Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

Eva Ellebaek; Trine Zeeberg Iversen; Niels Junker; Marco Donia; Lotte Engell-Noerregaard; Özcan Met; Lisbet Rosenkrantz Hölmich; Rikke Sick Andersen; Sine Reker Hadrup; Mads Hald Andersen; Per Thor Straten; Inge Marie Svane

doi:10.1186/1479-5876-10-169

Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

Eva Ellebaek, Trine Zeeberg Iversen, Niels Junker, Marco Donia, Lotte Engell-Noerregaard, Özcan Met, Lisbet Rosenkrantz Hölmich, Rikke Sick Andersen, Sine Reker Hadrup, Mads Hald Andersen, Per Thor Straten, Inge Marie Svane

102 Citations (Scopus)

Abstract

Background: Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.Methods: This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day.Results: Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3-4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission.Conclusion: Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

Original language	English
Journal	Journal of Translational Medicine
Volume	10
Pages (from-to)	169
ISSN	1479-5876
DOIs	https://doi.org/10.1186/1479-5876-10-169
Publication status	Published - 21 Aug 2012

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Ellebaek, E., Iversen, T. Z., Junker, N., Donia, M., Engell-Noerregaard, L., Met, Ö., Hölmich, L. R., Andersen, R. S., Hadrup, S. R., Andersen, M. H., Thor Straten, P., & Svane, I. M. (2012). Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. Journal of Translational Medicine, 10, 169. https://doi.org/10.1186/1479-5876-10-169

Ellebaek, E, Iversen, TZ, Junker, N, Donia, M, Engell-Noerregaard, L, Met, Ö, Hölmich, LR, Andersen, RS, Hadrup, SR, Andersen, MH, Thor Straten, P & Svane, IM 2012, 'Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients', Journal of Translational Medicine, vol. 10, pp. 169. https://doi.org/10.1186/1479-5876-10-169

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title = "Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients",

abstract = "Background: Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.Methods: This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day.Results: Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3-4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission.Conclusion: Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.",

author = "Eva Ellebaek and Iversen, {Trine Zeeberg} and Niels Junker and Marco Donia and Lotte Engell-Noerregaard and {\"O}zcan Met and H{\"o}lmich, {Lisbet Rosenkrantz} and Andersen, {Rikke Sick} and Hadrup, {Sine Reker} and Andersen, {Mads Hald} and {Thor Straten}, Per and Svane, {Inge Marie}",

year = "2012",

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day = "21",

doi = "10.1186/1479-5876-10-169",

language = "English",

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journal = "Journal of Translational Medicine",

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TY - JOUR

T1 - Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

AU - Ellebaek, Eva

AU - Iversen, Trine Zeeberg

AU - Junker, Niels

AU - Donia, Marco

AU - Engell-Noerregaard, Lotte

AU - Met, Özcan

AU - Hölmich, Lisbet Rosenkrantz

AU - Andersen, Rikke Sick

AU - Hadrup, Sine Reker

AU - Andersen, Mads Hald

AU - Thor Straten, Per

AU - Svane, Inge Marie

PY - 2012/8/21

Y1 - 2012/8/21

N2 - Background: Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.Methods: This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day.Results: Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3-4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission.Conclusion: Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

AB - Background: Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.Methods: This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age <70, measurable and progressive disease and no involvement of the central nervous system. Six patients were treated with lymphodepleting chemotherapy, TIL infusion, and 14 days of subcutaneous low-dose IL-2 injections, 2 MIU/day.Results: Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3-4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission.Conclusion: Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

U2 - 10.1186/1479-5876-10-169

DO - 10.1186/1479-5876-10-169

M3 - Journal article

C2 - 22909342

SN - 1479-5876

VL - 10

SP - 169

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

ER -

Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients

Abstract

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