British lournalo/Huemutology. 1991, 79,Suppl. 1 . 96-104

Combination of cytokines: current status and future prospects L. KANZ, W . BRUGGER, K . BROSSA N D R . MERTELSMANN Albert-Ludwigs-University Medical Center, Department o j Hematology/Oncology, Freiburg, Germany

~~

Summary. Clinical trials with individual cytokines and extensive in vitro studies have provided the basis for the in vivo use of these molecules in combination. Animal models, with haemopoietic growth factors as well as preliminary studies in humans-as shown by our studies with the sequential use of IL-3 and GM-CSF in patients receiving intensive chemotherapy-indicate that the selection of the appropriate

cytokines could optimize haematological responses according to particular clinical requirements. That immunotherapy with IL-2 can induce regression of disseminated human malignancies serves as an encouraging starting point for combinations with other cytokines with the goal of improving the therapeutic efficacy and reducing toxicity. Future prospects of combination therapy will be discussed.

Improved understanding of host biology, immunology and tumour pathophysiology raises the possibility of introducing new treatment modalities for cancer patients: the stimulation of host defence mechanisms as well as effects to directly affect tumour growth and differentiation. In addition, amelioration of cancer treatment associated morbidities offers new possibilities for improving quality of life for many patients as well as options for increased dose intensity regimens with the potential of achieving higher cure rates for some patient groups.. IL-2 has received the most attention of the cytokines that stimulate the immune response. Based on the observation that IL-2 may mediate tumour regression in some patients with malignant melanoma (MM) and renal cell carcinoma (RCC).trials have been initiated to study possible advantages of IL-2 given in combination with other cytokines such as the interferons. The haemopoietic growth factors have provided exciting new possibilities for cancer treatment. Based on extensive in vitro studies, it has only recently become possible to study recombinant haemopoietic growth factors in vivo. Several of these cytokines have entered clinical trials: G-CSF, GM-CSF and Epo are currently in a n advanced stage of testing and IL1, IL-3 and M-CSF have recently been introduced and are studied for their clinical potential. The main questions to be asked are, whether these molecules may mitigate cancer therapy and cancer related immuno- and myelosuppression, augment non-specific mechanism of host resistance, and indirectly improve antitumour responses and survival by reducing toxicity and thus altering the definition of the maximum tolerated doses of conventional chemotherapeutic regimens.

This article will briefly summarize some of the potential roles of the cytokines with particular focus on preclinical and clinical data on the combined use of haemopoietic growth factors. HAEMOPOIETIC GKOWTH FACTORS I N CI,INICAI, ONCOLOGY One of the major therapeutic roles of haemopoietins in clinical oncology so far defined, is the treatment of insufficient haematopoiesis. Clinical studies have clearly documented the effect of recombinant human erythropoietin in correction of anaemia of cancer (Ludwig et a / . 1990: Oster et a / . 1990a. b). Haemopoietins currently under active clinical investigation for acceleration of bone marrow recovery following intenstive chemo- or radiotherapy include G-CSF and GM-CSF (Antman et al. 1988: Gabrilove et al. 1988: Herrrnann et al. 1989: Lindemann et a / . 1989): IL-3 has been studied in patients with normal haematopoiesis and in patients with bone marrow failure syndromes (Ganser et a / , 1990a). These studies demonstrated the capacity of these recombinant cytokines to accelerate haematopoietic recovery. The in vivo stimulatory effects of human haematopoiesis are summarized in Table I: it is ofparticular importance that IL-3 revealed a dose dependent increase in platelet counts as well as reticulocyte counts in most patients (Ganser et ul. 1990a). In addition, several trials documented a decrease in the incidence and severity of infections in patients receiving CSFs, resulting in a significant shortening of the patients' stay in the hospital (e.g. Herrmann et al. 1989). Haemopoietins are also being evaluated for the stimulation of haematopoiesis in bone marrow failure syndromes. GMCSF has been studied in several trials to overcome pancytopenia in aplastic anaemia. The value of this growth factor.

