Misc

Chimeric antigen receptor (CAR)-engineered T-cell therapy can induce a high remission rate for B-cell tumors and multiple myeloma. However, a significant number of patients experience a relapse after a transient response. To improve the efficacy of CAR-T cell therapy, genetic modification focused on epigenetic factors and cytokine signaling has been actively explored to confer long-lived potential and resistance to exhaustion of CAR-T cells. Studies are also underway to prevent or mitigate therapeutic toxicities, such as cytokine release syndrome, which inevitably increase in proportion to the therapeutic effect. In addition, the risk of developing T-cell malignancies after CAR T-cell therapy is better understood, and there is increasing interest in the long-term safety of the therapy. Here, I will review recent studies and future directions in CAR T-cell therapy with respect to the above perspectives.

T細胞に対する二重特異性抗体（BsAb）はCD3抗体を介して抗腫瘍活性をT細胞に賦与するが，長期的な治療効果は未だ不十分である。T細胞に最適な抗腫瘍効果を誘導するには複合的なシグナルが必要であり，我々はBsAb，共刺激分子，サイトカインなどの分子群を同時に表面に搭載したナノサイズの細胞膜由来膜小胞の作製技術を確立した。B細胞性造血器腫瘍に対し，CD19を標的としたBsAbに加え，共刺激分子（CD80，4-1BBL），T細胞の増殖・長期生存に関わるサイトカイン（IL-7，IL-15）を搭載した膜小胞は，T細胞に抗原特異的な抗腫瘍活性を効率よく誘導した。また抗PDL1抗体，CTLA4抗体，IL-12，IL-18など腫瘍微小環境に作用する分子を搭載し，腫瘍内マクロファージの改変や免疫抑制シグナルの解除を行えることを示した。この手法は従来の抗体医薬と比較して多面的な免疫制御シグナルを誘導できる。

Chimeric antigen receptor (CAR)-engineered T cell therapy has shown significant efficacy against hematological malignancies; however, its long-term efficacy remains suboptimal. Furthermore, solid tumors are highly resistant to CAR-T cell therapy. Cytokine signaling is important for anti-tumor activity of T cells. Modulating cytokine signaling can improve the efficacy and safety of CAR-T cell therapy. We will review representative studies on manipulating CAR-T cell functions using cytokine signaling.