Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase

Trine Zeeberg Iversen; Lotte Engell-Noerregaard; Eva Ellebaek; Rikke Sick Andersen; Stine Kiaer Larsen; Jon Bjoern; Claus Zeyher; Cécile Gouttefangeas; Birthe Moerk Thomsen; Bente Holm; Per Thor Straten; Anders Mellemgaard; Mads Hald Andersen; Inge Marie Svane

doi:10.1158/1078-0432.ccr-13-1560

Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase

Trine Zeeberg Iversen, Lotte Engell-Noerregaard, Eva Ellebaek, Rikke Sick Andersen, Stine Kiaer Larsen, Jon Bjoern, Claus Zeyher, Cécile Gouttefangeas, Birthe Moerk Thomsen, Bente Holm, Per Thor Straten, Anders Mellemgaard, Mads Hald Andersen, Inge Marie Svane

80 Citations (Scopus)

Abstract

Purpose: To investigate targeting of indoleamine 2,3 dioxygenase (IDO) enzyme using a synthetic peptide vaccine administered to patients with metastatic non-small cell lung cancer (NSCLC). Experimental Design: In a clinical phase I study, we treated 15 HLA-A2-positive patients with stage III-IV NSCLC in disease stabilization after standard chemotherapy. Patients were treated with imiquimod ointment and subcutaneous vaccinations (100 μg IDO5 peptide, sequence ALLEIASCL, formulated in 900 mL Montanide). Primary endpoint was toxicity. Clinical benefit and immunity were assessed as secondary endpoints. Results: No severe toxicity was observed. One patient developed a partial response (PR) after one year of vaccine treatment, whereas long-lasting stable disease (SD) ≥ 8.5 months was demonstrated in another six patients. The median overall survival (OS) was 25.9 months. Patients demonstrated significant improved OS (P = 0.03) when compared with the group of patients excluded because of HLA-A2 negativity. IDOspecific CD8+ T-cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. Fluorescenceactivated cell sorting analyses demonstrated a significant reduction of the Treg population (P = 0.03) after the sixth vaccine (2.5 months) compared with pretreatment levels. Furthermore, expression of IDO was detected in nine of ten tumor biopsies by immunohistochemistry. High-performance liquid chromatography analyses of kynurenine/tryptophan (Kyn/Trp) ratio in sera were performed. In long-term analyses of two clinical responding patients, the ratio of Kyn/Trp remained stable. Conclusions: The vaccine was well tolerated with no severe toxicity occurring. A median OS of 25.9 months was demonstrated and long-lasting PR+SD was seen in 47% of the patients. Clin Cancer Res; 20(1); 221-32.

Original language	English
Journal	Clinical Cancer Research
Volume	20
Issue number	1
Pages (from-to)	221-232
Number of pages	12
ISSN	1078-0432
DOIs	https://doi.org/10.1158/1078-0432.ccr-13-1560
Publication status	Published - 1 Jan 2014

Keywords

Adenocarcinoma
Adjuvants, Immunologic
Aged
Cancer Vaccines
Carcinoma, Non-Small-Cell Lung
Disease-Free Survival
Female
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
Kaplan-Meier Estimate
Kynurenine
Lung Neoplasms
Lymphatic Metastasis
Male
Middle Aged
Statistics, Nonparametric
T-Lymphocytes, Regulatory
Treatment Outcome
Tryptophan
Vaccination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/1078-0432.ccr-13-1560

Cite this

Iversen, T. Z., Engell-Noerregaard, L., Ellebaek, E., Andersen, R. S., Larsen, S. K., Bjoern, J., Zeyher, C., Gouttefangeas, C., Thomsen, B. M., Holm, B., Thor Straten, P., Mellemgaard, A., Andersen, M. H., & Svane, I. M. (2014). Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase. Clinical Cancer Research, 20(1), 221-232. https://doi.org/10.1158/1078-0432.ccr-13-1560

Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase. / Iversen, Trine Zeeberg; Engell-Noerregaard, Lotte; Ellebaek, Eva et al.

