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

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 mg 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 ¼ 0.03) when compared with the group of patients excluded because of HLA-A2 negativity. IDOspecific CD8 þ T-cell immunity was demonstrated by IFN-g Elispot and Tetramer staining. Fluorescenceactivated cell sorting analyses demonstrated a significant reduction of the Treg population (P ¼ 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 PRþSD was seen in 47% of the patients.

Role of indoleamine 2,3-dioxygenase in health and disease

“…IDO1-positive tumour cells). This novel approach has recently been the subject of a Phase I clinical trial in metastatic lung cancer patients [268].…”

“…In addition to siRNA, the ability of the anti-inflammatory compound ethyl pyruvate to inhibit tumour growth in mice is linked to its ability to inhibit NF-κB and IDO1 gene expression [434]. A further novel IDO1-targeted anti-cancer therapeutic employed in a recent Phase I clinical trial involved vaccination of metastatic lung cancer patients with an IDO1 peptide, which was tolerated by the patient group and produced long-lasting disease stabilisation [268].…”

Small molecule drugs with immunomodulatory effects in cancer

“…A phase I study treated 15 HLA-A2-postive patients with metastatic NSCLC with IDO5 vaccines administered every 14 days for 2.5 months and subsequently monthly. 31 The vaccine was well tolerated with no grade 3/4 toxicities reported. Vaccinated patients had longer survival than vaccineuntreated patients (25.9 vs. 7.7 months, p D 0.03).…”

Indoleamine 2,3-dioxygenase vaccination

“…The study comprised 15 HLA-A2 C patients with advanced NSCLC who were vaccinated with an IDO-derived A2 peptide in Montanide adjuvant (www.clinicaltrials.gov; NCT01219348). 4 The vaccine was well tolerated with manageable side effects and no CTCAE grade 3/4 toxicities. Local reactions at the vaccine site occurred in 90% of patients, most likely due to Montanide 5 and Imiquimod.…”