Correspondence: Professor Dr R. Mertelsrnann. University Medical Center, Department of Internal Medicine 1. Hugstetter Str. 55, 7800 Freiburg, Germany.

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Combination of Cytokines Table I. III wivo properties ofhaemopoietins in clinical trials

C-CSF

CM-CSF

11,-3

EPO

Neutropoiesis -Migration -Activation Eosinopoiesis Monopoiesis Lymphopoiesis Erythropoiesis Thrombopoiesis Sources of haemopoietins tested: EPO: Behring/InCen ( G I 27):G-CSF: Amgen ( E . coli):GM-CSF: Behring/Immunex ( E . coli): IL-3: Behring/Immunex (yeast).

* Synergistic activity with early acting growth factors.

however. appears to be limited to those patients with residual haematopoiesis (Champlin rt al. 1991: Nissen r t al. 1988). Very impressive results are reported for the treatment of congenital agranulocytosis (Kostmann syndrome) with GCSF: the application of G-CSF resulted in the correction of agranulocytosis, accompanied by the resolution of preexisting chronic infections (Welte et ul. 1990). Applications of cytokines (G-CSF. GM-CSF, IL-3) in myelodysplastic syndromes have been described to increase peripheral blood cell counts (Ganser r t d . 1989. 1990b: VadhanKaj et ul, 1987). An an increase in leukaemic blast cells was observed in some patients treated with CSFs, some trials that are currently being conducted combine cytokines and low dose cytosine-arabinoside in the subset of patients considered at risk of leukaemic progression. Cytokines have also been shown to enhance haematopoietic recovery after bone marrow transplantation (Mertelsmann r t nl. 1990) and to increase the circulating pool of peripheral blood haemopoietic stem cells (Socinski r t aI. 1988) that might be harvested as a n alternative to marrow cells for transplantation (Gianni rt aI. 1989). COMBINATIONS OF FIAEMOPOIETIC GKOWTH FACTOKS:rrv VITKO STUDIES The distinctive pattern of respone to individual haemopoietic growth factors-as analysed in vitrn and in vivo-provided the opportunity to explore the use of combinations of these cytokines. Many in vitro studies have shown that in fact additive or synergistic effects on haematopoiesis could be observed using a wide range of growth factor combinations (see Table 11). IL-I which displays no colony stimulating activity by itself, acts synergistically with CM-CSF. IL-3 and M-CSF in the stimulation ofearly haemopoietic progenitor cells. The action of IL-1 in potentiating the function of IL-3/GM-CSFis likely to be due to the induction of secondary growth factors, including IL-6 (Leary et a/, 1988) and G-CSF (Schaafsma et al. 1989). IL-6 as well as G-CSF have been shown to act as synergistic

