FUGUE

- 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,

474

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].

clinical

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

CR+PR %

6 5 8 9 8 6 S 1 6

60

;: 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

~LL~~~r

of

pffzjeJit~

21 40 6 36 72 94

CR n

PR tl

CR+PR 46

I

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

CRIPR %

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

lymphocytes

plus IL2.

PR I1

CRcPR %

6

0

7

0

1 0

17 0

50

0

19

3%

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

kf

%

Ref

%

&f

46 35 22 12 42 73 30 15 15 2

t673 [971 :;:;

74

[671

47

I673

24

t671

21

1671

[671 /671 (971 [671

36 78

1671 [671

31 67

;t;;

11

i671

12

[671

t671

2

I671

1

W71

6 2.5 1.5 2.5 68

b73

11

1671

6

[671

::;;

I

WI

2

f671

75

WI

50.5

W71

2 3s 44 69

WI r971 167:

72

[671

40

t671

73

I671 1671 ii;;

86 55 25

1671 1671 f671

57 75 35

WI

IO

[671

13 23 2

WI WI WI

8 5 6

%

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

distress

Pleural effPlsion requiring thoracocentesis Arrythmias Treatment

associated death

Diarrhea Anemia requiring T~ombocytopenia Chills Disorientation

transfusion

32 22

[971

:z;; 1971

10 Somnolence Coma Pruritus Hypothyroidism

TIL plus IL2

&Afcpfus IL2

:28

t:;;

i2 10-29

[441

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-

479

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

could

be

used

in monitoring

for

almost

patients

any

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).

References

in-

undergoing

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.

1 Ahah R, Malloy B, Sherrod A (1988) Therapy of disceminated NK-resistant tumor by the synergistic effects of recombinant interleukin-2 and tumor necrosis factor. J Biol Resp Mod 7, 140 Allison MA, Jones EJ, McGuffey P (1989) Phase II trial of outpatient Interleukin-2 in malignant lym-

phoma, chronic lymphocytic leukemia and selected solid tumors. J Clin Oncol 7, 75 Anichini A, Mazzocchi A, Fossati G, Parmiani G (1989) Cytotoxic T lymphocyte clones from periphera1 blood and from tumor site detect intratumor hetAnalysis of erogeneity of melanoma cells. specificity and mechanisms of interactions. J Zmmunol 142, 3692 Aoki T, Tashiro K, Miyatake S, Kinashi T, Nakano T, Oda Y, Kikuchi H, Honjo T (1992) Expression of murine interleukin 7 in a murine glioma cell line results in reduced tumorigenicity in rive. fruc N&l Acad Sci USA 89, 3850 Atkins MB, Gould JA, Allegretta M, Li JJ, Dempsey RA, Rudders RA, Parkinson DR, Reichlin S, Mier JW (1986) Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease. J Chin Oncol 4, 1380 Atzpodien J, Kijrfer A, Evers P. Franks CR, KniiverHopf J, Lopez Hanninen E, Fischer M, Mohr H, Dallmann I, Hadam M, Poliwoda H. Kirchner H (1990) Low dose subcutaneous recombinant interleukin-2 in advanced human malignancy: a phase II outpatient study. Mol Biother 2, 18 Bajorin D, Chapman P, Kunicka J (1988) Phase I trial of antiGD3 mouse monoclonal antibody and IL2 in patients with melanoma. Proc Am SOC Clin 0;icui 7, 250 Bar MH, Sznol M, Atkins MB, Ciobanu N, Micetich KC, Boldt DH. Margolin KA, Aronson FR. Rayner

480

AA, Hawkins MJ, Mier JW, Paietta E, Fisher RI, Weiss GR, Doroshow JH (1990) Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine activated killer cells. J Clin Onc01 8, 1138 9 Bernstein