In: Clinical Cancer Research, Vol. 20, No. 1, 01.01.2014, p. 221-232.

Research output: Contribution to journal › Journal article › Research › peer-review

Iversen, TZ, Engell-Noerregaard, L, Ellebaek, E, Andersen, RS, Larsen, SK, Bjoern, J, Zeyher, C, Gouttefangeas, C, Thomsen, BM, Holm, B, Thor Straten, P, Mellemgaard, A, Andersen, MH & Svane, IM 2014, 'Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase', Clinical Cancer Research, vol. 20, no. 1, pp. 221-232. https://doi.org/10.1158/1078-0432.ccr-13-1560

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abstract = "Purpose: To investigate targeting of indoleamine 2,3 dioxygenase (IDO) enzyme using a synthetic peptide vaccine administered to patients with metastatic non-small cell lung cancer (NSCLC). Experimental Design: In a clinical phase I study, we treated 15 HLA-A2-positive patients with stage III-IV NSCLC in disease stabilization after standard chemotherapy. Patients were treated with imiquimod ointment and subcutaneous vaccinations (100 μg IDO5 peptide, sequence ALLEIASCL, formulated in 900 mL Montanide). Primary endpoint was toxicity. Clinical benefit and immunity were assessed as secondary endpoints. Results: No severe toxicity was observed. One patient developed a partial response (PR) after one year of vaccine treatment, whereas long-lasting stable disease (SD) ≥ 8.5 months was demonstrated in another six patients. The median overall survival (OS) was 25.9 months. Patients demonstrated significant improved OS (P = 0.03) when compared with the group of patients excluded because of HLA-A2 negativity. IDOspecific CD8+ T-cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. Fluorescenceactivated cell sorting analyses demonstrated a significant reduction of the Treg population (P = 0.03) after the sixth vaccine (2.5 months) compared with pretreatment levels. Furthermore, expression of IDO was detected in nine of ten tumor biopsies by immunohistochemistry. High-performance liquid chromatography analyses of kynurenine/tryptophan (Kyn/Trp) ratio in sera were performed. In long-term analyses of two clinical responding patients, the ratio of Kyn/Trp remained stable. Conclusions: The vaccine was well tolerated with no severe toxicity occurring. A median OS of 25.9 months was demonstrated and long-lasting PR+SD was seen in 47% of the patients. Clin Cancer Res; 20(1); 221-32.",

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author = "Iversen, {Trine Zeeberg} and Lotte Engell-Noerregaard and Eva Ellebaek and Andersen, {Rikke Sick} and Larsen, {Stine Kiaer} and Jon Bjoern and Claus Zeyher and C{\'e}cile Gouttefangeas and Thomsen, {Birthe Moerk} and Bente Holm and {Thor Straten}, Per and Anders Mellemgaard and Andersen, {Mads Hald} and Svane, {Inge Marie}",

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doi = "10.1158/1078-0432.ccr-13-1560",

language = "English",

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pages = "221--232",

journal = "Clinical Cancer Research",

issn = "1078-0432",

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T1 - Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase

AU - Iversen, Trine Zeeberg

AU - Engell-Noerregaard, Lotte

AU - Ellebaek, Eva

AU - Andersen, Rikke Sick

AU - Larsen, Stine Kiaer

AU - Bjoern, Jon

AU - Zeyher, Claus

AU - Gouttefangeas, Cécile

AU - Thomsen, Birthe Moerk

AU - Holm, Bente

AU - Thor Straten, Per

AU - Mellemgaard, Anders

AU - Andersen, Mads Hald

AU - Svane, Inge Marie

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Purpose: To investigate targeting of indoleamine 2,3 dioxygenase (IDO) enzyme using a synthetic peptide vaccine administered to patients with metastatic non-small cell lung cancer (NSCLC). Experimental Design: In a clinical phase I study, we treated 15 HLA-A2-positive patients with stage III-IV NSCLC in disease stabilization after standard chemotherapy. Patients were treated with imiquimod ointment and subcutaneous vaccinations (100 μg IDO5 peptide, sequence ALLEIASCL, formulated in 900 mL Montanide). Primary endpoint was toxicity. Clinical benefit and immunity were assessed as secondary endpoints. Results: No severe toxicity was observed. One patient developed a partial response (PR) after one year of vaccine treatment, whereas long-lasting stable disease (SD) ≥ 8.5 months was demonstrated in another six patients. The median overall survival (OS) was 25.9 months. Patients demonstrated significant improved OS (P = 0.03) when compared with the group of patients excluded because of HLA-A2 negativity. IDOspecific CD8+ T-cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. Fluorescenceactivated cell sorting analyses demonstrated a significant reduction of the Treg population (P = 0.03) after the sixth vaccine (2.5 months) compared with pretreatment levels. Furthermore, expression of IDO was detected in nine of ten tumor biopsies by immunohistochemistry. High-performance liquid chromatography analyses of kynurenine/tryptophan (Kyn/Trp) ratio in sera were performed. In long-term analyses of two clinical responding patients, the ratio of Kyn/Trp remained stable. Conclusions: The vaccine was well tolerated with no severe toxicity occurring. A median OS of 25.9 months was demonstrated and long-lasting PR+SD was seen in 47% of the patients. Clin Cancer Res; 20(1); 221-32.

AB - Purpose: To investigate targeting of indoleamine 2,3 dioxygenase (IDO) enzyme using a synthetic peptide vaccine administered to patients with metastatic non-small cell lung cancer (NSCLC). Experimental Design: In a clinical phase I study, we treated 15 HLA-A2-positive patients with stage III-IV NSCLC in disease stabilization after standard chemotherapy. Patients were treated with imiquimod ointment and subcutaneous vaccinations (100 μg IDO5 peptide, sequence ALLEIASCL, formulated in 900 mL Montanide). Primary endpoint was toxicity. Clinical benefit and immunity were assessed as secondary endpoints. Results: No severe toxicity was observed. One patient developed a partial response (PR) after one year of vaccine treatment, whereas long-lasting stable disease (SD) ≥ 8.5 months was demonstrated in another six patients. The median overall survival (OS) was 25.9 months. Patients demonstrated significant improved OS (P = 0.03) when compared with the group of patients excluded because of HLA-A2 negativity. IDOspecific CD8+ T-cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. Fluorescenceactivated cell sorting analyses demonstrated a significant reduction of the Treg population (P = 0.03) after the sixth vaccine (2.5 months) compared with pretreatment levels. Furthermore, expression of IDO was detected in nine of ten tumor biopsies by immunohistochemistry. High-performance liquid chromatography analyses of kynurenine/tryptophan (Kyn/Trp) ratio in sera were performed. In long-term analyses of two clinical responding patients, the ratio of Kyn/Trp remained stable. Conclusions: The vaccine was well tolerated with no severe toxicity occurring. A median OS of 25.9 months was demonstrated and long-lasting PR+SD was seen in 47% of the patients. Clin Cancer Res; 20(1); 221-32.

KW - Adenocarcinoma

KW - Adjuvants, Immunologic

KW - Aged

KW - Cancer Vaccines

KW - Carcinoma, Non-Small-Cell Lung

KW - Disease-Free Survival

KW - Female

KW - Humans

KW - Indoleamine-Pyrrole 2,3,-Dioxygenase

KW - Kaplan-Meier Estimate

KW - Kynurenine

KW - Lung Neoplasms

KW - Lymphatic Metastasis

KW - Male

KW - Middle Aged

KW - Statistics, Nonparametric

KW - T-Lymphocytes, Regulatory

KW - Treatment Outcome

KW - Tryptophan

KW - Vaccination

U2 - 10.1158/1078-0432.ccr-13-1560

DO - 10.1158/1078-0432.ccr-13-1560

M3 - Journal article

C2 - 24218513

SN - 1078-0432

VL - 20

SP - 221

EP - 232

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 1

ER -

Long-lasting Disease Stabilization in the Absence of Toxicity in Metastatic Lung Cancer Patients Vaccinated with an Epitope Derived from Indoleamine 2,3 Dioxygenase

Abstract

Keywords

UN SDGs

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