Polyethylene‐glycol‐modified interleukin‐2 is superior to interleukin‐2 in locoregional immunotherapy of established guinea‐pig tumors

Mattijssen, V.; Balemans, L. T. M.; Steerenberg, P. A.; Mulder, P.H.M. de

doi:10.1002/ijc.2910510524

Cited by 36 publications

(12 citation statements)

References 22 publications

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“…Finally, it should be noted that IL2-containing IC are only one method of providing enhanced IL2-related effects. IT injection of liposomal IL2 or polyethylene glycol-modified recombinant IL2 have both been shown to induce significant antitumor effects against both primary and distant non-injected tumors in animal models [27,31]. Comparison of IL2-containing IC to other methods of increasing the delivery of IL2 are indicated to understand the relative efficacy and toxicities related to these modalities.…”

Section: Discussionmentioning

confidence: 99%

“…Again, even in the absence of mature T cells, IT hu14.18-IL2 resulted in significant antitumor effects (p = 0.04 for IT IC vs. IT PBS, days [22][23][24][25][26][27][28]. IC treatment also resulted in a significant survival advantage where 3 of 5 IC-treated mice were still alive on day 79, while PBS-treated mice required euthanasia between days 22-40 due to large tumor burden (data not shown, p <0.0018, day 79).…”

Section: Effective It Response In the Absence Of T Cellsmentioning

confidence: 99%

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Intratumoral immunocytokine treatment results in enhanced antitumor effects

Johnson

Lum

Rakhmilevich

et al. 2008

Cancer Immunol Immunother

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Immunocytokines (IC), consisting of tumor-specific monoclonal antibodies fused to the immunostimulatory cytokine interleukin 2 (IL2), exert significant antitumor effects in several murine tumor models. We investigated whether intratumoral (IT) administration of IC provided enhanced antitumor effects against subcutaneous tumors. Three unique ICs (huKS-IL2, hu14.18-IL2, and GcT84.66-IL2) were administered systemically or IT to evaluate their antitumor effects against tumors expressing the appropriate IC-targeted tumor antigens. The effect of IT injection of the primary tumor on a distant tumor was also evaluated. Here, we show that IT injection of IC resulted in enhanced antitumor effects against B16-KSA melanoma, NXS2 neuroblastoma, and human M21 melanoma xenografts when compared to intravenous (IV) IC injection. Resolution of both primary and distant subcutaneous tumors, and a tumor-specific memory response were demonstrated following IT treatment in immunocompetent mice bearing NXS2 tumors. The IT effect of huKS-IL2 IC was antigen-specific, enhanced compared to IL2 alone, and dose-dependent. Hu14.18-IL2 also showed greater IT effects than IL2 alone. The antitumor effect of IT IC did not always require T cells since IT IC induced antitumor effects against tumors in both SCID and nude mice. Localization studies using radiolabeled 111 In-GcT84.66-IL2 IC confirmed that IT injection resulted in a higher concentration of IC at the tumor site than IV administration. In conclusion, we suggest that IT IC is more effective than IV administration against palpable tumors. Further testing is required to determine how to potentially incorporate IT administration of IC into an antitumor regimen that optimizes local and systemic anticancer therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Effective It Response In the Absence Of T Cellsmentioning

confidence: 99%

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Johnson

Lum

Rakhmilevich

et al. 2008

Cancer Immunol Immunother

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“…exogenous IL-2 to produce cytokines and to recruit Partial responses were also described in HNSCC paspecific and nonspecific immune effector mechanisms dents using combined perilymphatic and intratumoral , We analyzed locoregional immunotherapy in the IL-2 injections (2/36 patients) [9], intra-arterial IL-2 guinea pig line-10 tumor model |4j. In addition to IL-2, polyethylene glycol (PEG)-modificd IL-2 was also infusion (2/12 pi 10], and combined locore gional IL-2 and LÀK cell administration (3/14 pauscd, enhancing solubility and plasma half-life [5], tients) [11], The aim of the present study was to evaluIt was found that guinea-pigs with palpable tumors ate the feasibility and the local antitumor effects of on the flank and micrometastases in the regional intratumoral PEG-IL-2 injections in HNSCC, in a lymph nodes could be cured by intratumoral, but not schedule which had been found to be optimal in our perilymphatic, injections of PEG-IL-2, whereas IL-2 animal study [4],…”

