 hr after intraperitoneal administration (Burek et al., 1985), the levels in peritoneal fluid were approximately 50-fold higher. 3.1.8. Primary Hepatocellular Carcinoma Primary hepatocellular carcinoma (PHC) is a tumor for which only limited therapeutic options exist. The role of hepatitis B virus in etiology of some such patients provides an additional rationale for investigation in this disease. However, none of 16 patients treated with IFN-~tA responded (Sachs et al., 1985). 3.1.9. Glioblastoma Multiforme IFNs inhibit the growth of glioblastoma cells maintained in tissue culture and transplanted into nude mice (Cook et al., 1983; Tanaka et al., 1983). In these studies, IFN-fl has had a greater antiproliferative effect than IFN-cc Intramuscular injection of IFN-0t, resulted in a partial response in 7 of 17 patients with malignant gliomas (Mahaley et al., 1985). Trials in Japan defined an objective response rate of 40% of doses of 3-9 x 106 of IFN-fl in 20 patients (Nagai and Arai, 1984). Twelve patients with recurrent glioblastoma multiforme were entered on a Phase II study of IFN-[3. Treatment consisted of combined intravenous (10 x 106 units/day) and intratumor (1 x 10 6 qod) administration of IFN-fl~r over 3, 10-day cycles (Duff et al., 1986). No reductions in glioma size to > 50% occurred (Duff et al., 1986). 3.1.10. Carcinoid Nine patients with mid-gut carcinoid tumors were treated with buffy coat IFN-ct (Oberg et al., 1983). Patients with hepatic metastases had significant decreases in levels of 5-hydroxyindolacetic acid in urine and serum levels of human chorionic gonadotropin subunits and pancreatic polypeptides. This series has been extended to patients with pancreatic cholera (Oberg et al., 1985). Two patients had complete control of stool volume and normalization of vasoactive intestinal peptide (Oberg et al., 1985). One patient had complete regression of the metastatic pancreatic tumor. Since the biochemical abnormalities mediate symptoms in these diseases, IFN may be of benefit in decreasing hormone excretion and, in some patients, in mediating tumor regression. 3.1.11. Bladder Papillomatosis

Bladder papillomatosis is an attractive tumor in which to study new therapeutic modalities because of its pre-invasive character as well as the possibility of intravesical administration without systemic toxicity. Complete regressions in eight of eight patients, lasting from 4 to 46 months, were reported when the tumor base or surrounding tissue was injected transurethrally with IFN-~t (Eggermont et al., 1986). Another trial using systemic IFN-ct treatment of multiple bladder papillomas observed complete and partial tumor

Interferons in neoplastic diseases of man

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regressions, decreases in the recurrence of frequency rates, and recurrences with smaller papillomas (Scorticatti et al., 1982). IFN-~h, administered intravesically, at escalating doses of 50-200 x 106 units weekly resulted in complete responses in four of eight patients with carcinoma-in-situ (Torti and Lum, 1986). No local toxicity occurred with this route of administration.

3.1.12. Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a malignancy that carries a poor prognosis in patients with advanced disease. Although antibody titers to Epstein-Barr virus were not altered, two partial responses were seen in 13 patients with recurrent NPC treated with IFN-~t (Connors et al., 1985). Intravenous IFN-fl has also resulted in significant disease regression (Treuner et al., 1980). Thus, further evaluation of IFN in advanced NPC is warranted.

3.1.13. Cervical Carcinoma

Cervical carcinoma is another tumor associated with viruses which might be effectively treated. Invasive squamous cell carcinoma of the uterine cervix was treated in 15 patients with topical leukocyte IFN plus or minus intramuscular IFN (Krusic et al., 1981). Total regression of disease occurred in three patients, two had regression to histology in situ, and one patient had regression of micro-invasive disease.

