Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA 94143, USA.
Sci Transl Med. 2021 Apr 28;13(591). doi: 10.1126/scitranslmed.abd8836.
The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening "on-target/off-tumor" toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.
首批经临床批准的嵌合抗原受体 (CAR) T 细胞疗法在少数治疗选择有限的血液恶性肿瘤亚群中具有显著疗效。尽管这些临床成功令人振奋，但 CAR T 细胞在实体瘤中遇到了障碍，包括缺乏高度肿瘤特异性的靶抗原，从而有可能产生危及生命的“靶内/靶外”毒性，以及 T 细胞进入实体瘤和在抑制性肿瘤微环境中持续活性的问题。在这里，我们使用合成 Notch (synNotch) CAR 电路来提高治疗性 T 细胞的特异性和持续抗肿瘤活性。我们确定碱性磷酸酶胎盘样 2 (ALPPL2) 为一种在多种实体瘤中表达的肿瘤特异性抗原，包括间皮瘤和卵巢癌。ALPPL2 可以作为 CAR 治疗的唯一靶标，也可以与肿瘤相关抗原（如黑色素瘤细胞黏附分子 (MCAM)、间皮素或人表皮生长因子受体 2 (HER2)）结合，用于 synNotch CAR 组合抗原电路。与在人间皮瘤和卵巢癌小鼠模型中持续表达靶向相同抗原的 CAR 的 T 细胞相比，synNotch CAR T 细胞显示出对肿瘤负担的更好控制。这是通过 synNotch 控制表达来防止 CAR 介导的紧张信号来实现的，使 T 细胞能够维持长期记忆和非耗竭表型。总的来说，我们将 ALPPL2 确立为多种实体瘤的临床可行细胞治疗靶标，并展示了 synNotch CAR T 细胞的多方面治疗益处。
