Med Oncol. & Tumor Pharmacother. Vol 9 No.4 pp. 71-76,1992
`
`0736-0118190 $3.00 .... 00
`
`INTERLEUKIN-2 AND INTERFERON IN RENAL CELL CARCINOMA
`
`PETER WERSALL
`Department of General Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden
`
`(Submitted 23 December 1992; accepted 28 December 1992)
`
`Renal cell cancer (RCC) represents an unusual solid tumor for which no treatment other than surgical therapy has
`been effective. This tumor demonstrates a remarkably heterogeneous behaviour and rare reports of spontaneous
`regressions suggest an unusual sensitivity to host immunologic control. In recent years the rapid development in
`molecular genetics, growth factors and cytokine -
`lymphocyte interactions have increased the interest and
`possibilities for immunotherapy ofRCC.lnterleukin·Z (IL·Z) or Interferon alpha (IFNa) alone are only marginally
`active in RCC. Their different modes of action and their synergistic effects when used in experimental murine
`models prompted the investigation or combined 1L·2lINFa therapy in advanced RCC. The advantage of a
`combination of IL-Z and IFNa treatment as compared to LAK cell treatment seems to be that IL·Z and IFNa can
`be given at lower dosages without compromising the results in an outpatient setting. Tbis article reviews the use or
`IL·2 and IFNa in combination for treatment of RCC and discusses the current problems and future challenges in
`this field.
`
`Key Words: Renal cell cancer, Interferon, Interleukin-2, Prognostic factors.
`
`INTRODUCTION
`
`1,220 cases of renal cell carcinoma were registered in
`Sweden in 1988, i.e. 3% of all cancer cases in Sweden.
`RCC affects males twice as often as females. The aetio(cid:173)
`logical factors are not known. However, there seems to be
`an inherited genetic defect predisposing to renal cancer in
`studies of a few familiar occurrences. l Recent evidence
`indicates that deletions and translocation involving the
`short arm of chromosome 3 are important for the onco(cid:173)
`genesis and tumor progression of RCC.2 85% of kidney
`cancers are adenocarcinomas arising from the proximal
`tubules which may be subdivided into clear cell and granu(cid:173)
`lar cell carcinoma.
`Patients who have distant metastases from RCC have a
`poor prognosis, with a median survival of 10 months. 3 The
`clinical course of metastatic RCC is heterogeneous. Long(cid:173)
`lasting stable periods as well as rapid tumor growth and
`even spontaneous tumor regression may occur. Approxi(cid:173)
`mately 25% of patients with RCC have established distant
`metastases and an additional 25% regional lymph node
`mestatases at the time of diagnosis. 3 Surgical treatments
`
`*To whom correspondance should be sent: Dept of Clin Immunology
`and Transfusionmed, lnununhemotherapy Unit, Karolinska Hospital,
`Bo)( 60500, 104 01 Stockholm, Sweden
`
`are generally ineffective in curing metastatic disease. In
`addition, at least 50% of patients initially diagnosed with
`local disease, develop metastatic disease. Consequently
`there is an urgent need for an effective treatment of this
`malignancy.
`There are three possible forms of systemic treatment of
`renal cell carcinoma:
`1) Chemotherapy.
`2) Hormonal treatment.
`3) Immunotherapy.
`Responses to chemotherapy have proved to be ex(cid:173)
`tremely low. Vinblastin showed the highest activity in
`single agent treatment. The objective response rate rarely
`exceeded 16%. Attempts to improve these results by com(cid:173)
`bination chemotherapy have been unsuccessfu1.4
`Progesterons, androgens, or anti-estrogens, alone or in
`combination, induced less than 10% objective remissions
`in more than 700 treated patients (cumulative data from
`phase IIIIII trialS).4 Bon05 found that in more recent trials
`hormonal therapy led to objective remissions (partial re(cid:173)
`sponses) in < 5%. Therefore, it must be concluded that
`hormonal therapy is also of no value in the treatment of
`metastasized RCC.
