Abstract LB-172: A phase I clinical trial of RNF43 peptide-specific immune cell therapy combined with low-dose cyclophosphamide for patients with advanced solid tumors
Authors: Hijikata Yasuki , Okazaki Toshihiko , Inoue Hiroyuki , Tanaka Yoshihiro , Tani Kenzaburo , Kobayashi Shinichi , Yoshida koji 
Published: May 2015

Accumulated clinical studies have validated the efficacy of immunotherapies for patients with solid tumors. Although effective anti-tumor immune responses have been introduced in many clinical trial cases, several immunosuppressive factors such as regulatory T cells (Tregs) have been considered to inhibit induction of anti-tumor immunity.

We have developed new approach of immunotherapy in order to augment anti-tumor effect by expanding tumor-specific cytotoxic T cells (CTL), and eliminate Tregs by utilizing chemotherapy. We have recently reported the efficacy of multiplex vaccination with HLA-A*2402 restricted tumor-associated antigens peptides (TAA), preceded by the administration of low-dose cyclophosphamide (CPM) in order to eliminate Tregs. This time, we have been conducting a phase I clinical trial to study the utilization of CTL after CPM administration followed by a consequent administration of dendritic cells (DC) and IL-2. This study targets the novel HLA-A*0201 or HLA-A*2402-restricted TAA, RING finger protein 43 (RNF43), and is designed as a dose-escalation study of CTL. The purpose of this trial is to evaluate the safety and tolerability of the proposed method as primary endpoint and the efficacy including over all survival and immune responses as secondary endpoint.

11 patients with advanced solid tumors refractory to standard therapy were enrolled in this trial. They were HLA-A*2402 or A*0201 positive and exhibiting RNF43 expression levels in their tumor cells more than those in RNF43-positive control cell (HCT15). Primarily, severe adverse event greater than Grade 3 was not observed in our patients. Clinical responses of stable disease (SD) were observed in 8 out of 11 patients. Among them, 2 patients showed a decrease in the tumor markers with stabilized tumor sizes during the observed period, and 1 patient showed a mixed response. On the other hand, 3 other patients showed progressive disease (PD). The number of Tregs significantly decreased after the administration of CPM (p=0.033), and the higher decreasing rate of Tregs was related to the good clinical response. In CD107a/b mobilization assay, the ratio of RNF43-specific CD8 T cells in SD increased with time, conversely that in PD decreased (p=0.005). Also, in Intracellular Staining Assay, the ratio of IFN-g produced by RNF43-specific CD8 T cells was significantly correlated with clinical benefit (p=0.02), while TNF-α and IL-2 were not. Consequently, the combination of immunotherapy and CPM may induce tumor specific immune cells accompanied by the decreased number of Tregs.

In conclusion, this trial is tolerable and may be clinically efficient against advanced solid tumors. Further immunological assessment should be conducted in order to explore the valid biomarkers to predict clinical efficacy before treatment.

Citation Format: Yasuki Hijikata, Toshihiko Okazaki, Hiroyuki Inoue, Yoshihiro Tanaka, Kenzaburo Tani, Shinichi Kobayashi, koji Yoshida. A phase I clinical trial of RNF43 peptide-specific immune cell therapy combined with low-dose cyclophosphamide for patients with advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-172. doi:10.1158/1538-7445.AM2014-LB-172