Adoptive Immunotherapy With Tumor-Infiltrating Lymphocytes and Subcutaneous Recombinant Interleukin-2 Plus Interferon Alfa-2a for Melanoma Patients With Nonresectable Distant Disease: A Phase I/II Pilot Trial

Queirolo, Paola; Ponte, Marco; Gipponi, Marco; Cafiero, Ferdinando; Peressini, A.; Semino, Claudia; Pietra, Gabriella; Lionetto, R.; Vecchio, Stefania; Ribizzi, I; Melioli, Giovanni; Sertoli, M. R.

doi:10.1007/s10434-999-0272-4

Cited by 18 publications

(7 citation statements)

References 31 publications

(40 reference statements)

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“…Biological response modifiers such as IL-2, IFN-α, IFN-γ, and TNF-α, are all possible candidates. Clinical use of some of these compounds has resulted in a limited response and has been associated with marked toxicity (1)(2)(3)(4)(5). Agonistic immune-stimulatory antibodies, such as anti-CD3, were also evaluated for their antitumor activity in humans, with little success (6,7).…”

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confidence: 99%

Ferrocene‐induced lymphocyte activation and antitumor activity is mediated by redox‐sensitive signaling

et al. 2003

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Ferrocene, a stable, synthetic, iron-containing compound induces in vitro and in vivo activation of mouse lymphocytes and macrophages. Ferrocene also has a marked antitumor effect in mice, upon its administration intraperitoneally and in drinking water. Ferrocene's antitumor activity is attributed to its immune-stimulatory property. This conclusion is supported by adoptive transfer experiments demonstrating that immune cells from ferrocene-treated tumor-bearing mice elicit an antitumor effect in mice not treated with ferrocene. We postulate that the immune stimulatory effect of ferrocene is mediated by redox-sensitive signaling such as activation of p21ras. This postulation is supported by the following findings: Ferrocene generates H2O2 by autooxidation; N-acetylcysteine, a free-radical scavenger, reduces its antitumor effect; and it stimulates GTPase activity catalyzed by pure recombinant p21ras and activates ERK 1/2 in wild Jurkat T cells but fails to do so in the Jurkat T cells expressing p21ras in which cysteine 118 was replaced by serine. Lastly, ferrocene activates and translocates NF-kappaB in human PBM, a pathway which is mediated by ras. It is most plausible that additional redox-sensitive signaling proteins mediate the biological effects of ferrocene.

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confidence: 99%

Ferrocene‐induced lymphocyte activation and antitumor activity is mediated by redox‐sensitive signaling

et al. 2003

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“…[2,20] Treatments by low-dose subcutaneous administration and continuous infusion of IL-2 have been done in clinical studies. [18,21] Suitable enhancement of the duration time and a decrease of the maximum serum concentration are often meaningful in the point of decrease of toxicity. Pharmacokinetic parameters of IL-2 in serum and remaining in the dosing area were calculated by using with noncompartmental method after subcutaneous administration of free IL-2 and liposomal IL-2.…”

Section: Resultsmentioning

confidence: 99%

“…[8][9][10][11][12][13][14] Treatment using subcutaneous administration of IL-2 is now performed in clinical studies. [16][17][18] The efficacy of its direct injection into tumor (melanoma) has also been reported. [15] In this study, liposomal IL-2 was administered subcutaneously to mice, and the release of IL-2 into the systemic circulation and its elimination from the dosing area were investigated.…”

Section: Introductionmentioning

confidence: 97%

Continuous Release of Interleukin-2 from Liposomal IL-2 (Mixture of Interleukin-2 and Liposomes) After Subcutaneous Administration to Mice