97

factors with IL-3 in the initiation of proliferation of early haemopoietic progenitors (Ikebuchi et al. 1988): IL-3 itself does not stimulate haemopoietic cells into active proliferation, but rather is needed for the continued proliferation of progenitors after they have started cell division (Ikebuchi rt al, 1988). Combinations of GM-CSF with IL-3 or GM-CSF/IL-3 with later acting factors such as M-CSF also showed additive or synergistic actions on progenitors. The multitude of combinations used and the complexity of results published so far (using different culture conditions). however, illustrates the complexity of the regulation of haematopoiesis. suggesting a differential activity of various cytokines depending on the maturity level of the target cells. These results are consistent with a requirement for several haemopoietic growth factors for supporting the complete developmental programme of early stem cells. COMBINATIONS OF HAEMOPOIETIC GKOWTH FACTORS: IN vrvo STUDIES The in vitro data outlined above provided a powerful rationale for exploring the amplification of haematopoiesis by cytokine combinations in vivo. The demonstration that greater responses could be achieved with combinations of cytokines than by using high doses of single haemopoietic growth factors which may carry a risk of adverse reactions, have been important in designing in vivo studies. Experiments in mice showed synergistic myelopoietic actions after administration of various combinations of colony stimulating factors: moreover, IL- 1 synergized with GM-CSF or G-CSF to confer optimal radioprotection to the animals (see Table 111). In primate models, a synergistically enhanced stimulation of haematopoiesis. including thrombopoiesis. was observed with IL-3 and GM-CSF or G-CSF or IL-6. when given sequentially (see Table 111). In patients, combinations ofcytokines are just beginning to be evaluated. Encouraging results with G-CSF plus erythropoietin have been reported in AIDS patients receiving zidovudine (Miles et al, 1989): the combined use of these cytokines abrogated the neutropenia and anaemia in these patients. In preliminary studies we have shown that the sequential use of IL-3 and GM-CSF in patients treated with intensive chemotherapy not only accelerates recovery of neutrophils. but also results in a concomitant rise in platelets (Fig 1 ): when GM-CSF was used without prior IL-3 treatment, platelet recovery was delayed. IL-3 plus GM-CSF induced a dramatic increase in all peripheral progenitor cells (CFU-GEMM, CFIJC. BFU-B and CFU-Meg) as well as the appearance of up to 40% ofCD34 positive cells in the peripheral blood. These data will argue for the harvest of peripheral progenitor cells (Gianni et al, 1989) that might be used for rescue after highdose intensification chemotherapy (Neidhart et al, 1990). Based on the data summarized above, a combined/ sequential use of cytokines active on early stem cells (11.-I, 11,6,G-CSF) to drive them into cycle, followed by IL-3/GM-CSF to stimulate multipotential progenitors and finally the use of late-acting cytokines with lineage restricted potential, might

L. Kanz et a1

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Table [I. Effects of combinations of cytokines on in vitro haematopoiesis Combinations

Etrects of haematopoiesis

References

IL-1 + I L 3

Synergistic in support of early progenitors

Brandt et al. 1990: Ikebuchi et al. 1987. 1988: Koike et al. 1988: Moore et al, 1987b; Stanley et al. 1986: Takaue et al. 1990 Leary et al, 1988

Not synergistic in support of early progenitors IL- 1 + IL- 3 + M-CSF Synergistic in support of early progenitors

Bartelmez et al. 1989

IL-1 + M-CSF

Increase in immature monocytic colonies Synergistic in support of monocytic progenitors Synergistic in support of early progenitors

Zhou et al. 1988 Moore et al. 1987b Ponting & Dexter, 1988

IL- 1 + G-CSF

Synergistic in support of monocytic progenitors Synergistic in support of granulocytic colonies

Moore & Warren. 1987b Takaue et al. 1990

IL-1 +GM-CSF

Synergistic in support of early progenitors Synergistic in support of CFU-GEM

Hoang et al, 1988: Mochizuchi et al. 1987: Ponting et al. 1990 Schaafsma et al. 1989

+

Synergistic in support of CFU-Mix Synergistic in support of early progenitors

Gardner et al. 1990 Brandt et al. 1990: Ikebuchi cc al. 1987, 1988: Koike ef 01. 1988: Leary et al, 1988

+GM-CSF

Synergistic in support of granulocytic differentiation Caracciolo et al. 1987 No synergism Gardner et al. 1990; Schaafsma et al. 1989

+

Synergistic in support of monocytic colonies

Bot et al. 1989: Gardner et al, 1990

Synergistic in support of early progenitors Synergistic in support of granulocyte colonies

Ikebuchi et al, 1988; Takaue et al, 1990 McNiece et al. 1988: Paquette et al, 1988

Synergistic in support of CFU-GM colonies Synergistic in support of early progenitors

Ferrero et al. 1989: Hara & Namiki 1989: McNiece et al. 1989: Schaafsma et al. 1989 Ponting & Dexter, 1988

IL-6 I L 3

IL-6

L-6 M-CSF

G-CSF +IL-3 G-CSF +GM-CSF

G-CSF + IL-4

Enhanced CFU-C-colony formation

Vellenga et al. 1990

G-CSF M-CSF

Synergistic in support of early progenitors

Ponting & Dexter, 1988

IL-3 + GM-CSF

Synergistic in support of CFU-GM Additive/overlapping in support of CFU-GM Synergistic if given sequentially Poor colony formation

