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Clinical relevance of antigen spreading pattern induced by CHP-MAGE-A4 cancer vaccination

Aim: To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as a surrogate marker of patient survival. Materials & methods: 12 patients who had been injected with 300 μg of CHP-MAGE-A4 and 0.5 Klinische Einheit of OK-432 in more than five vaccinations were analyzed. Results: Increases in the anti-MAGE-A4-specific antibody response were observed in eight patients (66.7%), compared with six patients (50%) for anti-NY-ESO-1 and five patients (41.7%) for anti-MAGE-A3 after five vaccinations. We identified frequent antigen spreading following MAGE-A4 vaccinations without associations with the clinical response or patient prognosis. Conclusion: Antigen spreading pattern might reflect tumor shrinkage as a response to treatment and treatment history (clinical trial registration number: UMIN000001999). First draft submitted: 9 January 2016; Accepted for publication: 8 February 2016; Published online: 18 February 2016 Keywords: • antigen spreading • cancer vaccine • IgG subtypes • immunomonitoring • MAGE-A4

Cancer vaccines represent a promising antitumor immunotherapy, and numerous clinical trials of immunotherapy have been conducted since the discovery of tumor-specific antigens by Boon et al.  [1–3] . However, clinical responses to immunotherapy in clinical settings have been unsatisfactory and selection of those patients most likely to benefit from immunotherapy by monitoring specific biomarkers seems warranted. These biomarkers include serum lymphocyte count, immunoglobulin (Ig)G titer and serum ­amyloid acid level [4–6] . Antigen spreading is one of the immune responses seen during the process of cancer progression. These responses can be induced through tumor lysis, either in the natural course of tumor progression or through therapeutic interventions such as administration of anticancer agents or even immunotherapy, and thus can be used as proof of the presence of cancer or in immune monitoring.

10.2217/imt-2016-0007 © 2016 Future Medicine Ltd

However, few reports have referred to antigen spreading as a biomarker of immune response [7] , and information is lacking about this phenomenon with melanoma antigen gene (MAGE)-A4 vaccines for cancer patients. We carried out a clinical trial using a complex of recombinant MAGE-A4 protein and cholesteryl-bearing hydrophobized pullulan (CHP) in patients with MAGE-A4-expressing cancers [8] . The MAGE-A4 protein was identified in the process of cloning cytotoxic T-lymphocyte (CTL) epitopes of melanoma cells. MAGE-A4 is a cancer testis antigen (CTA) [9] and is reportedly expressed in various cancers [10–13] . MAGE-A4 has therefore been considered an available target antigen in various cancers. CHP is a developed antigen delivery vehicle that can be used to formulate nanoparticles, including protein antigens  [14] . Complexes of CHP nanoparticles that contain a tumor antigen present

Immunotherapy (Epub ahead of print)

Kengo Miyauchi1, Takahiro Tsuchikawa*,1, Masataka Wada1, Takehiro Abiko1, Noriaki Kyogoku1, Toshiaki Shichinohe1, Yoshihiro Miyahara2, Shinichi Kageyama2, Hiroaki Ikeda2, Hiroshi Shiku2 & Satoshi Hirano1 1 Department of Gastroenterological Surgery II, Division of Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Hokkaido, Japan 2 Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan *Author for correspondence: Tel.: +81 11 706 7714 Fax: +81 11 706 7158 tsuchi-t@ med.hokudai.ac.jp

part of

ISSN 1750-743X

Research Article  Miyauchi, Tsuchikawa, Wada et al. multiple epitope peptides to both the MHC class I and class II pathways. The aim of this study was to investigate the antigen spreading pattern in consecutive plasma samples from CHP-MAGE-A4-vaccinated patients and to clarify the clinical relevance of antigen spreading pattern as a s­urrogate marker for patient survival. Materials & methods Study design

A Phase I + II clinical trial of CHP-MAGE-A4 vaccine was designed to evaluate safety, immune responses and clinical responses. Primary endpoints were to evaluate safety and the optimal dose of vaccine. Secondary endpoints were to investigate the immunological and clinical responses. Immunological monitoring was performed by ELISA of patient plasma before and after the vaccination period. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 [15] . To assess the clinical response, computed tomography was performed before and after vaccination. Every measurable lesion was evaluated using the modified Response Evaluation Criteria in Solid Tumors, which differs from RECIST in that all evaluable lesions with diameter >10 mm are treated as target lesions. New lesions appearing after vaccination, and nontarget lesions that had grown to >10 mm were treated as target lesions. Appearance of a new lesion is not simply treated as progressive disease. The CHP-MAGE-A4 vaccine was injected subcutaneously for a total of six cycles at intervals of 2 weeks. In this vaccine, 300 μg of MAGE-A4 recombinant protein is complexed with 3.6 mg of CHP and 0.5 Klinische Einheit of OK-432 (Chugai ­Pharmaceuticals, Tokyo, Japan) as immune adjuvant. Thereafter, based on the decision of the patient, the vaccine was administered again. The protocol of this study was approved by the Medical Ethics Committee of Hokkaido University (Clinical trial registration number: UMIN000001999). The numbers of healthy volunteer were 24 for MAGE-A4 and 26 for NY-ESO-1 and MAGE-A3. Both vaccinated patients and healthy volunteers were approved by the institutional review board. Patient eligibility

Written informed consent was obtained from all patients at the time of enrollment in the study. The eligibility criteria for patients participating in the clinical trial were as follows: patients with a locally advanced, recurrent or metastatic tumor that had been histologically confirmed as a malignant lesion, and resistant to standard therapy; patients with tumors expressing MAGE-A4 antigen, as assessed immunohistochemically, as described later

10.2217/imt-2016-0007

in detail; Eastern Cooperative Oncology Group performance status of 0–2; age ≥20 years; expected life prognosis >4 months; adequate bone marrow, cardiac, pulmonary, hepatic and renal functions, including white blood cell count ≥2000/μl, hemoglobin ≥8.0 g/dl, platelet count ≥75,000/μl, total bilirubin level

Clinical relevance of antigen spreading pattern induced by CHP-MAGE-A4 cancer vaccination.

To investigate the antigen spreading pattern in the CHP-MAGE-A4-vaccinated patients and analyze the clinical relevance of antigen spreading pattern as...
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