3.2. HEMATOLOGICAL MALIGNANCIES 3.2.1. Hairy Cell Leukemia Hairy cell leukemia (HCL) is a B cell malignancy characterized by splenomegaly, pancytopenia, characteristic 'hairy cells' in the peripheral blood, and an increased incidence of fatal bacterial or fungal infections. Splenectomy can result in hematological improvement, but the disease usually progresses with median survival of 4 years (Golde, 1982). Initially, seven patients with progressive hairy cell leukemia were treated with partially purified leukocyte interferon (Quesada et al., 1984a). Three complete responses and four partial responses were observed and were maintained for over 12 months. Similar results have subsequently been reported with IFN-~q with significant improvements in hemoglobin, granulocyte, and platelet counts and decreases in infection (Ratain et al., 1985). Reduction of hairy cells in the peripheral blood may occur earlier within 1 month (Flandrin et al., 1985). Peripheral improvement in cytopenias may take much longer--from 2 to 6 months in marrow and peripheral circulation. Bone marrow biopsies in 5 of 16 patients after 6 months of therapy showed a > 50% decrease in the infiltration of leukemic cells (Naeim and Jacobs, 1985). Reduction in the abnormal reticular stroma with increase in the normal fat content in marrow may require more than 6 months (Naeim and Jacobs, 1985). Although an optimal dose and schedule are still not definite, the excellent therapeutic responses have resulted in licensure by the US Food and Drug Administration for this disease. Although duration of optimal treatment remains uncertain, the time required to induce objective response and persistence of hairy cells in the bone marrow even after 6 months suggests a need for relatively continuous treatment. Some evidence suggests, however, that maintenance treatment can be given on a weekly basis (Hofmann et al., 1985). The roles of IFN-fl and IFN-~ are currently under investigation.

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3.2.2. Multiple Myeloma Studies with partially purified preparations of leukocyte interferon have confirmed activity in this disease (Gutterman et al., 1980; Mellstedt et al., 1979; Osserman et al., 1981; Alexanian et al., 1982). The antiproliferative activity of natural and recombinant interferons against myeloma cell lines has provided rationale for continued investigation into the clinical usefulness of these agents (Aapro et al., 1983; Salmon, 1982). However, optimal doses, schedules, and patient populations have yet to be identified. For example, response rates of only 8-18% were observed when patients with advanced disease were treated on various schedules (Quesada et al., 1984b; Wagstaff et al., 1985; Costanzi et al., 1985). Although, when 27 patients who received 12 x 106 units/m 2 of rlFN-ctA intramuscularly daily were analyzed according to prior therapy, 7 of 14 (50%) of previously untreated patients had response documented (Quesada et al., 1986b). Similarly, patients who had received only phenylalanine mustard and prednisone had a 40% response rate (Costanzi et al., 1985). A lower dose (3 × 10 6 units) of buffy coat IFN-ct resulted in objective response in only 8 of 62 patients who had not received chemotherapy (Alexanian et al., 1982). Only 2 of 13 (15%) patients who had relapsed or failed prior chemotherapy had objective tumor regression (Quesada et al., 1986b). In all patients who had tumor response, there was restoration of levels of serum immunoglobulins, an effect infrequently seen with chemotherapy (Quesada et al., 1986b). Some complete responses can persist for over two years (Costanzi et al., 1985; Quesada et al., 1986b), an unusual event in myeloma. Thus, interferon may have a role in the treatment of early stages of multiple myeloma. 3.2.3. Lymphomas 3.2.3.1. Cutaneous T-Cell Lymphoma. IFN-ctA, 50 x 10 6 units 3 times per week, has been effective in patients with advanced cutaneous T-cell lymphoma (Bunn et aL, 1984). Nine objective partial responses lasting 3 months to > 25 months (median, 5 months) occurred in 20 evaluable patients. IFN may prove to be more effective for advanced refractory cutaneous T-cell lymphomas than any other reported agent. 3.2.3.2. Hodgkin's Disease. Eight patients with Hodgkin's disease were entered into a multi-institutional Phase II trial to evaluate the antitumor activity of leukocyte IFN (Merigan et al., 1978). Patients were treated at 1, 3 or 10 x 106 units. No responses of clinical significance occurred. IFN-fl and IFN-7 have not been assessed for their possible usefulness. 3.2.3.3. Non-Hodgkin's Lymphoma--Favorable Histologies. Initial reports described three partial responses in three patients with nodular poorly differentiated lymphomas with buffy coat IFN-~ (Merigan et al., 1978). This was extended with one complete response and two partial responses observed in seven evaluable patients (Louie et al., 1981). One patient had a second partial response on retreatment with interferon in spite of having received interval chemotherapy. Other investigators have reported response rates of 50% and 11% to partially purified preparations of alpha IFN (Gutterman et al., 1980; Horning et al., 1985) and of 20% to a partially purified preparation of beta IFN (Siegert et al., 1982), and a response rate of 35% to IFN-ctA (Quesada et al., 1984b). A greater than 50% response frequency occurred in a trial of IFN-0tA in 24 evaluable patients of whom 13 (54%) responded (Foon et al., 1984). All responding patients had been heavily pretreated with combination chemotherapy. Responses persisted for 2-7 months after cessation of therapy. Three patients who had relapsed after IFN was discontinued subsequently responded to a second course. This latter trial utilized a dose of 50 × 106/m2 intramuscularly 3 times weekly, a dose which required at least 50% reduction within 4 weeks in all patients. Equivalent effectiveness occurred in a trial with IFN-~E given subcutaneously at a much lower dose, 2 x l06 units/m E 3 times weekly (Wagstaff et al., 1985).

