TY - JOUR

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 μL 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. IDO-specific CD8(+) T-cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. Fluorescence-activated 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.

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 μL 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. IDO-specific CD8(+) T-cell immunity was demonstrated by IFN-γ Elispot and Tetramer staining. Fluorescence-activated 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.

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

VL - 20

SP - 221

EP - 232

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 1

ER -