Paquette et al, 1988: Ventura et al. 1990 McNiece et al. 1989: Takaue et al. 1990 Saeland et al. 1989 Sieff et al, 1989

IL-3 + M-CSF

Synergistic in support of early progenitors

Koike et al. 1986; McNiece et al. 1984: Morris et al. 1990: Zhou et al. 1988

Antagonistic action on CFU-GM

Vellenga et al, 1990

Synergistic in support of early progenitors

Migliaccio et al. 1988

Synergistic in support of early progenitors Enhanced CFU-M colony formation

McNiece et al. 1988 Bot el al. 1990: Caracciolo et al. 1989

+

IL-3

+ IL4

IL-3 +Epo

GM-CSF + M-CSF

be expected to offer maximal marrow stimulation and clinical responses. Moreover, the selection of the appropriate cytokines which act on the more differentiated cells, such as MCSF and erythropoietin, would be desirable to optimize the haematological response according to particular clinical requirements. In view of the complex network of interactive cytokines. however, the extrapolation of in vitro data on combination therapy with cytokines is somehow unpredictable, perhaps leading to unexpected responses, such as observed in mice treated with G-CSF which displayed a relocation of erythro-

poiesis from bone marrow to the spleen (Molineux et al. 1990). So far, most of the in vitro data on combination of cytokines do not consider extracellular matrix requirements or selective cell-cell interactions. As several colony stimulating factors are able to induce other cytokines that may have potential stimulatory or inhibitory effects, the combined in vivo application of haemopoietic growth factors might result in very complex interactions. Thus, combination therapy in patients has to be used with caution. It is presently unknown how the synergistic effects observed in vivo are being mediated: super-additive responses

Combination of Cytokines

99

Table 111. Etrects of combinations of cytokines on haematopoiesis in animals Combinations

Animal

FXects on haematopoiesis

References

IL-3. GM-CSF. M-CSF IL-I. GM, G IL-I. G IL-3. M IL-3. G IL-3. GM IL-3. G IL-1, IL-3. GM IL-6. G. GM. IL-3 IL-6. IL-3 GM. Epo

Mice Mice

Synergistic myelopoietic action Synergistic radioprotection Synergistic in rnyelosuppressed animals Synergistic on early progenitors Additive on neutrophils Synergistic on haemopoiesis (incl. platelets) Synergistic on haemopoiesis (incl.platelets) Platelet response Platelet response by IL-6 alone Synergistic on platelets Synergistic on platelets

Broxmeyer et al. 1988 Neta et a/. 1988 Moore et a/. 1987a Williams et a/. 1987 Ulich et al, 1990 Donahue et a/. 1988: Krumwieh et al. 1990: Krumwieh. 1990 Krumwieh. 1990 Monroy et al. 1988 Zeidler et a/. 1989 Geissler et a/. 1990

Mice

Mice Rats Primates Primates Primates Primates Primates Primates

Oster/Krumwieh.pers. cornrn.

IL-3 = Multi-CSF: GM= GM-CSF: G = G-CSF: M= M-CSF: Epo = Erythropoietin.

IL-3 Ow!' 3 2 5 0 u g h 2 S.C. x 1 0 /mm 15 1600 mg;2 mg/m2

GM-CSF 2 5 0 figIm2

ACD34 Platelets x 1 03/mm3

S.C.

f

~

50 m g / m 2

\\ 4

Y

10

5

200

.' 100

Pat. N.W. ~

~

0

5

10

_

300

_

15

may reflect direct and indirect effects on the progenitors. Synergistic factors such as IL-1 could modulate CSFs receptor numbers and affinity (Bartelmez & Stanley, 1985 ). Moreover, the ability of combinations but not the growth factors alone to stimulate primitive progenitors, such as shown for M-CSF plus G-CSF (Ponting & Dexter, 1988). is presently not fully understood. Current in vitro data suggest the importance of a sequential application of IL-3 and GM-CSF when given to patients, instead of a combined use. IL-3 and GM-CSF may compete for the same receptor on some cells (Park et a/. 1989a, b): this competition may alter the apparent number of functional receptors for each ligand. In addition, in vitro culture of CD34 positive cells demonstrated increased responsiveness to GMCSF following preculture with IL-3. Moreover, the sequential use of 11,-3 and GM-CSF is in accordance with the hypothesis that IL-3 may expand the GM-CSF sensitive population of progenitors. To date, neither the treatment with individual growth factors in patients after chemo-radiotherapy (excluding patients with blastic transformation of haematopoiesis) nor the long-term treatment of patients with Kostmann syndrome have given evidence to suggest that the treatment

