- In vitro studies nnd animal experiments showed the existecce of” a physiological immune response against tumors. Interle~ia-2 was the first ~~~~l~~ica~ agent which dernanst~~~ an anti-tumor effect by activating immune effecters. In vitro fE.2 may generate Lymphokin~ Activated Killer &AK) cells from peripheral blood ~ymph~ytes or Tumor infiltrating Lymphocytes [TIL) expanded from tumor. In melanoma and renal cell carcinoma, IL2 alone or associated with LAK cells or TIL, m~iated clinical responses. However, their clinical efficacy was associated with some toxicity related to a capillary leak syndrome. This implies nn ilu~rovement in the selection of patients and in the understanding of IL2 action. Future directions in immuoo?hernp~ included combination IL2 with other cytokines or rnon~~o~l ~tib~~ or chemotherapy. Lymphokine gene therapy is designed to introduce IL2 or other cytokine genes into tumor infiltrating lymphocytes or direcdy into tumots to reduce systemic toxicity and to achieve high local cyto~ne concentmtiu~ Animal models and the first human trials make this approach promising.

~~ter~e~In 2 f tumor jn~~~~

~yrn~~~~~s 1 jrnmuno~~~~y

REsurrp& - &at zwz&d de ~‘~~~~tioM de i’~~te~~~ukine-2 ea ~~~~~~~. De ~&~~~~ traiwux rdaP&?..cltez Iiuritwd montrent qu’tme r&anse ~mrn~niiu~~aat~~umora~eexiste de fagan ~h~s~a~~g~que. ~~nter~e~~e-2 a &d la prem@re cygakine s~nthdtisde par tes li~rnphac~tesT dent les prx+wi&t&antitumaraies ~auva~ent Ptre attributes ri ane s#~rnu~t~andu systsme immunitaire, In vitro, ~‘incu~atiaa de ~yrn~koc~tesda sung p&ip!t&+que pendant 3 jours avec de i’i1;2 g&t%? a’ei l~~hoki~e ~?~~~~d k&r (UK) canaries de Iyser des ce~~aiestumarales frazches defwmznon MN% restreinte. A partir de lymphocytes extru&s de tumeurs er incub& peadattt ~~~~ars semairtes avec de I%52, art pear a&et& des TE dattt Ia cytotoxicitd est parfois restreinte b la tumeur d’origine. Des rt$onses cliniques signifcatives ant pu Ztre obtenues dans le m&anome et le cancer du rein par l’administration d’lL.2 seule au associt?e li des UK ou ci &s TK N$anmoins, une toxicire”syst&mique fi&e ii an pk&om&te de fuite capibire est accrue au cows de ces essais c&igues. Aussi une meilleure s&e&m des ~at~euts et une rne~~~~u~cam~r~hens~on des m~an~smes d’action de I’B.2 devraient permettre de mien: cantr3ler ces traitemenrs. L’assoeiaritm de t XL? h d’aatres cytokines, des anticorps rn~aoc~a~~ cm B certains types de ch~m~athdra~~es canstitue des axes de twktrche uctueiie. .Led&eIoppement de lo th&apie &ttiqae par I’introduction des gPnes de cytakiaes dntrs des ?7& au dir~ctemeat dartr Ia rur#feara&t de r&d&e la ta&it& s~stdrn~q~eet ~aug~nte~ few &aa~~~trat~~~ iocale, repriSeate we Lewe vo& d’ave3ir: iutrdeukine-2 I lymphocytes WNtrant les tumeurs I immunoth&apie

~~~iarjo~~: ADCC, ant~~dF dependent celhdar cytotoxicity: GM-CSF, ~ra~ul~~~ ~crnphaga co~n~~stim~lating factor; IF& Intefferon: IL, inter~eukia; LAK cells, ~ymphokjne activated killer ~~~1s;mAb, mo~~ioaa1 antibody; MHC, Major ~i~to~em~ti~]itY Complex; MTD, Maximum tolerated dose; PBMC, peripheral blood mononuclear cells; sIL2R, soiuble IL2 receptor; T& mmM in~itratin~ lymphocytes: TNF. Tumor necrosis factor,


uction Biological response modifiers such as IL2 are novel agents used in cancer therapy. They differ from conventional chemo~erapy or ra~otherapy in that they are aimed at stimulating host defences rather than directly exerting an antitumor effect. During the 198Os, the cloning of cytokine genes enabled the production of large amounts of these substances and the beginning of clinical trials. Rosenberg first showed the clinical relevance of these treatments with his results obtained in cancer patients treated with IL2 1621. In this review, we shall try to define basic concepts and pre-clinical data in favor of the use of IL2 cancer. Clinical results and future directions will also be reviewed.

Rationale for immuwtherapy

in cancer

Evidence is accumulating in favor of the exist%tce of a physiological immune response against tumors in man. Cancer is associated with an accumulation of mutations affecting growth regulating proteins or oncogenes. Recent data suggest that these subtle changes, such as only one mutation in ras oncogene, can be recognized by T cells [40]. Exquisitely specific cytolytic T cell clones have been identified in melanoma [3, 851. Similarly, identi~cation of cytotoxic T lymphocytes (CTL) able to specifically recognize in an MHC-restricted fashion, the Mage 1 antigen associated with melanoma, has recently been described [91]. Autoantibodies against GD2 gangliosides, present in melanoma have also been found in the serum of cancer patients I93J. Therefore, if a B and T cell response directed against structures present in tumor cells can be demonstrated, one can wonder why tumors escape immune surveillance. A tolerance state, or anergy, of B and T cells has been demonstrated in various models 1731. In some cases, this inhibition could be abolished by eytskine administration such as IL2 [53, 791. This failure to limit tumor growth may also be explained by the high rate of tumor growth which exceeds the capacity for tumor rejection by the immune system. In this case, by activating the immune system, IL2 may help to amplify ~ns~nmor immunity 1271. Hnterleukin