Section: Introductionmentioning

confidence: 92%

“…However, a local indurative and erythema tous reaction after subcutaneous IL-2 or PEG-IL-2 injection in humans, resembling a delayed-type hyper sensitivity reaction and consisting of mononuclear cell infiltration, has been previously described [12]. In the line-10 guinea-pig tumor, in which we previously evalu ated intratumoral PEG-IL-2 therapy [4], an intense inflammatory reaction with eosinophils, T lympho cytes, macrophages and fibroblasts was observed at the site of regressing tumors (unpublished data). A n as sociation between eosinophilia and a favorable tumor response has been described in patients receiving sub cutaneous IL-2 and IF N a therapy [13], Tepper et al, provided evidence for eosinophil-mediated tumor-cell killing in vivo [14].…”

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confidence: 93%

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Intratumoral PEG-interleukin-2 therapy in patients with locoregionally recurrent head and neck squamous-cell carcinoma

Mattijssen¹,

Mulder²,

Graeff³

et al. 1994

Annals of Oncology

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Optimal regimes for local IL-2 tumour therapy

et al. 1996

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In this report we present studies on optimal regimes for regional IL-2 therapy, focused on dose, schedule and site of injection. Original data obtained in 2 murine tumur models show that all 3 factors are of importance. Anti-tumour responses ware most effective when IL-2 was administered regionally 5 to 10 times. at doses ranglng from 7.000 to 33,000 IU/day every day or every other day. This resulted in cure rates of more than 40% in mice bearing ascitlc tumur that had also disseminated to liver and lungs. The importance of these data is discussed in the light of previous results of our group. These results illustrate that the doses and schedules used in this study are not effective exclusively in these 2 tumour models but may have a more general applicability.o 1996 Wiley-Liss, Inc.The original therapy of tumours with Interleukin-2 (IL-2), introduced by Rosenberg et al. (1985), used systemically applied Lymphokine-activated killer cells (LAK cells; cancer patients' leukocytes incubated with IL-2) and high doses of systemically applied IL-2 to maintain LAK cytotoxicity. (1987) reported that in mice the therapeutic effect of IL-2 has a biphasic optimum, doses of 10-1,000 Units IL-2 and of > 100,000 Units IL-2 per day having a therapeutic effect, whereas no effects were obtained with doses of 1,000-100,000 Units IL-2 per day; (c) regional injections of IL-2, since the main function of IL-2 seems to be stimulation of the tumour-infiltrating lymphocytes (TILs) and local injections of low doses of IL-2 avoid the toxic side-effects observed with high, systemically applied doses of IL-2. A similar approach has been used by other groups (Forni et al., 1987;Bubenik and Indrova, 1987;Vaage, 1987; Dubinett ef al., 1993).We found that large numbers of DBA/2 mice with metastasized SL2 lymphoma comprising 4 1 0 % of the body weight could be cured (Maas et al., 1989(Maas et al., , 1991. In addition, we tested this form of IL-2 therapy in a number of other animal tumour models comprising transplanted lymphomas, mastocytoma, fibrosarcoma, breast cancer, stomach cancer, ovarian carcinoma and bladder carcinoma. Table I shows a complete list of tumour models in which we tested regional injections of low doses of IL-2. A high percentage of tumour-bearing animals were cured among 7/10 tested murine models and ACI rats bearing bladder carcinoma. This therapeutic regime also led to a high percentage of long-lasting or complete remissions in spontaneous bovine ocular squamous-cell carcinoma and exerted a therapeutic regression effect on the bovine vulva1 papilloma/carcinorna complex. Table I thus demonstrates that this form of IL-2 therapy was effective against the majority of the tested models and against a variety of tumour types.We now report experiments in which we try to establish the optimal conditions for this regional IL-2 therapy. The effect of different IL-2 doses, time intervals between doses, the number of doses and the importance of contact between IL-2 and tumour cells were studied in the DBA/2-SL2 lymphoma system and in...

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Polyethylene‐glycol‐modified interleukin‐2 is superior to interleukin‐2 in locoregional immunotherapy of established guinea‐pig tumors

Cited by 36 publications

References 22 publications

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Intratumoral immunocytokine treatment results in enhanced antitumor effects

Intratumoral PEG-interleukin-2 therapy in patients with locoregionally recurrent head and neck squamous-cell carcinoma

Optimal regimes for local IL-2 tumour therapy

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