TY - JOUR
T1 - A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors
AU - Hijikata, Yasuki
AU - Okazaki, Toshihiko
AU - Tanaka, Yoshihiro
AU - Murahashi, Mutsunori
AU - Yamada, Yuichi
AU - Yamada, Kazunari
AU - Takahashi, Atsushi
AU - Inoue, Hiroyuki
AU - Kishimoto, Junji
AU - Nakanishi, Yoichi
AU - Oda, Yoshinao
AU - Nakamura, Yusuke
AU - Tani, Kenzaburo
N1 - Funding Information:
This study was financially supported by Grant-in-Aid for Scientific Research of Japan Society for the Promotion of Science (YS24790708, YS22790651) and Ministry of Education, Culture, Sports, Science and Technology for the Coordination, Support and Training Program for Translational Research (08061012). Additionally, K.T. received a commercial research grant from OncoTherapy Science, Inc. in 2007. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Dr. Shinji Okano (Transplantation Center, Cleveland Clinic) for histological evaluation. The authors also thank Mieko Inada for monitoring the data, Kohei Odaira and Shinichi Kobayashi for immunological monitoring, and Hiroko Watanabe, Goki Eriguchi, Yasuo Matsubara and Lay Ahyoung Lim for performing statistical analysis.
Publisher Copyright:
© 2018 Hijikata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/1
Y1 - 2018/1
N2 - The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.
AB - The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.
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U2 - 10.1371/journal.pone.0187878
DO - 10.1371/journal.pone.0187878
M3 - Article
C2 - 29293510
AN - SCOPUS:85040006661
SN - 1932-6203
VL - 13
JO - PLoS One
JF - PLoS One
IS - 1
M1 - e0187878
ER -