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Objective responses occurred in 17 of 34 patients and only 1 patient required dose reduction. Thus, as in hairy cell leukemia, objective response can be achieved at a minimum dose level. Furthermore, in this latter trial, there was a tendency for patients who had had prior chemotherapy to have a lower response frequency (6 of 8 vs 11 of 16) (Wagstaff et al., 1985). Previously untreated patients with favorable lymphoma were evaluated at 12 x 106 units/m 2 intramuscularly 3 times weekly (O'Connell et al., 1986). Responses occurred in 7 of 16 patients (44%); median duration of response was over 5 months. Thus prior chemotherapy may not substantially influence potential for response in this disease. 3.2.3.4. Non-Hodgkin's Lymphoma--Unfavorable Histologies. Clinical trials have assessed the effect of IFN-ot on patients with non-Hodgkin's lymphomas of unfavorable histologies. Despite different doses, schedules, and preparations of IFN-ot, only limited effectiveness has been documented (Gutterman et al., 1980; Horning et a1.,1985; Foon et al., 1984; Leavitt et al., 1983). 3.2.3.5. Chronic Lymphocytic Leukemia ( C L L ). One of four patients (Gutterman et al., 1980) and three of nine (Misset et al., 1982) patients with CLL receiving 3-9 x 106 units IFN-0t intramuscularly a day or 1.5-6 × 10 6 units subcutaneously a day, respectively, had partial responses. Eighteen evaluable, previously treated patients received either 50 x 10 6 units/m2 or 5 x 10 6 units/m2 of rlFN-0tA intramuscularly 3 times a week, a dose based upon pretreatment platelet count (Foon et al., 1985). Two of 12 patients treated at the higher dose and none of six treated at the lower dose responded. Five nonresponding patients had a seeming acceleration of their disease while receiving IFN (Foon et al., 1985). Yet IFN-0t2 clearly has activity in this disease: in a trial utilizing 2 x 10 6 units/m 2 3 times weekly, 4 of 11 patients responded. Most of these patients had had prior chemotherapy (Wagstaff et al., 1985). In a separate trial of IFN-0tA intramuscularly 3 times weekly at a higher dose (12 x 10 6 units/m2), two of four patients had a decrease in lymphocytosis and one of four a partial response (O'Connell et al., 1986). Of possible importance was the observation that the response could not be sustained on a weekly schedule of administration. 3.2.3.6. Chronic Myelogenous Leukemia (CML). Seven patients with CML, five of whom were untreated and two, having had single-agent chemotherapy, were treated with IFN-~ (Talpaz et al., 1983a). In five patients, hematological remission was obtained to daily intramuscular injections of 9-15 x 10 6 units. In another study of nine patients with refractory chronic CML and severe thrombocytosis, none had a significant cytoreduction of the peripheral leukocyte count (Talpaz et al., 1983b). However, a decline in platelet counts, from a mean of 1.71 x 106/mm3 to a mean of 0.52 x 106/mm3, was seen in all patients. Thus, IFN-~ may be therapeutically useful in alleviating progressive thrombocytosis in advanced CML. Effectiveness of IFN-~t in CML has subsequently been confirmed in a trial which used IFN-~A (Talpaz et al., 1986). 3.2.3.7. Acute Leukemia. The role of IFN in the treatment of acute leukemias has not been as extensively studied. Objective benefit occurred in two of three patients with acute myelogenous leukemia (AML) and five of five with acute lymphocytic leukemia (ALL) treated with intravenous leukocyte IFN at 0.5-5 x 10 6 units/kg/day (Hill et al., 1979). However, only one partial response occurred in 10 patients with AML who received lymphoblastoid IFN (Rohatiner et al., 1983). 4. CONCLUSIONS Interferons have activity in inducing partial or complete disease regression in a broad range of human neoplasms (Table 3). Optimal doses, schedules, and routes for IFNs, however, remain to be defined. In addition, the role of IFNs in combination with other