`
`71
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`IMMUNOTHERAPY
`
`72 P. Wersilll
`
`Interferons
`
`Since the ftrst report of IFNo; (human leukocyte de(cid:173)
`rived) by Quesada et al. in 19836 numerous phase II and
`phase III studies using IFNo; derived from human leuko(cid:173)
`cytes or recombinant interferon (rIFN) have been publish(cid:173)
`ed. From these trials it can be concluded that neither the
`source of IFNo; nor the route of administration signifi(cid:173)
`cantly influenced its efficacy.7-ll
`
`Summarizing the results with rIFN, an overall remis(cid:173)
`sion rate of 14%, a median remission duration time of
`2.5-6 months, and median survival times of 9-18.5
`months were achieved in 465 patients.9 In patients with
`metastases to the lungs only, and with a good performance
`status, response rates of 40% can be achieved with IFNo;.lo
`On the other hand, IFNo; shows only little activity on
`metastases in bone, brain and liver. 10 In some studies, prior
`nephrectomy seemed to favourably influence the response
`rate, but this could not be confirmed by other authors. Few
`phase IIII trials of RCC using IFN~ or IFNy have been
`published. No evidence of superior activity compared to
`studies using interferon-o; was seen. II-13
`
`In vitro, IFNo; and IFNy show synergistic activity,14
`partly explained by the different cells surface receptors for
`both compounds, giving the basis for combining them in
`clinical trials. Two randomized studies that compared
`IFNo; and IFNyalone with IFNo; plus IFNyfailed to show
`a clinical relevant synergism of the combination in ad(cid:173)
`vanced RCc. 15-16
`
`INTERLEUKIN 2
`
`IL-2 was originally termed T cell growth factor and was
`first described in 1976 by Morgan et al. .16 In 1983 Rosen(cid:173)
`bergl7 at the National Cancer Institute (NCI) first applied
`this substance as anti-tumor drug in man, since in vitro
`studies and studies in animal models bad shown a strong
`anti-tumor activity ofIL-2.IS Since that time, IL-2has been
`widely tested in human malignancies alone or in combi(cid:173)
`nation therapy. The rates of objective remission (CR+PR)
`in single agent therapy ofRCC rarely exceed 20% and are
`in the same range as in IFNa mono therapy.
`
`The contribution oflyrnphokine activated killer (LAK)
`cells to the therapeutic efficacy has still not been clarified.
`There seems to be no increase in the total number of
`responding patien ts although it bas been claimed that there
`may be a higber percentage of complete responses wben
`rIL-2 is combined with LAK cells. 19
`
`COMBINA nON THERAPY WITH IL-2 AND
`IFNo;
`
`To achieve an improved therapeutic index there bas
`been some interest in combining interferon with IL-2. The
`rationale for the combined use of these agents was the
`following: The combination ofIL-2 and IFNo; in vitro and
`in animal experiments had greater antitumor effects than
`did either agent alone.20
`IFNo; bas both immunomodulatory and antiprolifera(cid:173)
`tive activities and acts through another surface receptor
`than IL_2.21
`
`IFNo; may augment the immunogenicity of tumor cells
`by enhancing their expression of HLA class I antigens and
`tumor associated antigens making them more susceptible
`to IL-2 sensitized T-Iyrnphocytes.22
`The investigations at the NCI wbich demonstrated the
`same activity of a combination therapy of IL-2 and IFNo;
`as for IL-2 and LAK cells in patients with renal cell cancer
`led to extensive investigation of this form of therapy
`25 on the use of
`(Table 1). Today there are many reports23
`-
`rIL-2 and rIFNo; in combination. These pbase I trials used
`different administration schedules of rIL-2 (continuos in(cid:173)
`fusion versus bolus) and different doses of each cytokine.
`IL-2 in combination with IFNo; also leads to response
`rates which are in the range of 20% in unselected patients
`(Table 1). Patient selection (good performance status and
`low tumor load) seems to be responsible for more favour(cid:173)
`able results as reported by some investigators. The side
`effects of IL-2 are dose dependent and highest after bolus
`injection. In the continuos infusion schedule used by West
`et al., 26 IL-2 side effects were reduced, but still substantial.
`Lower dos~es of IL-2 and IFNo; as described by Atzpo(cid:173)
`dien et at.' can reduce the side effects and simplify
`administration.
`The advantage of a combination therapy of IL-2 and
`IFNo; treatment as compared to LAK cell treatment seems
`to be that IL-2 and IFNo; can be administered in an
`out-patient setting in lower dosages without compromis(cid:173)
`29
`ing the results. 27
`-
`
`CURRENT PROBLEMS AND FUTURE CHAL(cid:173)
`LENGES WITH CYTOKINE THERAPY
`
`All conventional cytotoxic drugs are tested at the maxi(cid:173)
`mum tolerated dose. When IL-2 was first investigated this
`was the approach used, despite the demonstration from
`IFNo; that this was not the best way to get maximum
`benefit using cytokines.3o.31 The only trial to provide ex(cid:173)
`tensive dose-response escalation using IL-2 and IFNo;
`showed a bell-shaped dose response with lower responses
`33 In view of
`at high compared with intermediate doses.32
`•
`this it may be that the optimum dosing schedule has yet to
`be defined. This will require a means for determining the
`
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`Table 1. IL-2 and IFN-yin the treatment of renal cell cancer.