Fig 1. Sequential use of IL-3 (days 1-5) and GM-CSF (days 6-1 5) in a patient with small cell lung cancer, treated with intensive chemotherapy. 0 . White blood cells: platelets: A, CD34 positive cells in peripheral blood.

..

with CSFs results in leukaemic transformation or in a marked depletion of mature cells of other lineages. In mice, even excess levels of haemopoietic growth factors-studied in transgenic mice or in irradiated mice repopulated with transfected haemopoietic cells-did not lead to leukaemic development or depletion of stem cells (Metcalf, 1990). However, these observations may not be valid for combination therapy with cytokines which recruit more stem cells and might result in competition for commitment of stem cells: their clinical use. therefore, must be carefully monitored. So far, only the application ofIL-3-either alone (Ganser et a/. 1990a) or in combination with GM-CSF (see Fig 1)-to patients with suppressed thrombopoiesis results in an increase of platelets. As in vitro data indicate that megakaryocytopoiesis might be regulated specifically by a cytokine(s) different from IL-3 and GM-CSF. a great deal of work is currently done to define the cytokines responsible for megakaryocyte development. Eventually, there are prospects for the possible identification and characterization of a CSF specific for the megakaryocytic lineage (Hoffman et a/. 1987; Kanz et a/, 1989: Metcalf et a/, 1990; Zeidler et a/. 1990). The cloning of a Meg-CSF and its combined use with cytokines with activity on early stem cells, such as IL-1. or cytokines

100

L. Kunz et al

which seem to act on more differentiated megakaryocytes. such as IL-6 (Asano et al. 1 9 9 0 Zeidler et al. 1989). would greatly facilitate the treatment of patients with decreased platelet production. COMBINATION OF IL-2 WITH OTHER CYTOKINES IL-2 and alpha-interferon are known to mediate tumour regression in some patients with malignant melanoma and renal cell carcinoma. The potential clinical use of IL-2 depends on its ability to activate endogenous cells able to exert antitumour effects: it induces T-cell and B-cell activation, resulting in the secondary induction of other lymphokines, including IL-4 (Howard et al. 1983),TNF (Nedwin et al, 1985)and interferon gamma (Farrar et al. 198 1).IL-2 also directly augments the cytotoxicity of human monocytes (Malkovsky et al. 1987) and stimulates the activation of lymphokine activated killer (LAK) cells (Phillips & Lanier, 1986). Most of the IL-2 induced cytolytic activity was found to be mediated by natural killer (NK) cells (Phillips & Lanier. 1986). Initial clinical studies with IL-2 were performed by Rosenberg and colleagues using adoptive immunotherapy with high-dose IL-2 and ex vivo activated LAK cells (Rosenberg et al. 1985. 1987). Antitumour activity could also be demonstrated in patients receiving IL-2 therapy without LAK-cells. indicating that exogenous LAK cells are not an absolute requirement for antitumour activity of IL-2. Overall responses achieved by IL2 treatment with or without LAK cells ranged from 0-50% in KCC and 11-50% in MM (Dutcher et al. 1989: Fischer et al, 1988: Lotze et al, 1986). The antineoplastic activity of the interferons seems to result from both a direct inhibitory effect on cell growth and an indirect effect by modification of the immune system (Brodeur & Merigan. 1975: Herberman et al. 1982: Schnaper et al. 1983). The most impressive clinical results with interferon alpha have been achieved in hairy cell leukaemia (Queseda et al. 1984) and chronic myelogenous leukaemia (Talpaz et al. 1986). Other indications for which interferon alpha has proved promising include multiple myeloma, T-cell lymphoma and B-non-Hodgkin-lymphoma (Bunn et al. 1984: Foon et al. 1984). Preliminary studies suggest possible advantages of IL-2 given in combination with interferon alpha (Buddet al. 1989: Lee et al, 1989: Rosenberg e l aJ. 1989: Veelken et al, 1990). interferon beta (Krigel et al. 1990: Paolozzi et al. 1989) or interferon gamma (Hu et al. 1990: Kedman et al, 1990). Preclinical data have demonstrated antitumour synergism for these combinations (Cameron et al. 1988: Chouaib et al. 1988). In clinical phase I trials, the combination of IL-2 with tumour necrosis factor and monoclonal antibodies, so far, have not been promising (Bajorin et al, 1988:Markowitz et al, 1989: Schwartzberg et al, 1989). WHAT ARE FUTURE PROSPECTS FOR COMBINATION THERAPY? Combination of haemopoietic growth factors might enhance retrovirus-mediated gene transfer into haemopoietic stem