2 in animal tumor models

In vitru, IL2 is a growth factor for T cells [52], B cells 1103j and NK cells [33]. It increases MHC [30] and non-MH~ restricted cytotoxicity [33].

Incubation of peripheral blood lymphocytes with IL2 for 3 days generated LAK cells able to kill fresh tumor cells in a non-MHC restricted fashion [IOI]. When IL2 was administered in ~ivo, it enhanced the immunogenicity of some tumors. Thus, the injection of IL2 in animals allowed detection of specific antitumor CTL not seen before its administration [Sl]. IL2 alone, or associated with LAK cells, mediated the regression of pulmonary or liver micrometastases from a variety of animal tumors [55]. In mice, high dose IL2 alone eradicated disseminated murine leukemia [Sl]. Irradiated tumor-bearing mice did not respond to high doses of IL2 but were sensitive to infusions of LAK cells with IL2, demonstrating that exogenous LAK cells can mediate antitumor effects and that IL2 alone is devoid of ~titumor activity in the absence of IL2-responsive cells [63]. Tumor-Infiltrating-Lymphocytes (TIL) are cells that infiltrate growing tumors and can be expanded by culturing single-cell suspensions obtained from tumors in IL2. After administration in animals, TIL were found to be 50-100 times more effective in treating established 3-day lung and liver metastases than LAK cells [64].


triais of IL2

Rosenberg et al were the first to report clinical responses to IL2 alone or LAK cells plus IL2 in cancer patients 162, 651. The most significant results were obtained in melanoma and renal cell carcinoma and, to a lesser degree, in hematopoietic malignancies. Several groups confirmed these preliminary data as summarized in tables I, II and III. In melanoma, the combination of LAK cells plus IL2 seemed, in one study, to be slightly superior in terms of survival as compared to IL2 alone [69]. In most cases, clinical responses appeared by the end of the first cycle. The duration of response may be significant: in the Rosenberg series, among 20 patients who achieved a complete response, nine remained free of disease after 13 to 75 months [69]. The maximal tolerated dose (MTD) of IL2 was for lo6 u/kg bolus administration and 3000 U/kg/h for continuous infusion [44]. This was the dose generally used for clinical trials. It seems that lower doses of IL2 decrease toxicity while maintaining clinical efficacy in renal cell carcinoma 16, 31, 72, 771. The mode and regimen of IL2 administration has been ~equently dis-

475 Table f. Responses in melanoma patients treated with IL2 alone or LAK ceils plus iL2. A~tf~~~S

lwode and sc~ed~fe ~~rn~e~ of Of fL2 ~~~~~~~~~o~ion pat~eItt~

West et at [Q7] Rosenberg et al [EiS] ~k~nson et at [SS]

Rosenberg @9] Dorval er ai [16] Bar et al [8] Dutcher er af [IS] Dutcher et al [19] Rosenberg et al [693

Alone Alone Alone Atone Alone LAK LAK LAK LAK

&iv) (boius~ @iv) ~bolus~ &iv)

10 I6 46

CR n

z 2

z 50 32 33 48

; I I I:

PR n


6 5 8 9 8 6 S 1 6


;: FE

14 19 2:

civ = continuousintm~enousinfusion: n = number of pati~nt$:CR = complete remission:PR = partial revision. Table 11, Res~nses in renal cell ca~~noma patients treated with IL2 alone or LAK cells plus IL2, A~tf~or~

Rosenberg Rosen~rg West et at Rosenberg

Mode and sclredule ‘of IL2 ~drnfi~~~t~at~o~ et at [65J et al [69]

[97] et al [65] Ro~et~~erg et al [69] Weiss et al 1961

Alone (bolus) Alone (bo~us~ Alone @iv) LAK LAK LAK




21 40 6 36 72 94

CR n

PR tl

CR+PR 46


0 6 3 8 17 II

S 18 50 33 35 17

: 4 5”

Table IZI, Responses in Iymphoma patients treated with IL2 or LAK ceils plus IL2. A~t~lQrS -_

West et af 1971 Rosenberg et al [69] Rosenbe~ et ai 1693 Allison a! al [2]

Mode stud scfied~fe of IL2 ad~zi~f~tr~ti~tt

Alone (civf Alone (bolus) LAK Alone (Low dose)

cussed. Some ar~~~~nt~ suggest that a c~nt~n~o~s

infusion reciter ensures better immunostim~la~ tiun than iv bolus infusion with comparable clinical results 183, 971. Bolus in~sion induces a transient serum peak of cytokines such as IFNg f29] not obse~ed with continuous intravenous @iv) infusion which may explain the lower toxicity reported with the civ regimes [82j. In the context of outpatient treatment, s/c or im, Il..” administration is ~lromising because of the constant and long lasting serum IL2 concentration but only 30% of the dose of IL2 administered was found in the serum [42]. Soiae authors have tried to increase LAK cytotoxic~ty by ~~~sur~ngNK puri~ed cells with fL2. Three labial r~po~ses were observed in a series of nine Fatients, after these Lanak cells were administered ilr viva i37].

