Nobuko Muraki

Abstract 2791: Advantages and clinical application of fibronectin CH296-stimulated T cells in cancer immunotherapy

Background: In adoptive T-cell therapy (ACT), the differentiation state of transferred T cells is considered to be crucial to the success of ACT-based approaches. It has been reported that less-differentiated T cells, which have a higher proliferative potential and less prone to apoptosis than more differentiated cells, are ideal for ACT transfer therapy. In this study, we compared the co-stimulation effects of fibronectin CH296 (FN-CH296, RetroNectin®) with that of anti-28Ab or anti-4-1 BB Ab on T-cell expansion and its phenotype. Furthermore, we examined persistence of T cells expanded by these methods in NOG® mice. In addition, we conducted phase 1 clinical study to evaluate the safety and efficacy of FN-CH296 stimulated T cell therapy in patients with advanced cancer. Methods: PBMCs were activated by various stimulation methods and cultured in gas-permeable culture bag CultiLife TM 215 and CultiLife TM Eva for 10-14 days. After that, each expanded cells were analyzed for its phenotypes, in vivo persistence and the ability of accumulation in lymph node. In clinical study, patients underwent FN-CH296 stimulated T cell therapy up to six times every two weeks and safety and antitumor activity of the ACT were assessed. In order to determine immune function, whole blood cytokine levels were analyzed prior to ACT and during the follow up. Results: Co-stimulation by FN-CH296 with anti-CD3Ab led to higher T-cell expansion and proportion of CCR7 + CD45RA + T cells than that by the others (anti-28Ab/anti-4-1BB Ab). In the experiment for engraftment of expanded T cells in NOG mice, human CD3 + cells were detected in all groups, but the proportion of CCR7 + CD45RA + and CD8 + T cells was significantly higher specifically in the FN-CH296 co-stimulation condition. In addition, higher accumulation of human CD3 + cells in lymph node of NOG® mice was observed when stimulated by the FN-CH296 co-stimulation condition. In phase 1 clinical trial, nine patients were enrolled and infused 1, 3, or 9×10 9 of T cells to each cohort group (3 patients in each group). As a result, there was no ACT-related serious adverse event in all doses and one patient achieved CR, one achieved PR, four had SD, and three had PD. The number of less-differentiated cells that was infused showed a strong positive correlation with the change in whole blood IFN-γ level after ACT treatment. Conclusion: These results indicated that FN-CH296 stimulated T cells therapy was very well tolerated with a level of efficacy that is promising and the FN-CH296 stimulation method for ex vivo T-cell expansion is useful as basic technology for adoptive T-cell therapy, as it can be expanded preferentially less-differentiated T cells. Citation Format: Takeshi Ishikawa, Satoshi Kokura, Tetsuya Okayama, Naoyuki Sakamoto, Mitsuko Ideno, Nobuko Muraki, Akiko Kato, Tatsuji Enoki, Junichi Mineno, Yuji Naito, Yoshito Itoh, Toshikazu Yoshikawa. Advantages and clinical application of fibronectin CH296-stimulated T cells in cancer immunotherapy. [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 2791. doi:10.1158/1538-7445.AM2014-2791