cells with the prospect of gene replacement therapy for certain genetic disorders affecting the haemopoietic system. Most haemopoietic stem cells reside in the non-proliferating state of the cell cycle: pretreatment of the bone marrow with IL-3 plus IL-6, which increase both stem cell cycling and the number of stem cells (Ikebuchi et al. 1988), has been shown to facilitate retroviral gene transfer (Bodine et al, 1989). Combination of cytokines could be relevant regarding their potency to increase non-specific resistance to microbial infections. The haemopoietins are known to induce a variety of functional changes in neutrophils, monocytes and eosinophils. which add to their effects on haemopoietic progenitor cells. Recently, Nagabhushan (1990)reported that mice with E. coli or Pseudomonas-inducedsepsis survived when GM-CSF therapy was combined with IL-6, known to be involved in immunoglobulin production and acute phase reactions. These observations provide further evidence that cytokines might serve to fight infections through augmentation of effector cells and stimulation of acute phase reactions. Finally, there are prospects of integrating cytokines into chemotherapy schedules in acute leukaemia: on the one hand they accelerate haemopoietic recovery following chemotherapy without affecting the regrowth of leukaemic cells (Ohno et al. 1990), and on the other hand they might recruit leukaemic cells into active cell cycle, making them more sensitive to cytotoxic chemotherapy. Again, this is an option for combination of cytokines. as for example 1L-3 plus IL-6 are known to rapidly recruit cells into cycle (Ikebuchi et al, 1988), and GM-CSF plus G-CSF are known to act synergistically on blast cells (Kelleher et al, 1987). Whether cytokines might even suppress leukaemia as shown in some animal models (Fabian et al. 1988: Tamura et ul. 1989) remains to be studied. Potential future directions for cytokines that stimulate the immune response. potentially enhancing immunosurveillance of neoplasms, such as IL-2 and the interferons, include studies with other cytokines. A combination awaiting clinical trials is IL-2 plus IL-4. Preactivation with IL-2 permits IL-4 to induce LAK cytotoxicity (Higuchi et al. 1989).Moreover, the ability to produce human chimaeric antibodies and bispecific antibodies has the potential to make combined IL-2 and antibody therapy more successful. The timing of cytokine administration (simultaneous versus sequential in either order) is another unsolved problem that might be very important in determining clinical efficacy. Finally, it is of utmost importance to develop a more complete biological understanding of the very complex pathophysiology of the cytokines, in order to be able to design new promising studies with lower toxicity and higher efficacy in patients with malignancies. REFERENCES Antman. K.S.. Griffin, 1.D.. Elias. A.. et ul(1988)Effect of recombinant human granulocyte-macrophage colony-stimulating factor on chemotherapy-induced rnyelosuppression. New Englund /aitmul a/ Medicine. 319, 593-598. Asano. S.. Okano. A.. Ozawa. K.. Nakahata. T.. Ishibashi. T..Koike. K., Kimura. H..Tanioka.Y..Shibuya. A.. Hirano. T.. Kishimoto. T..

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