10

11

I2

13

14

N, Levy R (1987) Treatment of a murine B-cell l~phoma with mon~lonal antibodies and IL2. J Irnrn~O~ 139. 971 Blay JY, Negrier S, Combaret V, Merrouche Y, Mercatello A, Moskovtchendo JF, Philip T, Favrot M (1992) Analyse des modifications des concentrations seriques de TNF, d’IL1 et d’IL6 au COWS de l’administration d’IL2. Correlation avec la reponse au traitement. Bali Cancer 79, 55 Blay JY, Favrot MC, Negrier S, Combaret V, Chouaib S, Mercatello A, Kaemmerlen P, Franks CR, Philip T (1990) Correlation between clinical response to IL2 therapy and sustained production of TNF. t.hCtZF Res 50. 2371 Bo!dt D, Mills B, Gemlo B, Holden H, Mier J, Paietta E, McMannis JD, Escobedo LV, Sniecinski I, Rayner AA, Hawkins MJ, Atkins MB, Ciobanu N, Ellis TM (1988) Laboratory correlates of adoptive immunotheapy with recombinant IL2 and lymphokine activated killer cells. Cancer Res 48, 4409 Colombo MP, Ferrari G, Stoppa~i~o A, Parenza M, Rodolfo M, Mavilio F. Parmiani G (1991) Granulocyte colony stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in viva. J Exp Med 173, 889 Demetri GD, Spriggs DR, Sherman ML, Arthur KA, Imamura K, Kufe DW (1989) A phase I trial of recombinant human tumor necrosis factor and interferon gamma: effects of combination cytokines administration in vivo. J Clin Oncol 7, 1545

15 Dillman RO, Oldham RK, Barth NM, Birch R, Arnold J, West WH (1990) Recombinant Interleukin-2 and adoptive immunotherapy alternated with dacarbazine therapy in melanomal: a National Biotherapy Study Group Trial. J Narl Cancer Insr 82, 1345 16 Dorval T, Mathiot C, Chosidow 0, Revuz J, Avril MF, Guillaume JC, Tursz T, Brandely M, Pouillart I? Fridman WH (1992) Phase II trial in metastatic melanoma; analysis of clinical and immunological parameters. ~~o~ec~no~ Z’fier 3, 63 17 Dorval T, Mathiot C, Brandely M, Escande MC, Fridman WH, Pouillart P (1992) Lack of effect of tumor infiltrating lymphocytes in patients with metastatic melanoma who failed to respond to interleukin-2. Eur J Cancer 28, 615 18 Dutcher JR Creekmore S, Weiss GR, Margolin K, Marlcowitz AB, Roper M, Parkinson D, Ciobanu N, Fisher RI, Boldt DH, Doroshow JH, Rayner A, Hawkins M, Atkins M (1989) A phase II study of interleukin-2 and lymphokine activated killer cells

in patients with metastatic C&a Oncol 7, 477

malignant

melanoma.

J

19 Dutcher JP, Gaynor ER, Goldt DH, Weiss GR. Doroshow JH, Bar MH, Sznol M, Mier J, Sparano J, Fisher RI, Weiss G, Margolin K, Aronso FR, Hawkins M, Atkins M (1991) A phase II study of high dose continuous infusion interleukin-2 with lymphokine-activated killer cells in patients with metastatic melanoma. 3 Clin Oncol 9, 641 20 Economou JS, Hoban M, Lee JD, Essner R, Swisher S, McBride W, Hoon DB, Morton DL (1991) Production of tumor.necrosis factor and interferon g in inteleukin-2 treated patients: correlation with clinical toxicity. Cancer Zmm~oi i~~~o~~r 34, 49 21 Eisenthal A, Cameron RB, Uppenkamp I, Rosenberg SA (1988) Effect of combined therapy with lymphokine-activated killer eels; interleukin-2 and specific monoclonal antibody on established B16 melanoma lung metastases. Cancer Res 48. 7140 22 Farace F, Mathiot C;-Brandely M, Tursz T, Dorval T, Pouillart P, Triebel ?, Hercend T, Fridman WH (1990) Phase I trial with recombinant interleukin-2 (rIL2): immune activation by rIL2 alone or following pretreatment with recombinant interferongamma. Clin Exp fmmunol 82, 194 23 Favrot MC, Combaret V, Negrier S, Philipp I, Thiesse B. Freydel C, Bijman JT, Franks CR, Mercatello A, Philip T (1990) Functional and immunophenotypic modifications induced by IL2 did not predict response to therapy in patients with renal cell carcinoma. J Biol Resp Mod 9, 167 24 Fearon ER. Pardoll DM, Itaya T, Golumbek P, Levitsky HI, Simons JW, Darasuyama H, Vogelstein B, Frost P (1990) Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell 60, 397 25 Fisher B. Packard BS, Read EJ, Carrasquillo JA, Carter CS, Topalian SL, Yang JC, Yolles P, larson SM, Rosenberg SA (1989) Tumor loc~ization of adoptively transferred indium-1 11 labeled mmor infiltrating lymphocytes in patients with metastatic melanoma. .I Clin Oncol 7, 250 26 Fraker DL, Langstein HN, Norton JA (1989) Passive immuniz~ion against tumor necrosis factor partially abrogates interleu~n-2 toxicity. J Exp Med 170, 1015 27 Fridman WH (1989) New immunotherapeutic approaches: the use of cytokines to stimulate the immune system or to control the growth of malignant lymphoid cells. Eur 3 Cancer Clin Oncol 25, 1525 28 G~sbacher B, Bannerji R, Daniels B. Zier I(, Cronin K, Gilboa E (1990) Retroviral mediated ginterferon gene transfer into tumor cells generates potent and long lasting antitumor immunity. Cancer Res SO, 7820