`
`Interleukin-2 and Interferon in carcinoma 73
`
`Authors
`
`Year
`
`Dose X 106/m2 schedule
`
`IL-2
`
`IFM- .U
`
`Patients
`evaluable
`
`CRn
`
`PRn
`
`CR+%
`
`Rosenberg et at. 46
`
`1989
`
`Talpaz et aL 47
`
`1989
`
`Markowitz et al.48
`
`1989
`
`Mittelman et aL 49
`
`1989
`
`Altzpodien et al. 25
`
`1990
`
`Bartsch et al. 5O
`
`Figlin et aL 2 8
`
`1990
`
`1990
`
`Lindemann et al. 29
`
`1990
`
`1-4.5 U i.v.
`X 8 h. 5 days
`1-3IU
`X 4 days
`2-3IU
`X 4 days
`0.5-7 U
`x 4 days/week
`9IU
`2 X daily x 2 days
`1.8 IU X 2 x daily
`x 5 days weekly .
`18IU
`day 8-12
`2IU
`day 1-4 weekly
`(for 4 weeks. 6 week
`intervals)
`3IU
`day 1-4
`
`Upton et aL 51
`
`1990
`
`1-2IU
`5 days/week
`
`Mittelman et aL 52
`
`1990
`
`3U
`
`Morant er al. 53
`
`1990
`
`3U
`
`Picbert et aL 54
`
`1990
`
`Ilson et aL 55
`
`1992
`
`3U
`x 4 days
`
`3U
`x 4 days/week
`x 3 weeks
`
`3-6
`X 8 h. 5 days
`2-10
`(3 to 5 week intervals)
`
`2-10
`(3 to 4 week intervals)
`
`6-12
`
`5
`3 x weekly
`for 6 weeks
`
`10
`day 1-5
`6
`day 1. 4 weekly
`
`6
`day: 1,4
`(2 week intervals)
`3-12
`day 1, 3, 5/week
`(3 to 5 week intervals)
`5
`(4 days/week)
`6 days 1, 3,5,8, 10, 12
`(4 week intervals)
`6
`(2 week intervals)
`
`5
`x 4 days/week
`x3 weeks
`
`35
`
`32
`
`14
`
`19
`
`14
`
`19
`
`22
`
`24
`
`12
`
`7
`
`6
`
`6
`
`28
`
`4
`
`not
`available
`
`2
`
`3
`
`7
`
`3
`
`4
`
`3
`
`3
`
`7
`
`3
`
`2
`
`2
`
`3
`
`31
`
`22
`
`21
`
`21
`
`36
`
`19
`
`32
`
`4
`
`50
`
`42
`
`33
`
`12
`
`Total
`
`206
`
`12(6%)
`
`37(18%)
`
`optimal immunomodulatory dose which today is still
`missing.
`A major issue for the clinician for the future will be to
`define the biological characteristics of responding pa(cid:173)
`tients, allowing one to decide either their eligibility or their
`exclusion from the therapeutic protocol after the first
`course of therapy, or even prior to therapy. This would also
`help to design more relevant protocols for nonresponding
`patients.
`In vitro, it has been shown that IL-2-activated lympho(cid:173)
`cytes kill LAK-susceptible cells, in a non MHC-restricted
`manner, after contact between target and effector cells. 34
`
`However, the exact mechanism of the in vivo antitumoral
`effect of IL-2 in humans remains unclear. Although cy(cid:173)
`tolytic activity of LAK cells has been found in some
`reports to correlate with the in vivo antitumoral effect, 26.35
`several recent studies failed to demonstrate any correlation
`between the lytic capacity of peripheral blood lympho(cid:173)
`cytes and the clinical response in vivo. 36
`.37 Moreover,
`observations that human LAK cells apparently do not
`move to sites of metastatic tumors suggests the possible
`involvement of soluble factors in the antitumoral effect of
`8Blay et at. found that the clinical response
`IL-2 in vivo. 37.3
`to IL-2 + LAK therapy in patients with metastatic renal
`
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`74 P. Werstlll
`
`Table 2. Suggested tools for response prediction in renal cell
`cancer.
`
`to each patient, in accordance with his own tumor cbarac(cid:173)
`teristics.
`
`Parameter
`
`Author
`
`REFERENCES
`
`Rebound lymphocytosis
`Rebound lymphocytosis
`Thyroid dysfunction and anti-microsomal
`antibodies
`Serum 1NF concentrations
`Serum IL-2 concentration
`
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`Banerjee 1991
`
`Atkins 1990
`
`Blay 1990
`Wersall 1991
`
`cell carcinoma is correlated to a higber 1NF concentration
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`West reported that patients responding to adoptive cel(cid:173)
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`characterisation will require a parallel analysis of the
`mononuclear cell population in the blood and in the tumor,
`together with the characterisation of malignant cells. In the
`future this might also imply an adaptation of the therapy
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