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modalities of cancer treatment, such as chemotherapy and other biological response modifiers, has just begun to be defined. Definition of ultimate therapeutic roles in human malignant disease will depend upon outcome over the next 5 years of Phase II and Phase III trials. The greatest therapeutic use will be derived by combining IFNs with other cancer treatment modalities, drugs, and biologics. The antiproliferative effect of IFNs in vitro has been enhanced when given with tumor necrosis factor (Sugarman et al., 1985). IFNs have enhanced the expression of tumorassociated antigens; this may have a role in combination with monoclonal antibodies for imaging or therapeutic purposes (Ziai et al., 1985; Liao et al., 1982; Greiner et al., 1984). Combinations of Type I and Type II IFNs have resulted in an enhanced antiproliferative effect in vitro and in vivo in both the mouse (Fleischmann et al., 1979, 1980; Zerial et al., 1982) and human systems (Czarniecki et al., 1984). Our investigations into the effects of combinations of Type I and Type II IFNs have demonstrated a synergistic antiproliferative effect in 9 of 10 human cell lines of various histogenesis, including cells that differed in their sensitivities to each IFN (Schiller et aL, 1986). We have demonstrated enhanced antiproliferative effects of interferons produced by recombinant DNA technology at elevated temperatures against human bladder carcinoma cell lines (Groveman et al., 1984). This enhanced effect confirmed an earlier result which used naturally produced IFN-~ and assessed not only antiproliferative but also antiviral effects (Heron and Berg, 1978). Based upon these results, we have initiated a Phase I trial to confirm the safety of these two modalities. No augmented pyrexia has occurred, which has allowed planning of a Phase II trial. Evidence in vitro and in vivo suggests that IFN may be more effective against tumor growth when given with cytotoxic chemotherapeutic agents. Synergistic activity against colony formation was observed with the combination of vinblastine and IFN-ctA (Aapro et al., 1983). An additive or subadditive effect was observed with the other cytotoxic agents tested. IFN-fl was assessed in seven continuous cell lines; it synergistically potentiated the cytotoxic effects of 5FU on three human neoplastic cell lines, whereas in two others the combination was additive, and, in two, neither synergistic nor additive effects were observed (Miyoshi et al., 1983). In rico, human lymphoblastoid interferon enhanced the antitumor activity of suboptimal doses of cyclophosphamide and adriamycin on a human breast tumor xenograft growing in nude mice (Balkwill and Moodie, 1984). For mouse tumors, IFNs and chemotherapy have resulted in increased survival when compared with either modality alone (Gresser et aL, 1978). There seems little doubt that interferons will remain the prototypic biological therapeutic treatment of neoplastic diseases. Interferons have a level and spectrum of therapeutic activity in neoplastic diseases which is comparable to cytotoxic drugs currently in oncologic clinical practice. The level of activity of IFN-~ in hematologic malignancies makes it useful for hairy cell leukemia and probably myeloma and lymphoma. In conjunction with surgery, IFN-~t may have therapeutic application in renal carcinoma and melanoma. Although the side-effects of fatigue and anorexia are troublesome, when compared with cytotoxic agents, no residual toxicities for vital organs occur. With improved preclinical models and better understanding of the mechanism of antitumor action, it can be anticipated that the therapeutic index of interferons may improve (Table 4). Finally, IFN-fl and IFN-y have continued promise of being therapeutically useful in other malignancies. A TABLE3. Antitumor Effectiveness in Phase H trials Chronic leukemias Myeloid Hairy cell Lymphomas Favorable T-cell Multiple myeloma

Renal carcinoma Malignant melanoma Breast carcinoma Glioma Bladder carcinoma

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TABLE4. Challenge 1986-1990 •

• •

Determine therapeutic role Individual types Comparison Combinations Define mechanism of action Identify optimal biological dose Confirm safety and tolerance Cause of limiting toxicities Clarify role in life-threatening toxicities Significance of antibody

r e a s o n a b l e p o s t u l a t e is t h a t each m e m b e r o f the I F N f a m i l y will h a v e a u n i q u e s p e c t r u m o f t h e r a p e u t i c activity. U l t i m a t e t h e r a p e u t i c a p p l i c a t i o n will c o m e in c o m b i n a t i o n w i t h the e s t a b l i s h e d effective m o d a l i t i e s o f s u r g e r y , r a d i a t i o n , a n d c h e m o t h e r a p y . T h e c h a l l e n g e for the n e x t five years is n o t o n l y to d e t e r m i n e t h e r a p e u t i c role b u t also to define m e c h a n i s m o f a n t i t u m o r a c t i o n ( T a b l e 4). T h i s w o u l d r e s u l t in i d e n t i f i c a t i o n o f m o r e r a t i o n a l dose s c h e d u l e s a n d in improved patient tolerance.

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