481 29 Gemlo

BT, Palladino MA, Jaffe HS, Espevik TP, Rayner AA (1988) Circulating cytokines in patients with metastatic cancer treated with recombinant interleukin-2 and lymphokine-activated killer cells. Cancer Res 48, 5864

30 Gillis S, Smith K (1977) Long term culture of tumour-specific cytotoxic T cells. Nature 268, 154 31 Goldstein D, Sosman JA, Hank JA, Weil-Hillman G, Moore KH, Borchert A, Bechhofer R, storer B, Kolher PC, Levitt D, Sondel PM (1989) Repetitive weekly cycles of interleukin-2: effect of outpatient treatment with a lower dose of interleukin-2 on nonmajor histocompatibility complex restricted killer activity. Cancer Res 49, 6832 32 Golumbek PT, Lazenby AI, Levitsky HI, Jaffee LM, Karasuyama H, Baker M, Pardoll DM (199l).Treatment of established renal cancer by tumor cells engineered to secret interleukin4. Science 254, 713 33 Grimm EA, Mazumder A, Zhang HZ, Rosenberg SA (1982) Lymphokine-activated killer cell phenomenon. Lysis of natural killer- resistant fresh solid tumour cells by interleukin-2 activated autologous human peripheral blood lymphocytes. J Exp Med 155, 1823 34 Grimm EA, Ramsey KM, Mazumder A, Wilson DJ, Djeu JY, Rosenberg SA (1983) Lymphokine activated killer cell phenomenon. II precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus-derived lymphocytes, and natural killer cells. J Exp Med 157. 884 35 Gutterman 9, Fine S, Quesada i (1982) Recombinant leukocyte A interferon: pharmacokiretics, sing!e dose tolerance, and biologic effects in cancer patients. Ann Int Med 96, 549 36 Hlnninen EL, Kiirfer A, hadam M, Schneekloth C, Dallman I, Menzel T, Kirchner H, Poliaoda H, Atzpodien J (1991) Biological monitoring of low dose interleukin 2 in humans: Soluble interleukin 2 receptors, cytokines, and cell surface phenotypes. Cancer Res 50, 6312 37 Hercend T, Farace F, Baume D, Charpentier F, Droz JP, Triebel F, Escudier B (1990) Immunotherapy with lymphokine activated natural killer cells and recombinant interleukin-2: a feasibility trial in tnetastatic renal cell carcinoma. J Biof Resp Mod 9, 546 38 Jablons D, Bolton E, Mertins S, Rubin M, Pizzo P, Rosenberg SA, Lotze MT (1990) ILZbased immunotherapy alters circulating neutrophil Fc receptor expression and chemotaxis. J Immunol 144,363O 39 Jacobs SK, Komblith PL, Kantrowitz AB, Greenaald ES, Wiemik PH (1987) Treatment of cancer with lymphokine-activated killer cells and interleukin-2. N Engl J &led 317, 962

