Department of Medicine, Biotherapeutics Development Lab, Roger Williams Medical Center, Boston University School of Medicine, Providence, Rhode Island.
Prostate. 2014 Feb;74(3):286-96. doi: 10.1002/pros.22749.
Adoptive immunotherapy by infusion of designer T cells (dTc) engineered with chimeric antigen receptors (CARs) for tumoricidal activity represents a potentially highly specific modality for the treatment of cancer. In this study, 2nd generation (gen) anti-prostate specific membrane antigen (PSMA) dTc were developed for improving the efficacy of previously developed 1st gen dTc for prostate cancer immunotherapy. The 1st gen dTc are modified with chimeric immunoglobulin-T cell receptor (IgTCR) while the 2nd gen dTc are engineered with an immunoglobulin-CD28-T cell receptor (IgCD28TCR), which incorporates a CD28 costimulatory signal for optimal T cell activation.
A 2nd gen anti-PSMA IgCD28TCR CAR was constructed by inserting the CD28 signal domain into the 1st gen CAR. 1st and 2nd gen anti-PSMA dTc were created by transducing human T cells with anti-PSMA CARs and their antitumor efficacy was compared for specific activation on PSMA-expressing tumor contact, cytotoxicity against PSMA-expressing tumor cells in vitro, and suppression of tumor growth in an animal model.
The 2nd gen dTc can be optimally activated to secrete larger amounts of cytokines such as IL2 and IFNγ than 1st gen and to proliferate more vigorously on PSMA-expressing tumor contact. More importantly, the 2nd gen dTc preserve the PSMA-specific cytotoxicity in vitro and suppress tumor growth in animal models with significant higher potency.
Our results demonstrate that 2nd gen anti-PSMA designer T cells exhibit superior antitumor functions versus 1st gen, providing a rationale for advancing this improved agent toward clinical application in prostate cancer immunotherapy.
通过输注嵌合抗原受体 (CAR) 工程设计的杀伤肿瘤的效应器 T 细胞（dTc）进行过继免疫治疗，代表了一种潜在的高度特异性治疗癌症的方法。在这项研究中，开发了第二代（gen）抗前列腺特异性膜抗原（PSMA）dTc，用于提高以前开发的第一代用于前列腺癌免疫治疗的 dTc 的疗效。第一代 dTc 经嵌合免疫球蛋白-T 细胞受体（IgTCR）修饰，而第二代 dTc 则经免疫球蛋白-CD28-T 细胞受体（IgCD28TCR）修饰，该受体包含 CD28 共刺激信号，以实现最佳 T 细胞激活。
通过将 CD28 信号域插入第一代 CAR 中，构建了第二代抗 PSMA IgCD28TCR CAR。通过转导抗 PSMA CAR 来创建第一代和第二代抗 PSMA dTc，并比较它们在 PSMA 表达肿瘤接触时的特异性激活、对 PSMA 表达肿瘤细胞的体外细胞毒性以及在动物模型中抑制肿瘤生长的能力。
第二代 dTc 可以被最佳地激活，从而分泌出比第一代更多的细胞因子，如 IL2 和 IFNγ，并在 PSMA 表达的肿瘤接触物上更强烈地增殖。更重要的是，第二代 dTc 保留了 PSMA 特异性的细胞毒性，并且在动物模型中具有更高的抑制肿瘤生长的效力。
我们的结果表明，第二代抗 PSMA 设计的 T 细胞表现出比第一代更好的抗肿瘤功能，为将这种改进的药物推进到前列腺癌免疫治疗的临床应用提供了依据。
