A Progress Report on the Treatment of 157 Patients with Advanced Cancer Using Lymphokine-Activated Killer Cells and Interleukin-2 or High-Dose Interleukin-2 Alone

Rosenberg, Steven A.; Lotze, Michael T.; Muul, Linda; Chang, Alfred E.; Avis, F. P.; Leitman, Susan F.; Linehan, W. Marston; Robertson, Cary N.; Lee, Roberta E.; Rubin, Joshua T.; Seipp, Claudia A.; Simpson, Craig D.; White, Donald E.

doi:10.1056/nejm198704093161501

Cited by 2,526 publications

(856 citation statements)

References 18 publications

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“…Initial rIL-2 schedules were developed using chemotherapy guidelines in which the maximum tolerable dose was given by intravenous bolus or continuous infusion over a few days. Despite encouraging results (response rates of 14-30%, with complete and lasting remissions in approximately 3-5% of patients), the use of highdose rIL-2 results in severe toxicity and some drug-related fatalities (Rosenberg et al, 1987;West et al, 1987). Lower doses of rIL-2 given both alone and in combination with rIFNa were associated with less acute toxicity, although with similar response rate and immunological activity as high-dose schedules (Caligiuri et al, 1990;Schneekloth et al, 1993;Vlasveld et al, 1993).…”

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confidence: 99%

Effectiveness of very low doses of immunotherapy in advanced renal cell cancer

Buzio

Palma²,

Passalacqua³

et al. 1997

Br J Cancer

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Summary Twenty-one nephrectomized patients with metastatic renal cell cancer were treated with recombinant interleukin 2 (rlL-2) and interferon alpha (rlFNa). rlL-2 was administered s.c. at a dose of 1 x 106 U im-2 every 12 h on days 1 and 2, followed by 0.5 x 106 IU twice daily on days 3-5; rlFNa-2 was given i.m. as 1.8 x 106 IU m-2 on days 3 and 5 of each week for 4 consecutive weeks. The cycle was regularly repeated at 4-month intervals and continued ad libitum in patients showing some response and in patients with progressing disease. Of 20 patients evaluable for treatment response, one (5%) had a complete response and three (15%) showed partial response. Three patients (15%) achieved stable disease and 13 (65%) were evaluated as having progressive disease. The estimated actuarial 44-month survival rate was 44%. Toxicity was limited to WHO grades 1 and 2 only.

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Effectiveness of very low doses of immunotherapy in advanced renal cell cancer

Buzio

Palma²,

Passalacqua³

et al. 1997

Br J Cancer

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“…Capillary leak syndrome is a major side-effect of high-dose IL-2 therapy, characterised by retention of extravascular fluid and hypotension (Siegel and Puri, 1991). It has been observed in humans (Siegel and Puri, 1991; Margolin et al, 1989;Rosenberg et al, 1987) al., 1985) and tumour necrosis factor (TNF)-ca (Kahaleh et al, 1988); and finally, vasodilation due to IL-2-induced production of nitric oxide (NO) Ochoa et al, 1992), leading to systemic hypotension followed by pulmonary hypertension and oedema.There have been several reports of therapies that combine IL-2 with agents that might ameliorate the capillary leakage. However, the added drugs also opposed the anti-tumour effects of IL-2.…”

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confidence: 99%

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NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

Orucevic

Lala

1996

Br J Cancer

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Summary We tested whether NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, can prevent interleukin 2 (IL-2)-induced capillary leakage in tumour-bearing mice without compromising the therapeutic benefits of IL-2. C3H/HeJ female mice transplanted s.c. with 2.5 x 105 C3-L5 mammary carcinoma cells were treated with: nothing, IL-2 (ten injections of 15 000 Cetus units i.p. every 8 h), L-NAME (0.1, 0.5, or 1 mg ml-1 drinking water), IL-2+L-NAME (0.1 or 0.5 or 1 mg ml-' drinking water).Therapies were given in one round (IL-2, days 10-13; L-NAME, days 9-13) or in two rounds (IL-2, days 10-13 and 20-23; L-NAME, days 9-13 and days 19-23) after tumour transplantation. Capillary leakage was measured from the water contents of the pleural cavities, lungs, spleen and kidneys. Effects of the therapies on the primary tumour size and the number of spontaneous lung metastases were also recorded. NO production was measured as the nitrite+nitrate levels in the serum and in the pleural effusion. After the first round of therapies, addition of L-NAME significantly reduced IL-2-induced pulmonary oedema and water retention in the spleen in a dose-dependent manner. It also significantly reduced the IL-2-induced rise in NO levels in the serum and pleural fluid, but did not affect IL-2-induced pleural effusion or water retention in the kidney. At later stages of tumour growth (day 23), tumours themselves induced significant fluid retention in the lungs and the kidney, which was not aggravated further with the second round of IL-2 therapy. At this time, L-NAME therapy alone ameliorated tumour-induced pulmonary oedema. During both rounds of therapy different doses of L-NAME alone caused a reduction of primary tumour growth as well as spontaneous lung metastases, which improved further with the addition of IL-2. The combination therapy was at least as effective as IL-2 therapy. In summary, L-NAME had anti-tumour effects in vivo, reduced the severity of IL-2-induced capillary leakage in some organs and did not compromise anti-tumour efficacy of IL-2 therapy. Thus, L-NAME could be a valuable adjunct to IL-2-based cancer therapy.Keywords: capillary leak syndrome; interleukin 2 cancer immunotherapy; mammary adenocarcinoma; nitric oxide; NG-nitro-L-arginine methyl ester Interleukin 2 (IL-2) therapy, alone or in combination with ex vivo-generated lymphokine-activated killer (LAK) cells, can cause tumour regression in mice (Rosenberg et al., 1985;Ettinghausen et al., 1988) and in man (Rosenberg, 1989;Fisher et al., 1988; Dutcher et al., 1989;Parkinson et al., 1990). Widespread clinical use of IL-2 has been limited by the low rate of complete remission and by severe toxicity Siegel and Puri, 1991). Capillary leak syndrome is a major side-effect of high-dose IL-2 therapy, characterised by retention of extravascular fluid and hypotension (Siegel and Puri, 1991). It has been observed in humans (Siegel and Puri, 1991; Margolin et al., 1989;Rosenberg et al., 1987) al., 1985) and tumour necrosis factor (TNF)-ca...