40 Jung S, Schluesener HJ (1991) Human T lymphocytes recognize a peptide of single point-mutated, oncogenic ras protein. J Exp Med 173. 273 4.1 Kolitz JE, Merstelsmann M (1991) The immunotherapy of human cancer with interleukin-2 Present mtus and future directions. Cancer Invest 9, 529 42 Konrad MW, Hemstreet G, Hersh EM, Mar&l PWA. Merstelmann R, Kolitz JE, Bradley EC (1990) Pharmacokinetics of recombinant interleukin-2 in humans. Cancer Res 40, 2009 43 Lantz 0, Grillot-Courvalin C, Schmitt C, Fermand JP, Brouet JC (1985) Interleukin-2 induced proliferation of leukemic human B cells. J Exp Med 161, 1225 44 Lotze MT, Matory YL, Ettinghausen SE, Rayner AA, Sharrow SO, Seipp CAY, Custer MC, Rosenberg SA (1985) In vivo administration of purified human interleukin-2. J Immunol 135, 2865 45 Lotze MT, Custer MC, Sharrow SO, Rubin LA, Nelson DL, Rosenberg SA (1987) In viva administration of purified human interleukin-2 to patients with cancer: development of interleukin-2 receptors positive cells and circulating soluble interleukin-2 receptors following interleukin-2 administration. Cancer Res 47, 2188 46 Lotze MT (i992) T Cell growth factors and the treatment of patients with cancer. Cfin Immunol Zmmunopathol 62, S47 47 Mathiot C, Robin E, Gey A, Weng X, Dorval T, Pouillart P, Sastre X, Zerbib M, Hamelin JP, Salmon R, Durand JC, Brandely M, Fridman WH (1992) Phenotypic and functional analysis of tumour-infiltrating lymphocytes from patients with melanoma and other metastatic cancers. Eur J Cancer 28, 345 48 McBride WH, Thacker JD, Comora S, Economou JS, Kelley D, Hogge D, Dubinett SM, Dougherty GJ (1992) Genetic modification of a murine fibrosarcoma to produce interleukin 7 stimulates host cell infiltration and tumor immunity. Cancer Res 52, 393 1 49 McIntyre CA, Chapman K? Reeder S, Dorreen MS. Bruce L, Rodgers S, Hayat K, Schreenivasan T, Sheridan E, Hancok SW, Rees_ RC (1992) _ ._ Treatment . of malignant melanoma and renal cell carcmoma with recombinant human interleukin-2: analysis pf cytokine levels in sera and culture supematants. fiir J Cancer 28, 58 50 Merluzzi VJ. Welte K, Savage DM (1983) Expansion of cyclophosphamide-resistant cytotoxic precursors in vitro and in vivo by purified hum:m interleukin-2. J Immunol 131, L 806 51 Mitchell MS, Kempf RA. Hare1 W, Shau H, Boswt 11 WD, Lind S, Bradley EC (1988) Effectiveness ar,d tolerability of low-dose cyclophosphamide and lo& dose intravenous interleukin-2 in disseminated melanoma. J Clin Oncol 6, 409