Kanaoka

Takahashi

Yoshikawa

et al. 2003

Drug Development and Industrial Pharmacy

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Recombinant interleukin-2 (IL-2) was strongly and almost completely adsorbed onto small and hydrophobic liposomes by simple mixing under optimal conditions (liposome: DSPC-DSPG; molar ratio, 10:1; 30-50 nm in size, ratio of IL-2 to liposome: 4.0 JRU/nmol lipid). This liposomal IL-2 displayed better distribution after intravenous administration in mice and improved therapeutic effect against experimental M5076 metastases, as reported previously. In this study, the elimination of IL-2 from the dosing area was investigated when the liposomal IL-2 was administered to mice subcutaneously. The results suggest that the release of IL-2 from this liposome was continuous and almost complete. The mean residence time (MRT) of IL-2 in the dosing area was 11.0 +/- 1.65 hr. This resulted in the 8-fold times enhancement of MRT in the systemic circulation by the presence of liposomes, and IL-2 was detected in the serum for 2 days. Using this liposomal IL-2 is expected to have the potential to decrease the number of injections and enhance the efficacy of IL-2 in immunotherapies and therapies against tumor.

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“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] In clinical pilot studies, durable responses have been reported in patients with metastatic cancer who were treated with infusions of TIL and IL-2, especially in patients with renal cell cancer and melanoma. [11][12][13][14][15][16][17][18][19][20][21] Unfortunately, the only randomized trial that attempted to ascertain whether IL-2 1 TIL was superior to IL-2 failed because of difficulties in growing TIL for the patients who were supposed to receive cell therapy. 22 Improvements in cell culture technology, especially the introduction of hollow-fiber bioreactors, allow for expansion of specific cell types with less frequent cell manipulation and less dedicated incubator space as compared to the use of gas permeable culture bags.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Human Tumor-Infiltrating Lymphocytes Expanded in Hollow-Fiber Bioreactors for Immunotherapy of Cancer

Malone

Schiltz

Mackintosh

et al. 2001

Cancer Biotherapy and Radiopharmaceuticals

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We attempted to grow tumor-infiltrating lymphocytes (TIL) from 34 fresh tumors of eight different histologies using flasks for the initiation phase and hollow fiber bioreactors to expand TIL to therapeutic numbers. Overall success rate was 76% (26/34) including melanoma (9/14, 64%) and renal cell carcinoma (11/11, 100%). The mean number of days required to reach successful initiation (1 x 10(9) TIL) for all tumor types was 29 +/- 16 days (mean +/- S.D.). Therapeutic doses of TIL required an average of 88 +/- 23 days (initiation plus expansion) with an average TIL number of 3.2 x 10(10) +/- 2.8 x 10(10). TIL phenotype was predominantly CD4+ in 53% (16/30) and CD8+ in 47% (14/30), renal cell carcinoma samples accounted for 12/14 of the predominantly CD8+ TIL. Cells bearing the natural killer (NK) phenotype represented only 0-7% of TIL while LAK phenotype represented 0-68% (mean 11 +/- 15%); LAK was the predominant phenotype in one patient with kidney cancer. Cytotoxicity tests showed consistent NK and LAK activity in addition to cytolysis of autologous tumor. Autologous tumor cell restricted cytolysis was noted for three TIL cultures. The overall success rate and characteristics of TIL were similar to our results with TIL expanded in semi-permeable plastic bags. This work confirms that hollow-fiber bioreactors are a suitable alternative to semi-permeable bags and roller bottle systems for the expansion of human TIL for therapeutic use in cancer patients.

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Adoptive Immunotherapy With Tumor-Infiltrating Lymphocytes and Subcutaneous Recombinant Interleukin-2 Plus Interferon Alfa-2a for Melanoma Patients With Nonresectable Distant Disease: A Phase I/II Pilot Trial

Abstract: Outpatient treatment with TIL plus rIL-2 and rIFN-alpha2a is feasible, although, within the context of the small sample size, the activity of the combination was no different from the reported activity of any of the components used alone.

Cited by 18 publications

References 31 publications

Ferrocene‐induced lymphocyte activation and antitumor activity is mediated by redox‐sensitive signaling

Ferrocene‐induced lymphocyte activation and antitumor activity is mediated by redox‐sensitive signaling

Continuous Release of Interleukin-2 from Liposomal IL-2 (Mixture of Interleukin-2 and Liposomes) After Subcutaneous Administration to Mice

Characterization of Human Tumor-Infiltrating Lymphocytes Expanded in Hollow-Fiber Bioreactors for Immunotherapy of Cancer

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