Advances in cell and gene therapy最新文献

The ongoing advent of genome editing with programmable nucleases, including zinc-finger nuclease (ZFN), TAL effector nuclease (TALEN), and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated RNA-guided endonuclease Cas9 (CRISPR/Cas9), have spurred the hematopoietic stem cell gene therapy (HSC-GT). In particular, CRISPR/Cas9-mediated gene editing revealed promising outcomes in several preclinical disease models including inherited and neoplastic hematological diseases. In this review, we focused on the utilization of the CRISPR/Cas9 system as a possible treatment option for hemoglobinopathies and hematological tumors. We summarize the recent advances with CRISPR/Cas9 and its therapeutic potential for genome editing in cells from hematopoietic origin. We also critically discussed the limitations inherent to the CRISPR/Cas9 and possible alternatives for the improvement of genome editing.

Recently, the anti-CCR4 antibody mogamulizumab (Moga, Kyowa Hakko Kirin Co., Ltd, Tokyo, Japan) was approved as a treatment for CCR4-positive adult T-cell leukemia-lymphoma (ATL) in Japan. We use Moga before or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with aggressive ATL. A recent retrospective analysis using a database from a nationwide survey showed that the use of Moga before allo-HSCT was associated with an increased risk of severe/steroid-refractory acute GVHD and inferior overall survival. Meanwhile, it was reported that a number of patients with chemotherapy-refractory ATL achieved disease control with Moga, including those who subsequently underwent allo-HSCT. To address these issues pertaining to Moga in transplant-eligible patients with ATL, a key opinion leader (KOL) meeting comprising hematologists and transplant physicians was conducted by Kyowa Hakko Kirin Co., Ltd. in Japan. The goal of this KOL meeting was to design a framework to guide decision-making on the use of Moga in transplant-eligible patients with ATL. KOLs first presented their experiences, and after a subsequent discussion, the KOLs agreed on the key scientific statement as summarized in this Expert Commentary. Our experiences suggest that a good number of patients benefited from Moga, achieving disease control that was often unattainable by conventional chemotherapies. However, as our statement is based largely on retrospective studies and real clinical practice, it requires further validation. Nevertheless, we believe that this statement should help efficiently guide decision-making concerning Moga use in transplant-eligible patients with ATL.

Adoptive therapy with chimeric antigen receptor (CAR)-modified T cells achieved remissions of so far refractory leukemia/lymphoma; however, the treatment of solid tumors still remains challenging. This is thought to be due to the hostile conditions of the tumor stroma and the repressive immune cell infiltrate. Most recently, CAR T cells are being used as redirected “living factories” to deposit immune-modulating cytokines in the tumor tissue aiming at converting the immune cell environment into a more favorite one to sustain a productive antitumor response. IL-18 releasing CAR- or T cell receptor (TCR)-modified T cells showed superior antitumor activities in several tumor models. Such IL-18 TRUCKs or “4th generation” CAR T cells are going to change our concepts of treating tumors and delivering drugs to predefined lesions in the near future.

As peripheral T-cell lymphomas (PTCL) are rare and heterogeneous groups of non-Hodgkin lymphomas, it is practically difficult to conduct randomized controlled trials to establish standard treatment strategies. There is still no consensus regarding the optimal treatment strategy for patients with PTCL. Moreover, the survival outcomes of PTCL, excluding anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma, remain disappointing although novel agents have become available recent years. The aim of this review is to summarize the information regarding hematopoietic stem cell transplantation (HSCT) for PTCL including both autologous (auto-) and allogeneic (allo-) HSCT. In the first-line setting, up-front auto-HSCT is generally recommended for patients with PTCL, especially with complete remission 1 (CR1). On the other hand, up-front allo-HSCT might be recommended for patients with high-risk PTCL, although the study incorporating up-front allo-HSCT is limited. In the salvage setting, auto-HSCT might be considered in patients with chemosensitive disease, especially with CR. Allo-HSCT might also be considered, although the data of allo-HSCT in the salvage setting is still limited. Further investigation to optimize the application of HSCT in patients with PTCL is warranted in the future.