482 52 Morgan DA, Ruscetti FW, Gallo R (1976) Selective in vitro growth of T lymphocytes from normal human bone marrow. Science 193, 1007 53 Mueller DL, Jenkins MK, Schwartz RH (1989) Clona! expansion versus clona! inactivation: a costimulatory signaling pathway determines the outcome of T cell antigen receptor occupancy. Ann Rev Immtutol 7, 445 54 Mule JJ, Yang J, Shu S, Rosenberg SA (1986) The antitumor efficacy of LAK cells and recombinant IL-2 in viva: direct correlation between reduction of established metastases and cytolytic activity of LAK cells. J Immuttol 136, 3899 55 Mule JJ, Yang JC, Lafreniere R (1987) Identification of cellular mechanisms or rational irt vivo during the regression of establisked pulmonary metastases by the systemic administration of high dose recombinant interleukin-2. J Immurzol 139, 285 56 Mule JJ, McIntosh JK, Jablons DM, Rosenberg SA (1990) Antitumor activity of recombinant interleukin 6 in mice. J .%p Med 171, 629 57 Nitta T, Oksenberg JR, Rao NA, Steinman L (1990) Predominant expression of T cell receptor Va7 in tumor infiltrating !ymphocy:es of uveal melanoma. Science 249, 672 58 Parkinson DR, Abrams JF, %emik PH, Rayner AA, Margolin KA, Van Echo D.4, Sznol M, Dutcher JP, Aronson FR, Doroshow J!!, Rt!:ins MB, Hawkins MJ (1990) interleukin-2 therapy in patients with metastatic malignant melanoma: A phase II study. J Clin Oncol 8, 1650 59 Pawelec G, Schwulera U, Lenz H, Owsianowski M, BiJhring HJ, Schlag H, Schneider E. Schaudt K, Ehninger G (1990) Lymphokmc :--lease, suppressor cell generation, cell surface markers, and cytotoxic activity in cancer patients receiving natural interleukin-2. Mol Biorlzer 2, 44 60 Porgador A, Tzehoval E, Katz A, Vadai E, Revel M, Feldman IM, Eisenbach L (1992) Interleukin-6 gene transfection ifit Lewis lung carcinoma tumor cells suppresses the malignant phenotype and confers immunotherapeutic competence against parental metastatic cells. C~IZCP).Res 52, 3679 61 Redman BG, Flaherty L, Chou TH, Nakeff A. Pillote Kaplan J K, (1991) Sequential dacartazine/ei:p!aiine and Interleukin-2 in metastatic melanoma: Immunological effects of therapy. J ImmunotAer 10, 147 62 Rosenberg SA. Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Richert CM (1985) Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 3 13, 1485

63 Rosenberg SA, Mule JJ, Spiess P, Reichert CM, Schwarz SL (1985) Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high dose recombinant interleukin-2. J Exp Med 161, 1169 64 Rosenberg SA, Spiess P, Lafreniere R (1986) A new approach to the adoptive immunotherapy of cancer with tumor infiltrating lymphocytes. Science 233, 1318 65 Rosenberg SA, Lotze MT, Muul LM,Chang AE, Avis FP, Leitman S, Linehan M, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CC, White DE. (1987) A progress report on the treatment of 157 patients with advanced cancer using lympholine-activated killer cells and interleukin-2 alone. N Engl J Med 316, 889

66 Rosenberg SA. Lotze MT, Yang JC, Linehan WM, Seipp C, Calabro S, Karp SE, Sherry RM, Steinberg S, White DE (1989) Combination therapy with interleukin-2 and alpha interferon for the treatment of patients with advanced cancer. J Clin Oncol 7, 1863 67 Rosenberg SA. Lotze MT, Yang JC, Aebersold PM, Linehan M, Seipp CA, White DE (1989) Experience with the use of high dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg 210, 474 68 Rosenberg SA, Aebersold P, Cometta K, Kasid A, Morgan RA, Moen R, Karson EM, Lotze MT, Topalian SL, Merino MJ, Culver K, Miler AD, Blaese RM, Anderson WH (1990) Gene transfer into humans - immunotherapy of patients with advanced melanoma using tumor-infiltrating lymphocytes modified by retrovira! gene transduction. N’Engl J Med 323, 570

69 Rosenberg SA (1992) The immunotherapy and gene therapy of cancer. J Cii:t Oncol 10, 180 F, 70 Roth C, Mir LM, Cressent M, Quintin-Colonna Belehradek J, Ley V, Fradelizi D, Kourilsky P (1992) Inhibition de la croissance tumorale induite par l’injection de cellules histo-incompatibles produisant de I’Interleukine-2. CR Acad Sci Paris 314, Serie Ill. 599 71 Schaafsma MR, Falkenburg JHF, Landegent JE, Duinkerken N, Osanto S, Raiph P, Kaushansky K, Wagemaker G, Van Damme J, Willemze R, Fibbe WE (1991) In viuo production of interleukin-5, granulocyte-macrophage-colony-stimulating factor, macrophage colony-stimulating factor and interleukin-6 during intravenous administration of high dose interleukin-2 in cancer patients. Blood 78, 1981 72 Schoof DD, Gramolini BA, Davdson DL, Massaro AF, Wilson RE, Eberlein TJ (1988) Adoptive immunotherapy of human cancer using low-dose interleukin-2 and lymphokine-activated killer cells; Cancer Res 48, 5007 73 Schwartz RH (1989) Acquisition of immunologic self tolerance. Cell 57, 1073