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“…[23][24][25][26][27][28][29][30] IL-2 is the primary cytokine responsible for the activation and clonal expansion of CD8 ϩ cytotoxic T lymphocytes (CTLs), which are the primary effector cells that target tumors in an antigen-specific manner. 2 IL-12 functions to activate and clonally expand natural killer (NK) cells, which kill tumors in a major histocompatibility complex (MHC)-independent fashion.…”

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Regional treatment of hepatic micrometastasis by adenovirus vector-mediated delivery of interleukin-2 and interleukin-12 cDNAs to the hepatic parenchyma

et al. 1999

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We hypothesize that adenovirus (Ad) vector-mediated delivery of the human interleukin-2 (IL-2) cDNA (AdIL2) or the murine IL-12 cDNA heterodimer (AdIL12) would produce high concentrations of cytokines in the local hepatic milieu to induce host responses sufficient to inhibit the growth of experimental colon carcinoma-derived hepatic metastases. Ad vectors administered intravenously, which is a route known to deliver Ͼ90% of the vector to the hepatic parenchyma, achieved significant levels of each cytokine locally, with minimal levels in the sera. To examine the therapeutic effect, the AdIL2 and AdIL12 vectors were evaluated in a hepatic metastasis model that was established by injecting 3 ϫ 10 4 cells from the poorly immunogenic syngeneic C26 colon carcinoma cell line into the right lobe of the livers of BALB/c mice. Animals received AdIL2, AdIL12, or control virus (10 8 plaque-forming units each) intravenously for 2 days after tumor implantation, and tumor growth was compared with naive controls. The AdNull control tumors measured 116 Ϯ 25 mm 2 at 2 weeks. The control virus showed no significant antitumor effect. In marked contrast, both AdIL2 and AdIL12 vectors that were delivered regionally had significant antitumor effects, with AdIL2-treated animals having an average tumor size of 16 Ϯ 8 mm 2 ; AdIL12-treated tumors measured 6 Ϯ 6 mm 2 (P Ͻ .01, both compared with control). Both the AdIL2 and AdIL12 vectors provided a significant survival advantage by log-rank analysis (P Ͻ .01), but only AdIL12 translated into an increase in mean survival from 27 (naive control) to 37 days. To evaluate whether these antitumor effects were T-cell-mediated, splenocytes from AdIL2-treated, AdIL12-treated, and naive control groups were stimulated in vitro with ␥-irradiated C26 tumor cells for 5 days and tested for C26 tumor cell cytolysis by an in vitro cytotoxicity assay. Splenocytes from both AdIL2-and AdIL12-treated animals showed a dose-dependent, T-cell-mediated, specific cytolysis of CT26 cells. AdIL12 and to a lesser extent AdIL2 induced natural killer cell activity, as determined by a dose-dependent increase in lysis of the natural killer-specific target cell YAC-1. Overall, these data suggest that regional Ad-mediated delivery of IL-2 and IL-12 cDNAs may be useful for local tumor control and may warrant further investigation as a potentially useful adjuvant for the treatment of hepatic micrometastasis.

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A Progress Report on the Treatment of 157 Patients with Advanced Cancer Using Lymphokine-Activated Killer Cells and Interleukin-2 or High-Dose Interleukin-2 Alone

Cited by 2,526 publications

References 18 publications

Effectiveness of very low doses of immunotherapy in advanced renal cell cancer

Effectiveness of very low doses of immunotherapy in advanced renal cell cancer

NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, ameliorates interleukin 2-induced capillary leakage and reduces tumour growth in adenocarcinoma-bearing mice

Regional treatment of hepatic micrometastasis by adenovirus vector-mediated delivery of interleukin-2 and interleukin-12 cDNAs to the hepatic parenchyma

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