Impact of dendritic cell vaccines pulsed with Wilms’ tumour-1 peptide antigen on the survival of patients with advanced non-small cell lung cancers

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Abstract

Purpose

Dendritic cell (DC)-based vaccines have been expected to serve as new therapeutic approaches for advanced non-small cell lung cancers (NSCLCs); however, their clinical outcomes have not been fully elucidated. We report a single-centre clinical study analysing factors affecting the survival of patients with advanced NSCLCs who received DC vaccines pulsed with or without Wilms’ tumour protein-1 (WT1) peptide.

Methods

Among 62 patients with previously treated inoperable or postoperatively relapsed NSCLCs who met the inclusion criteria, DCs from 47 (76%) patients who showed HLA-A2402/0201/0206 were pulsed with one or more corresponding WT1 peptide antigens. DC vaccines were intradermally injected biweekly.

Results

Clinical responses based on response evaluation criteria in solid tumours (RECIST) were found in 31 (50%) patients at 3 months after the first DC vaccine (complete response: 1 (1.6%), partial response: 4 (6.5%), stable disease: 26 (41.9%)). Median survival time was 27 months (82% in 1 year and 54% in 2 years) from initial diagnosis, and that was 12 months (48% in 1 year and 22% in 2 years) from the first DC vaccination. Importantly, multivariate analyses revealed that only two factors, blood haemoglobin and the use of WT1 peptides, significantly affected the overall survival of patients from both initial diagnosis and first vaccination.

Conclusions

This study is the first to suggest that DC vaccines pulsed with WT1 may hold a significant impact to prolong the overall survival of patients with advanced NSCLCs.

Introduction

Lung cancer is the most commonly diagnosed malignancy, and it is the leading cause of death in males among developed countries. Non-small-cell lung cancers (NSCLCs) account for approximately 85% of all lung cancer cases.1 The prognosis of patients with NSCLCs remains unsatisfactory: usually less than 12–13 months of median survival time (MST) despite the use of available therapeutics.2, 3, 4, 5, 6, 7 Therefore, the development of new and preferably less invasive therapeutics against NSCLSs has been much desired.

Since the first report regarding tumour-associated antigens (TAAs),8 a number of clinical trials using synthetic peptides encoding TAA, namely ‘cancer peptide vaccines’, have been performed worldwide.9 These studies demonstrated the safety of and possible immune responses against administered peptides, however, the clinical outcome, including the antitumour effect as well as the prolongation of survival, has been largely limited.10 Although the exact cause of such limited clinical efficacy has been undetermined, the dysfunction of professional antigen-presenting dendritic cells (DCs) in a tumour-bearing host has been suggested as a possible mechanism by which a tumour can escape immune surveillance.11

To overcome such dysfunction of DCs in tumour-bearing individuals in vivo, cell-based vaccines have been developed to manipulate and activate TAA-pulsed autologous DCs ex vivo.12, 13, 14, 15 A number of reports have demonstrated early promising results against advanced malignancies,16 including NSCLCs,17, 18, 19, 20 however, the clinical efficacy, as well as factors affecting it, have been still largely undetermined.

Therefore, we here retrospectively analysed the clinical data of inoperable or postoperatively relapsed NSCLC patients who were vaccinated with OK-432-activated DCs21, 22 with or without Wilms’ tumour gene-1 (WT1) peptide antigen, a potent TAA,23, 24 before moving to a well-controlled prospective trial.

Section snippets

Patients

A total of 62 NSCLC patients who had been initiated on DC vaccines (usually 1 × 107 cells/dose) between January 2007 and May 2011 at Seren Clinic Tokyo were retrospectively examined. All patients were diagnosed as inoperable due to primary tumour spread or postoperative relapse and agreed to be involved in this study with written informed consent. Patients were eligible in this study if they met the safety criteria, including a white blood cell (WBC) count of 2500 cells/μl or more, haemoglobin (Hb)

Patient characteristics

The clinical characteristics of the patients are summarised in Table 1. Among the 62 patients, 54 (87%) had initially received at least one standard therapy, including surgery for 17 (27%) patients; the remaining eight (13%) had early palliative care (EPC). Some standard chemotherapy regimens, including platinum doublet, were continued in 36 patients during DC vaccination. The mean survival time (MST) from the initial diagnosis was 27 months (survival: 82% at 1 year, 95% CI = 72–91 and 54% at 2 

Discussion

We here report an analysis of the survival of 62 patients with advanced NSCLCs who were treated mainly with WT1-pulsed DC vaccine combined with or without STT. The key observations obtained in this study were as follows: (1) patients well-tolerated multiple DC vaccinations, and no serious adverse event was observed; (2) although several factors significantly affected survival from the initial diagnosis, only the Hb and the use of WT1 peptide were essential factors in patient survival from the

Conflict of interest statement

Professor Y. Yonemitsu is also a member of the Board of Directors on Science and Medicine at Tella Inc. Dr. Ishidao is a Chief of Research and Development Division at Tella Inc.

Acknowledgments

This report is dedicated to the patients who participated in our studies and also to their primary oncology doctors. We also thank current and former members of Seren Clinic Tokyo for their contributions, Ms. Ayako Ikeda, Ms. Eri Yanagida, and Dr. Takeshi Tomoda. No funding supported for this study.

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