483 74 Schwa~zentruber

75

76

77

78

79

80

81

82

83

84

85

86

DJ, Topalian SL, Mancini M, Rosenberg SA (1991) Specific &ease of granulocyte-macmphage colony-stimulating factor, tumor necrosis factor-a, and IFN-g by human tumor-infiltrating lymphocytes after autologous stimulation. J IntinunoI 146, 3674 Shinoli E, Eisenthal A, Sachs D, Rosenberg SA ( 1987) Antibody-dependant cellular cytotoxicity mediated by murine lymphocytes activated in recombinant interleukin-2. J hnmunol 138, 1992 Smyth MJ, Pietersz GA, McKenzie IF (1988) Increased antitumor effect of immunoconjugates and tumor necrosis factor in v&o. Cancer Res 48, 3607 Sondel PM, Kolher PC, Hank JA, Moore KH, Rosenthal NS, Sosman JA, Bechhofer R, Storer B (1988) Clinical and immunological effects of recombinant interleukin-2 given by repetitive weekly cycles to patients with cancer. Cancer Res 48, 2561 Sceis RG, Urba WJ, VanderMolen LA, Bookman MA, Smith II JW, Clark JW, Miller RL, Crum ED, Beckner SK, I&Knight JE, 0~01s RF, Stevenson HC, Young RC, Longo DL (1990) Intraperitoneal lymphokine activated killer cells and interleukin-2 therapy for malignancies limited to the peritoneal cavity. J G&z Oncul 8, 1618 Tada T, Ohseki S, Utsumi K, Takiuchi H, Muramatsu M, Li XF, Shimizu 3, Fujiwara H. Hamaoka T (1991) Transforming growth factor-b induced inhibition of T cell function. J bnrnunol 146, 1077 Tepper RI, Pattengale PK, Leder P (1989) Murinein&eukin4 displays potent anti-turn@@@ activity BI viva Cell 57, 503 Thompson JA, Peace DJ, Klarnet JP, Kern DE, Greenberg PD, Cheever MA (1986) Eradication of disseminated murine leukemia by treatment with high dose interieukln-2. J lmmunol 137, 3675 Thompson IA, Lee UJ. Cox WW, Lindgren CG, Coltins C, Neraas KA, Dennin RA, Fefer A (1987) Recombinani interleukin-2 toxicity, ph~a~okineti~s, and immunomoduiato~ effects in a phase I trial. Cancer Res 47, 4202 Thompson JA, Lee DJ, Lindgren CG, Benz LA, Collins C, Shuman WP, Levitt D, Fefer A (1989) Influence of schedule r:f interleukin-2 administration on therapy with interleukin-2 and lymphokine activated killer cells. Cancer Res 49, 235 Tiberghien P, Racadot h, Deschaseaux ML, Delain M, Voillat L, Billet M, Flesh M, Rozenbaum A, Brandely M, Cahn JY, Nerve P (1992) Interleukin-2 induced increase of a mhtnoclonal B-cell lymphocyto&s. Catlcer 69, 2583 Topalian SL, Solomon D,Rosenberg SA (1989) Tumor specific cytolysis by lymphocytes infiltrating human melanoma. J f~mur~ol 142, 3714 Topalian SL, Solomon D, Avis FP, Chang AE, Freerksen DL, Linehan WM. Lotze MT, Robertson