~~~?~~erQf p~tielit~

CR n

i?R n


2 I1

0 0



2 0 3 3

100 0 57 42

The results obtained with Tumor ~~~l~ating Lymphocytes plus IL2 melanoma patients are detailed in table IV. Dotval et al treated patients non responsive to IL2 ft is notew~~y that these patients were able to generate TIL, although no clinical response was observed 1171.TIL toxicity was lower than that reported with the dose IL2 regimen, most likely due to the shorter duration of IL2 therapy after TIL infusion. The main Iimitation of TIL therapy is tbe need to have an accessible fresh tumor from each patient, and the delay in growing app~priate number of TIL. Intracavity therapy offers the possibility to achieve high local IL2 condensations and is designed to reduce systemic taxicity. Part&X responses were documented in 2110 patients with ovarian cancers and 5112 patients with colon car-

476 TableIv.Responses in melanoma patients treated with tumor infiltrating Authors

Number of^ patients

CR n

Topalian er al [86f Dorval ec al 1171 Rosenberg et al 1691


plus IL2.







1 0

17 0





cinema who received intraperitoneal instillation of IL2 1781. nevertheless, this route of administration led to substantial systemic toxicity and development of peritoneal fibrosis. Intrapleural administration of IL2 led to clinical resolutions of malignant pleural effusions in S/11 patients with primary lung carcinomas. Six of the responses were durable [99]. Intracerebral administration of IL2 was carried out in patients with recurrent glioblastomas. Partial responses were observed but increased cerebral edema limits this approach 139, 1001.

