Development of a novel redirected T-cell–based adoptive immunotherapy targeting human telomerase reverse transcriptase for adult T-cell leukemia

Abstract

Key Points The efficacy and safety of a novel redirected T-cell–based adoptive immunotherapy targeting hTERT for patients with adult T-cell leukemia. hTERT-specific T-cell receptor gene-transduced CD8+ T cells lyse ATL cells, but not normal cells, both in vitro and in vivo.

Development of Engineered T Cells Expressing a Chimeric CD16-CD3ζ Receptor to Improve the Clinical Efficacy of Mogamulizumab Therapy Against Adult T-Cell Leukemia

“…The HEK 293T cell line (RIKEN BioResource Center, Tsukuba, Japan) was maintained in DMEM (Sigma Aldrich) supplemented with 10% FBS (Biowest) and 2 mmol/L L-glutamine (Sigma Aldrich), and employed for production of infectious lentivirus particles. K562 (ATCC), Jurkat (ATCC), the human T-lymphotropic virus type-I (HTLV-1) immortalized and IL-2-independent T-cell lines MT-1, MT-2, MT-4, TL-MAT, TL-Su, and Hut 102, (25) and the IL-2-independent ATL cell line ATN-1 (25) were cultured in RPMI1640 (Sigma Aldrich) supplemented with 10% FBS, 2 mmol/L L-glutamine, and penicillin/streptomycin (Biowest). B-lymphoblastoid cell lines (LCL) were established by transformation of peripheral blood B lymphocytes with Epstein Barr Virus (EBV).…”

“…cCD16z gene-transduced T cells (cCD16z-T cells) were established as described elsewhere (23 (25) and subsequently subjected to functional assays.…”

Novel immunotherapy for adult T-cell leukemia/lymphoma: Targeting aurora kinase A

“…5 In response to these challenges, we focused upon adoptive transfer therapy using genemodified T cells with hTERT-specific T-cell receptor (TCR) alpha and beta genes obtained from our previously established CTL clone. 4 These gene-modified T cells successfully and specifically killed hTERT-positive ATL tumor cells without unwanted adverse effect upon normal cells, including "steady state" (non-proliferating) haematopoietic progenitor cells. 4 Of the alternate ATL tumor-associated antigens, Aurora kinase A (AURKA) , expressed by ATL tumor cells express at supra-normal levels, is now under investigation.…”

“…4 These gene-modified T cells successfully and specifically killed hTERT-positive ATL tumor cells without unwanted adverse effect upon normal cells, including "steady state" (non-proliferating) haematopoietic progenitor cells. 4 Of the alternate ATL tumor-associated antigens, Aurora kinase A (AURKA) , expressed by ATL tumor cells express at supra-normal levels, is now under investigation. 6 AURKA is a serine/threonine kinase that plays a crucial role in regulating mitosis.…”

“…It has been reported that ATL cells express numerous tumor antigens, including NY-ESO-1, MAGE-A3, MAGE-A4, each of which are recognized by T cells. 1 We previously demonstrated that human Telomerase Reverse Transcriptase (hTERT) is also upregulated in ATL cells, 4 and that circulating hTERT-specific T cells responsive to ATL tumor cells were detectable in the peripheral blood of ATL patients. Unfortunately, we found previously that hTERT peptide vaccination resulted in limited clinical responses.…”