Immunotherapy of intraperitoneal cancer with interleukin 2 and lymphokine-activated killer cells reduces tumor load and prolongs survival in murine models

Ottow, R. T.; Steller, E. P.; Sugarbaker, Paul H.; Wesley, Robert; Rosenberg, Steven A.

doi:10.1016/0008-8749(87)90038-4

Cited by 33 publications

(11 citation statements)

References 18 publications

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“…The generation of lymphokine-activated killer (LAK) cells exhibiting a broad spec trum of cytotoxicity against fresh and cul tured tumor cells by incubation of lymphoid cells with interleukin-2 (IL-2) is well known [1], An adoptive transfer of these LAK cells was effective in controlling tumor growth and metastasis in experimental animal mod els [2], One critical factor in successful adoptive immunotherapy is the potency of the IL-2-induced cytotoxic effector cells [3]. Although T cells and natural killer (NK)-like cells are primarily involved as the precursors of the LAK cells, other cell populations also play an important role in the modulation and activation of the killer lymphocytes [4].…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E<sub>2</sub> from Macrophages of Murine Splenocyte Cultures Inhibits the Generation of Lymphokine-Activated Killer Cell Activity

et al. 1991

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The present work investigated the association between prostaglandin E₂ (PGE₂) from macrophages and its inhibition of murine lymphokine-activated killer (LAK) cell generation. The coculture of indomethacin with interleukin-2 (IL-2) augmented LAK cell activity in an indomethacin dose-response manner, and diminished PGE₂ content in the corresponding culture supernatant in a reverse dose-response manner. The correlation between the increase in LAK cell activity and the decrease in PGE₂ content was highly significant. Identical results were obtained with diclofenac. A profound inhibition of LAK cell activity by exogenous PGE₂ in a dose-response manner was detected. Polyclonal anti-PGE₂ antiserum augmented in a dose-dependent manner the LAK cell activity, by neutralizing PGE₂ in the medium. A reduction of PGE₂ content in the culture supernatant was also detected when the macrophage subpopulations were cultured and was indomethacin dose-dependent. In comparison with that of normal mouse splenocytes, the incubation of whole splenocytes of tumor-bearing mice, which contained a greater subpopulation of macrophages (24% vs. 12 %), produced a greater PGE₂ content and a correspondingly depressed LAK cell activity. Additionally, PGE₂ reduced protein kinase C (PKC) activity along with LAK cell activity generated from macrophage-depleted T cells and natural-killer-like cells. These results overall indicate that PGE₂ from macrophages in murine splenocyte cultures inhibits the LAK cell generation, and PKC may be involved in the inhibition mechanism.

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Section: Introductionmentioning

confidence: 99%

Prostaglandin E<sub>2</sub> from Macrophages of Murine Splenocyte Cultures Inhibits the Generation of Lymphokine-Activated Killer Cell Activity

et al. 1991

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“…Many studies have been performed to improve the results and/or reduce treatment-related toxicity. In both experimental tumour models and human cancer patients it has been shown that S.C. or regional IL-2 administration results in better tolerance of the treatment without apparent loss of therapeutic efficacy (Ottow et al, 1987;Steis et al, 1990;Vaage, 1991;Sleijfer et al, 1992;Ravaud et al, 1994;Sone and Ogura, 1994). Also, evidence is accumulating that doses of less than 10% of the maximum tolerated dose are therapeutically effective (Cortesina et Bruton and Koeller, 1994;Yang et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

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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“…administration of IL-2 was shown to be dose-dependent, very effective, and the number of activated cells in the peritoneal exudate very high [67,90], This observation correlated with significant antitumor effects seen in the i.p. tumor models with low dose IL-2 therapy in comparison to systemic tumor models [91]. Because of the pharmacokinetic advantage of i.p.…”

Section: Tumor Necrosis Factor (Tnf)mentioning

confidence: 99%

“…micrometastatic immunogenic as well as nonimmunogcnic tumors of different histology in various strains of mice. IL-2 + LAK therapy was effective in irradiated mice as well as in immunedeficient nude mice [90][91]. Moreover, IL-2 + LAK therapy had synergistic antitumor effects when combined with cyclophosphamide [93], Antitumor effects could also be augmented by initiating an inflammatory response at the tumor site and by augmenting LAK lysis through the mecha nism of antibody dependent cellular cytotoxicity (ADCC) by the addition of monoclonal antibodies [94][95][96].…”

Section: Tumor Necrosis Factor (Tnf)mentioning

confidence: 99%

Intraperitoneal Chemotherapy and Immunotherapy

Eggermont¹,

Sugarbaker

1991

Oncol Res Treat

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The major goal of intraperitoneal (i.p.) cancer treatment is the generation of optimal concentrations of antitumor agents at the site of the tumor. Maximal local antitumor effects must be attained with minimal systemic levels of the anticancer agents. This is true for both regional chemotherapy and regional immunotherapy. Intraperitoneal chemotherapy has been used, with limited success for about 30 years. This mode of therapy is complex and the modest results are probably largely due to procedure associated problems and the fact that it has been applied mostly in a setting with a large tumor burden. The ideal moment to apply i.p. therapy may well be in the adjuvant setting, immediately after resection of the primary tumor in ovarian or gastrointestinal cancer. In this way, most problems associated with i.p. therapy after debulking for recurrent disease such as tumor load, adhesions, unequal distribution of the drug, drug resistance and subperitoneal disease can be circumvented, and no extra surgical procedures for the placement of the catheter will be required.

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Immunotherapy of intraperitoneal cancer with interleukin 2 and lymphokine-activated killer cells reduces tumor load and prolongs survival in murine models

Cited by 33 publications

References 18 publications

Prostaglandin E<sub>2</sub> from Macrophages of Murine Splenocyte Cultures Inhibits the Generation of Lymphokine-Activated Killer Cell Activity

Prostaglandin E<sub>2</sub> from Macrophages of Murine Splenocyte Cultures Inhibits the Generation of Lymphokine-Activated Killer Cell Activity

Optimal regimes for local IL-2 tumour therapy

Intraperitoneal Chemotherapy and Immunotherapy

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