Tumor Immunotherapy Program, Campbell Family Institute for Breast Cancer Research, Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Takara Bio, Inc., Kusatsu, Japan.
Nat Med. 2018 Mar;24(3):352-359. doi: 10.1038/nm.4478. Epub 2018 Feb 5.
The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor (TCR) engagement (signal 1), co-stimulation (signal 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic contain a CD3z (TCR signaling) domain and co-stimulatory domain(s) but not a domain that transmits signal 3 (refs. 13, 14, 15, 16, 17, 18). Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor β-chain (IL-2Rβ) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling (CD3z) and co-stimulatory (CD28) domains (hereafter referred to as 28-ΔIL2RB-z(YXXQ)). The 28-ΔIL2RB-z(YXXQ) CAR-T cells showed antigen-dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, which promoted their proliferation and prevented terminal differentiation in vitro. The 28-ΔIL2RB-z(YXXQ) CAR-T cells demonstrated superior in vivo persistence and antitumor effects in models of liquid and solid tumors as compared with CAR-T cells expressing a CD28 or 4-1BB co-stimulatory domain alone. Taken together, these results suggest that our new-generation CAR has the potential to demonstrate superior antitumor effects with minimal toxicity in the clinic and that clinical translation of this novel CAR is warranted.
嵌合抗原受体（CAR）修饰的 T 细胞（以下简称 CAR-T 细胞）对 B 淋巴细胞抗原 CD19 具有特异性，在难治性 B 细胞恶性肿瘤患者中显示出令人印象深刻的临床反应。然而，针对其他恶性肿瘤的 CAR-T 细胞的治疗效果尚未带来显著的临床获益。尽管 CAR-T 细胞的肿瘤归巢效率低下和各种免疫抑制机制会阻碍 CAR-T 细胞效应器的反应，但目前的 CAR 构建物所传递的信号可能仍然不足以充分激活抗肿瘤 T 细胞功能。最佳的 T 细胞激活和增殖需要多种信号，包括 T 细胞受体（TCR）结合（信号 1）、共刺激（信号 2）和细胞因子结合（信号 3）。然而，目前正在临床试验中测试的 CAR 构建物包含 CD3z（TCR 信号）结构域和共刺激结构域，但不包含传递信号 3 的结构域（参考文献 13、14、15、16、17、18）。在这里，我们开发了一种新型的 CAR 构建物，该构建物能够在抗原刺激后诱导细胞因子信号。这种新一代的 CD19 CAR 编码了白细胞介素（IL）-2 受体β链（IL-2Rβ）的截断胞质结构域和 STAT3 结合的酪氨酸-X-X-谷氨酰胺（YXXQ）基序，以及 TCR 信号（CD3z）和共刺激（CD28）结构域（以下简称 28-ΔIL2RB-z(YXXQ)）。28-ΔIL2RB-z(YXXQ) CAR-T 细胞表现出抗原依赖性的 JAK 激酶和 STAT3 和 STAT5 转录因子信号通路的激活，这促进了它们的增殖并防止了体外的终末分化。与表达 CD28 或 4-1BB 共刺激结构域的 CAR-T 细胞相比，28-ΔIL2RB-z(YXXQ) CAR-T 细胞在液体和实体肿瘤模型中具有更好的体内持久性和抗肿瘤作用。总之，这些结果表明，我们的新一代 CAR 有可能在临床上具有更好的抗肿瘤效果，同时毒性最小，有必要对这种新型 CAR 进行临床转化。
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