Toxicity is directly related to IL2 since LAK, or TIL cell infusion alone did not induce systemic toxicity. This toxicity include> constant fever which appears 2-4 hours after the start of IL2 infusion and ceases 6 hours after treatment [SZ]. Neurotoxicity, cytopenia, hypotension and a capillary leak syndrome, whose most serious sequelae are pulmonary edema, are also observed (table V). The capillary leak syndrome is similar to that which occurs in Gram-negative septicemia, sug-

Table Y. Toxicity of IL2 treatment. IL2 alone






46 35 22 12 42 73 30 15 15 2

t673 [971 :;:;









[671 /671 (971 [671

36 78

1671 [671

31 67











6 2.5 1.5 2.5 68















2 3s 44 69

WI r971 167:






I671 1671 ii;;

86 55 25

1671 1671 f671

57 75 35




13 23 2


8 5 6


Hypotension requiring vasopressors Weight gain > 10% body wt Oliguria Elevated creatinine Respiratory


Pleural effPlsion requiring thoracocentesis Arrythmias Treatment

associated death

Diarrhea Anemia requiring T~ombocytopenia Chills Disorientation


32 22


:z;; 1971

10 Somnolence Coma Pruritus Hypothyroidism

TIL plus IL2

&Afcpfus IL2



i2 10-29


g t671 1671 [671 ;::I

gesting that cytokines, such as TNFa, induced by 11.2 is wivo, may contribute to the toxicity. Indeed it was shown that high doses of TNFa resulted in a severe syndrome similar to septic shock [89]. TNFa and IFNg combination in clinical trials in man induces severe pulmonary complications similar to the IL2 leak syndrome [14]. In some studies, passive immunization against TNF inhibited some toxic effects but not the antitumor effect of IL2 [26]. However, other factors appear to be involved in these undesirable effects. In mice, AntiTNF antibodies were only partially protected against the side effects of IL2 treatment [88]. However, early results of human trials in which patients were pre-treated with TNFa, prior to receiving rIL2 have not shown an increase in toxicity beyond what would be expected from each cytokine individually [41]. If TNFa or other cytokines are definitely incriminated in these side effects, soluble cytokine receptors may be used to neutralize them. Different regimens have been proposed to reduce this toxicity. Since the side effects of IL2 are dose-related, protocols which include lower doses of IL2 while maintaining efficacy are of great interest [6]. No increase in plasma TNF concentration was observed after low dose s/c IL2, which may reflect the lower toxicity of this regimen [36]. Continuous intravenous infusion of IL2 rather than bolus infusion may be less toxic, but this question is very controversial [95, 971. Lastly, bz vitro studies showed that IL2 can promote growth of tumor cells [43, 871. Until now, only one observation indicated an in vivo IL2-induced reversible increase in peripheral monoclonal B cell lymphocytosis in a B cell lymphocytic non-Hodgkin’s lymphoma 1841. Moreover, this may result from an enhanced circulation (and not an enhanced proliferation) of neoplastic B cells from, the lymph nodes into the circulation.

Analysis of immunological effects of IL2 treatment alone or in combination with adoptive immunotherapy Evidence for activation of the immune system following IL2 therapy In all patients receiving IL2, lymphocytopenia was observed during the first hours of treatment. This lymphocytopenia may not be principally cortisol-mediated, as it is not suppressed by metapyrone [5]. This phenomenon was followed by

