Phase I Clinical Trial of Fibronectin CH296-Stimulated T Cell Therapy in Patients with Advanced Cancer

Takeshi Ishikawa,Tatsuji Enoki,Tetsuya Okayama,Kazuhiro Katada,Toshikazu Yoshikawa,Kazuhiko Uchiyama,Junichi Mineno,Nobuaki Yagi,Mitsuko Ideno,Naoyuki Sakamoto,Hideyuki Konishi,Kazuhiro Kamada,Osamu Handa,Satoshi Kokura,Tomohisa Takagi,Naohisa Yoshida,Kazuko Uno,Yoshito Itoh,Yuji Naito

doi:10.1371/journal.pone.0083786

Abstract

BackgroundPrevious studies have demonstrated that less-differentiated T cells are ideal for adoptive T cell transfer therapy (ACT) and that fibronectin CH296 (FN-CH296) together with anti-CD3 resulted in cultured cells that contain higher amounts of less-differentiated T cells. In this phase I clinical trial, we build on these prior results by assessing the safety and efficacy of FN-CH296 stimulated T cell therapy in patients with advanced cancer.MethodsPatients underwent fibronectin CH296-stimulated T cell therapy up to six times every two weeks and the safety and antitumor activity of the ACT were assessed. In order to determine immune function, whole blood cytokine levels and the number of peripheral regulatory T cells were analyzed prior to ACT and during the follow up.ResultsTransferred cells contained numerous less-differentiated T cells greatly represented by CD27+CD45RA+ or CD28+CD45RA+ cell, which accounted for approximately 65% and 70% of the total, respectively. No ACT related severe or unexpected toxicities were observed. The response rate among patients was 22.2% and the disease control rate was 66.7%.ConclusionsThe results obtained in this phase I trial, indicate that FN-CH296 stimulated T cell therapy was very well tolerated with a level of efficacy that is quite promising. We also surmise that expanding T cell using CH296 is a method that can be applied to other T- cell-based therapies.Trial RegistrationUMIN UMIN000001835

Highlights

Adoptive T cell transfer (ACT) is currently one of the few immunotherapies that can induce objective clinical responses in a significant number of patients with metastatic solid tumors [1]
These findings suggest that the persistence and proliferative potential of transferred T cells play a role in clinical response and that lessdifferentiated T cells are ideal for adoptive T cell transfer therapy (ACT) transfer therapy
Anti-CD3/IL-2/FN-CH296stimulated T cells contained a higher quantity of less-differentiated T cells and in vivo persistence of these cells was significantly higher than cells stimulated by other methods [13]

Summary

Methods

The protocol for this trial and supporting TREND checklist are available as supporting information; see Checklist S1 and Protocol S1. Cell products were assessed for viability by trypan blue exclusion assay for sterility by the BacT/ALERT (bioMerieux, Durham, NC, USA) microbiological detection system, and endotoxin by a kinetic turbidimetric LAL assay Both sterility and endotoxin tests were contracted to FALCO Biosystems (Kyoto, Japan). Venous blood was obtained from subjects before the start of therapy (baseline) and during follow-up one which occurred at 4 weeks (2 treatments) and after 6 cultured cell administrations. Cultured lymphocytes were administered on days 1 and 15, and we conducted immunemonitoring to evaluate the safety of the treatment 4 weeks after the 2nd adoptive cell transfer was done. Two transfers are usually sufficient to assess the safety of novel ACT since further treatments can be beneficial, patients could receive up to four more transfers every two weeks unless they had unacceptable toxic effects, disease progression, or withdrew consent (Fig. 1). All statistical analyses were performed with SPSS software (version 20) for Windows (IBM Corporation, Illinois, U.S.A.)

Results

Conclusions

Introduction

Discussion