CN. Seipp CA, Simon P, Simpson CG. Rosenberg SA (1988) Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interieukin-2 A pilot study. J Clin Oncol 6. 839 87 Touw I, Drossers L, Lowe&erg B (1987) The proliferative response of B cell chronic I~ph~yti~ leukemia to interIeukin-2: functional characterization of the interleukin-2 membrane receptors. Blood 69, 1667 88 Tracey KJ, Fong Y. Hesse DG, Manogue KR, Lee AT, Kuo GCf Lowry SF, Cerami A (1987) Anti cachectin-TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nur@re 33& 662 89 Tracey KJ, Vlassra H, Cerami A (1989) Cachectinltumor necrosis factor. Lancer i, 1122 90 Ubhi SS, Horsburgh T, Veitch PS, Bell PRF (1991) Changes in biochemical laboratory investigation in patients treated with constant infusion recombinant interleukin-2_ Anricancer Res 1 I, 2059 91 Van Der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, Knuth B, Boon T (199 1) A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 254, 1643 92 Voss SD. Hank JA, Nobis CA, Fisch P, Sosman JA, Sondel PM (1989) Serum levels of low affinity interleukin-2 receptor molecule (TAC) during IL-2 therapy reflect systemic lymphoid mass activation. Cancer Immunol Immunother 29, 261 93 Watanabe T, Puke1 CS, Takeyama H, Lloyd LO, Shiku H. Li LTC, Travassos LR, Oettgen HF. Old LJ (1982) Human melanoma antigen AH is an autoantigenic ganglioside related to GD2. J Exp &fed 156, 1884 94 Weil-Hilman G, Fish P, Prieve AF, Sosman J, Hank JA, Sondel PM (1989) Lymphokine-activated killer activity induced by in viva interleukin-2 therapy: Predominant role for lymphocytes with increased expression of CD2 and Leu 19 antigens but negative expression of CD16 antigens. Cancer Res 49, 3680 95 Weiss GR, Margolin K, Aronson FR, Sznol M, Atkins MB, Dutcher JP, Fisher RI (1989) A randomized phase II trial of continuous infusion interIL-2 plus injection bohls leukin-2 or lymphokine-activated killer cells for advanced renal cell carcinoma. Proc Am Sac Clin Oncol 8. 131 96 Weiss GR, margolin KA, Aronson FR, Sznol M, Atkins MB, Dutcher JP, Gaynor ER, Boldt DH, Doroshow JH, Bar MH, Hawkins MJ, Demchak PA, Gucalp R. Fisher RI fl992> A ~domized phase II trial of continuous infusion interleukin-2 or bolus injection interleukin-2 plus Iymphokine-activated killer cells for advanced renal cell carcinoma. .! Clifl Oncol 10, 275

484 97 West WH, Tatter KW, Yannelli JR, Aeshall CD, Osr DW, Thurman GB, Oldham RK (1987) Constant infusion recombinant interleukin-2 in adaptive immunotherapy of advanced caucer. N Engl J Med 316, 898 98 Wiebke EA, Rosenberg SA, Lotze M (1988) Acute immunologic effects in interleukin-2 therapy in cancer patients: decreased delayed type hypersensitivity response and decreased proliferative response to soluble antigens. J Clin Uncol 6, 1440 99 Yasumoto K, Miyazaki K, Nagashima A, lshida T, Kuda T, Yano T, Sugimachi K, Nomoto K (1987) induction of lymphokine activated killer cells by intmpleural instillations of recombinant interleukin-2 in patients with malignant pleurisy due to lung cancer- Cancer Res 47, 2184

100 Yoshida S, Tanaka R, Takai N, Ono K (1988) Local administration of autologous lymphokine-activated killer and recombinant Interleukin-2 to patients with malignant brain tumors. Cancer Res ~18, 5011 101 Yroti I, Wood TA, Spiess PJ, Rosenberg SA (1980) In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol 12.5, 238 102 Zoumbos NC, Gascon P, Djeu JY, Trost SR, Young NS (1985) Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med 312, 257 103 Zubler RH, Lowenthal JW, Erard F, Hashimoto N, Devos R, MacDonald HR (1984) Activated B cells express receptors for and proliferate in response. to pure interleukin 2. J Exp Med 160, 1 S70

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...
1MB Sizes 0 Downloads 0 Views