marked lymphocytosis after IL2 discontinuation, with a ratio from 2-20 as compared to tbe value prior to IL2 treatment [45]. Lymphocytes and NK Cells were predominantly increased as reflected by the increased population expressing CD3, CD56, CD16, CD8, CD25 in peripheral blood mononuclear cells (PBMC) [22, 45, 591. The relative increase in NK cells was the prominent feature in most patients [22]. This lymphocytosis was IL2 dose-dependent until it reached a plateau at a dose of IL2 lower than the MTD [22]. By 1 hour after IL2 administration, a rise in serum soluble IL2 Receptor (sIL2R) was observed [45,92]. This increase in serum IL2 receptor level has not been observed in the serum of normal individuals treated with endotoxins or in cancer patients treated with IFNg (Wagner and Nelson, unpublished data). The appearance of sIL2R in serum precedes the detection of mononuclear cells expressing the a chain of IL2 receptor (CD25) by 7-10 days. These CD25 positive cells may account for up to 35% of the circulating mononuclear cells in the peripheral blood after prolonged IL2 treatment [45]. Their role has yet to be established. A suppressive activity on hematopoietic cells has been attributed to these cells [102]. Non neutralizing anti-recombinant IL2 antibodies frequently develop following both SCand iv bolus administration of IL2 [5]. Natural IL2 may be less immunogenic [82], although natural human IFNa does induce an antibody response in treated patients [35]. Induction of cytokines: When IL2 is injected in vivo, it induces the secretion of several soluble mediators including ILl, TNFa, IFNb and g, IL6, GM-CSF and M-CSF [20, 29, 711. This induction often depends on the regimen of IL2 administration. Thus, continuous intravenous infusion of IL2 does not induce detectable IFNg in serum WI, in contrast with bolus injections [29]. A recent study demonstrated that IL2 induced an increase in serum concentrations of IL1 and TNP in 95 and 75% of patients, respectively. Serum IL6 levels transiently increased in 33% of patients receiving civ infusion of IL2. Serum concentrations of IL1 and TNF remained elevated 48 hours after :he end of IL2 infusion [lo] and were claimed to correlate with response to treatment 1111. Immunosuppressive activity of IL2 Paradoxically, IL2 may enhance and/or induce activities in several animal and suppressive

478 human models. IL2 administration has induced: decreased PBMC proliferarive responses to soluble antigens [98]; decreased delayed type hypersensitivity responses to recall antigens [98]; decreased polymorphonuclear chemotaxis and Fc receptor expression [38]. The role of these phenomena in IL2 therapy and clinical responses remains unknown. Properties of LAK cells and TIL LAK activity against NK cell resistant fresh tumors and malignant cell lines is mostly mediated by CD3-CD56+ CD16+ cells such as activated NK [34]. Nevertheless, other cell populations such as CD8+CTL may contribute to LAK activity in a non-MHC restricted fashion [41]. When LAK cells are generated in vitro, CD16 membrane expression diminishes during culture. Withdrawal of CDl6+ cells has no effect on the cytotoxic activity of LAK cells [94]. Twenty-four hours after IL2 administration, a loss of LAK precursors was transiently observed followed by the expansion of PBMC with the LAK cell phenotypes and functiona! activity [82]. TIL able to specifically recognize, in an MHCrestricted fashion, the autologous tumor, have been reported in melanoma and in breast cancer [74, 851. In melanoma, TIL predominantly includes a population of CTL (CD8+, CD3+), whereas in renal cell carcinoma, the phenotype is more heterogeneous and essentially MHC non-restricted [47]. In vivti, an oligoclonal expansion of TIL with a specific Vb gene rearrangement of TCR may exist spontaneously [57]. In viva, an increased frequency of TIL with antitumour activity has been reported after IL2 treatment [Sl].

Combination with chemotherapy In anima! tumor models, preliminary results show that chemotherapy did not impede IL2 immunostimulation [50]. As immunotherapy and chemotherapy may select different tumrrr escape mechanisms, their association is promising. In melanoma, IL2 plus DTIC or IL2 plus cyclophosphamide give results similar to IL2 alone [ 15, 511. In a small series of melanoma patients treated with DTIC-CisDDP-IL2, 40% partial responses were observed [61].

