Tax-Targeting Dendritic Cell Therapy for ATL: A Phase Ia/Ib Clinical Study
Authors: Shiratsuchi Motoaki , Fukuda Tetsuya , Iino Tadafumi , Hasegawa Atsuhiko , Yasunaga Jun-ichirou , Watanabe Ken , Hirata Akie , Utsunomiya Hayato , Ohno Hirofumi , Ishida Takashi , Akashi Koichi , Matsuoka Masao , Kannagi Mari , Suehiro Youko 
Published: October 2019

Abstract
Background: Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive peripheral T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). Although most patients respond to initial therapy, relapse is inevitable and the overall prognosis is dismal. Therefore, we developed a novel immune therapy consisting of autologous dendritic cells (DC) pulsed with Tax peptides (ATL-DC-101) to prevent relapse. The used peptides are corresponding to the major epitopes of HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) that potentially act as anti-ATL effectors. Mogamulizumab is an anti-CCR4 antibody, which binds to ATL cells and regulatory T cells. A preceding pilot study suggested the safety of ATL-DC-101 monotherapy, and then we conducted a phase Ia/Ib study to investigate safety and efficacy of ATL-DC-101 combined with mogamulizumab.
Methods: ATL patients pretreated and stable for at least 4 weeks were enrolled. Peripheral blood mononuclear cells were obtained by apheresis and differentiated into DC, which was pulsed with Tax-peptides. The study consisted of 2 cohorts, i.e., Ia and Ib phase, in which patients were assigned ATL-DC-101 monotherapy and ATL-DC-101 combined with mogamulizumab, respectively. The protocol consisted of three subcutaneous injections of ATL-DC-101 at 2-week intervals. Mogamulizumab was administered once before ATL-DC-101 in Ib phase. The primary endpoint of the study was to evaluate safety and feasibility of ATL-DC-101. The secondary endpoints were anti-tumor effects, progression-free survival (PFS), overall survival (OS), and time to next treatment, estimated by Kaplan-Meier method. The safety and disease status were accessed at day 56 and followed until 2 years.
Results: Six aggressive ATL patients who were in stable condition by previous therapies were enrolled in this study from 2015 to 2016. Frequent DC- related toxicities were mild injection site reaction (n=5, 83.3%), decreased WBC count (n=3, 50%), and liver damage (n=2, 33.3%), all of which were grade 1 or 2. Notably, 2 patients (1 in each cohort) with partial response (PR) after chemotherapy were converted into complete response (CR) after ATL-DC-101. The 2-year PFS and OS were both 83.3%. All three patients who received ATL-DC-101 monotherapy (Ia) maintained CR for more than two years. Although one patient in phase Ib developed progressive disease after one year, the other two patients remained in CR. Interestingly ATL cells in a relapsed case harbored deletion of Tax gene, which resulted in the loss of the target peptide presentation. After a median follow-up of 29 months, 5/6 patients are alive without any additional chemotherapy after ATL-DC-101.
Conclusions: ATL-DC-101 was well tolerated and successfully maintained CR more than 2 years in 5/6 patients irrespective of additional mogamulizumab, indicating that this therapy could be a safe and effective long-lasting maintenance therapy even for elderly ATL patients. Currently, we are preparing Phase II trial to confirm anti-tumor effects of ATL-DC-101 monotherapy.

Disclosures
Shiratsuchi: Kyowa Hakko Kirin Co.Ltd: Research Funding; Chugai Pharmaceutical Co.Ltd: Research Funding; Daiichi Sankyo Co.Ltd: Research Funding. Fukuda:Chugai Pharmaceutical: Speakers Bureau. Ishida:Kyowa Hakko Kirin Co.Ltd: Honoraria, Research Funding; Celgene K.K: Honoraria, Research Funding; Bayer AG: Research Funding; Mundiparma K: Honoraria. Akashi:Ono Pharmaceutical: Research Funding; MSD: Research Funding; Taiho Pharmaceutical: Research Funding; sanofi: Research Funding; Celgene: Research Funding, Speakers Bureau; Eli Lilly Japan: Research Funding; Novartis pharma: Research Funding; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding; Asahi-kasei: Research Funding; Chugai Pharma: Research Funding. Matsuoka:Bristol Myers Squibb: Research Funding. Suehiro:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Takeda Pharmaceutical: Research Funding.