Combination with other cytokines Cytokines such as TNF, IFNg, IL4, IL6, IL7 have demonstrated antitumor efficacy in murine models [28, 48, 56, 801. Moreover, in vitro studies and animal experiments suggest a synergistic antitumor effect between IL2 and other cytokines such as TNFa and IFNg [l]. In human melanoma and renal cell carcinoma, a phase I clinical trial combining IL2 plus IFNa showed a slight benefit in terms of clinical responses when compared to each cytokine alone [66]. In a phase I/II clinical protocol, objective antitumor effects were noted in patients with melanoma, renal cell carcinoma, and breast cancer treated with combinations of IL2 and IL4 [46]. Combination with monoclonal antibodies By increasing vascular permeability, IL2 may facilitate the intratumor diffusion of monoclonal antibodies (mAb) [76]. IL2 which enhances ADCC may also improve the efficacy of mAb [75]. Thus, in mice with a B-lymphoma, treatment with IL2 and antiidiotypic antibody directed against the tumor cells significantly increased the survival of the tumor-bearing mice [9]. Moreover, when a specific anti-B16 melanoma monoclonal antibody was combined with LAK cells, a significant enhancement in the efficacy of LAK cells to reduce established liver metastases was observed [21]. A phase I clinical trial combining associated murine anti-GD3 mAb and IL2 was conducted in human melanoma. Definitive conclusions have not yet been reached [7]. Lymphokine gene therapy Introduction of IL2 gene into TIL After transducing the gene coding for resistance to neomycin in human TIL, Rosenberg showed that these cells may be recovered from tumor deposits as much as 64 days after re-administration [68]. This homing of TIL to tumor deposits was also demonstrated when these TIL were labelled with Indium 1251. These experiments led several groups to introduce lymphokine genes such as IL2 or TNF into TIL to achieve high local tumor concentrations of these cytokines and to reduce systemic toxicity [69]. Introduction of IL2 gene into tumor Fearon showed that the introduction of the IL2 gene in a murine colon cell line increased recog-


nition of the tumor by the host system and allowed rejection of wild syngeneic tumor (not transfected with IL2) when hosts were pre-immunized with IL2 producing tumor [24]. These observations were reproduced when tumors were transfected with other cytokines such as IL4, IFNg, IL6, IL7, GM-CSF [4, 13, 28, 32, 601. Another approach consists of using allogeneic or xenogeneic tumors transfected with cDNA encoding IL2, as vector cells, to produce transient high concentrations of IL2 in the tumor environment. This local IL2 production lasts until allogeneic or xenogeneic tumors are rejected. In a murine mastocytoma and lung carcinoma model, it was demonstrated that high dose IL2 produced by allogeneic cells can protect against tumor growth [70]. In contrast to individual lymphokine gene therapy described above, in this method the same cells dividual. Improvement IL2 therapy




in monitoring





Lymphokine gene therapy is promising although ethical considerations must be taken into account. IL2 has been introduced into clinical trials and the preliminary results have demonstrated that immunotherapy may have a place in cancer therapy. We must now optimize this approach to make is safe and suitable for routine use.

Acknowledgments This work was supported by the Institut Curie, Association pour la Recherche sur le Cancer (ARC), Institut Scientifique Roussel (Roussel-Uclaf, Romainville, France).




Up until now we have no test available to predict clinical response to IL2 treatment or to control toxicity. In contrast with animal model observations, most authors did not find any correlation between clinical results and modification in PBMC phenotyping or LAK cytotoxic activity in PBMC during treatment [12, 23, 541. Nevertheless, for some investigators, differences in serum cytokine concentrations before and after IL2 treatment may be observed between responder and non-responder patients. For example, 48 hours after the end of IL2 treatment, TNF and IL1 levels in serum were found to be significantly higher in responders to IL2 treatment [IO]. Howzver, this is not consistent with the findings of othler groups

WI. Lastly, it is clear tha’t IL2 has extra-immunologic effects. It induces ACTH, cortisol, prolactin and growth hormone secretion [46] and alSO alters hcpatic and renal function [go]. By its systemic action, IL2 behaves like a hormone. A better understanding of this extra-immunologic effect and its role in the antitumor effect and toxicity would be useful.

Conclusion Manipulation of the immune system is just beginning and a better understanding of specific antitumor immunity will lead to new developments.

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Current status of interleukin-2 therapy in cancer.

In vitro studies and animal experiments showed the existence of a physiological immune response against tumors. Interleukin-2 was the first immunologi...
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