Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-003959.
In the USA, more than 50% of patients with ovarian cancer die within 5 years of diagnosis, highlighting the need for therapeutic innovations. Mesothelin (MSLN) is a candidate immunotherapy target; it is overexpressed by ovarian tumors and contributes to malignant/invasive phenotypes, making tumor antigen loss disadvantageous. We previously showed that MSLN-specific T cell receptor (TCR)-engineered T cells preferentially accumulate within established tumors, delay tumor growth, and significantly prolong survival in the ID8 mouse model that replicates many aspects of human disease. However, T cell persistence and antitumor activity were not sustained. We therefore focused on Fas/FasL signaling that can induce activation-induced cell death, an apoptotic mechanism that regulates T cell expansion. Upregulation of FasL by tumor cells and tumor vasculature has been detected in the tumor microenvironment (TME) of human and murine ovarian cancers, can induce apoptosis in infiltrating, Fas (CD95) receptor-expressing lymphocytes, and can protect ovarian cancers from tumor-infiltrating lymphocytes.
To overcome potential FasL-mediated immune evasion and enhance T cell responses, we generated an immunomodulatory fusion protein (IFP) containing the Fas extracellular binding domain fused to a 4-1BB co-stimulatory domain, rather than the natural death domain. Murine T cells were engineered to express an MSLN-specific TCR (TCR), alone or with the IFP, transferred into ID8 tumor-bearing mice and evaluated for persistence, proliferation, cytokine production and efficacy. Human T cells were similarly engineered to express an MSLN-specific TCR (TCR) alone or with a truncated Fas receptor or a Fas-4-1BB IFP and evaluated for cytokine production and tumor lysis.
Relative to murine T cells expressing only TCR, T cells expressing TCR and a Fas-4-1BB IFP preferentially persisted in the TME of tumor-bearing mice, with improved T cell proliferation and survival. Moreover, TCR/IFP T cells significantly prolonged survival in tumor-bearing mice, compared with TCR-only T cells. Human T cells expressing TCR and a Fas-4-1BB IFP exhibit enhanced functional activity and viability compared with cells with only TCR.
As many ovarian tumors overexpress FasL, an IFP that converts the Fas-mediated death signal into pro-survival and proliferative signals may be used to enhance engineered adoptive T cell therapy for patients.
在美国，超过 50%的卵巢癌患者在诊断后 5 年内死亡，这凸显了治疗创新的必要性。间皮素（MSLN）是一种候选免疫治疗靶点；它在卵巢肿瘤中过度表达，并有助于恶性/侵袭性表型，使肿瘤抗原丢失处于不利地位。我们之前的研究表明，MSLN 特异性 T 细胞受体（TCR）工程化 T 细胞优先在已建立的肿瘤内积累，延迟肿瘤生长，并在 ID8 小鼠模型中显著延长存活时间，该模型复制了许多人类疾病的方面。然而，T 细胞的持久性和抗肿瘤活性并没有持续。因此，我们专注于 Fas/FasL 信号，它可以诱导激活诱导的细胞死亡，这是一种调节 T 细胞扩增的凋亡机制。在人类和小鼠卵巢癌的肿瘤微环境（TME）中已经检测到肿瘤细胞和肿瘤血管中 FasL 的上调，它可以诱导浸润的 Fas（CD95）受体表达的淋巴细胞凋亡，并可以保护卵巢癌免受肿瘤浸润淋巴细胞的侵害。
为了克服潜在的 FasL 介导的免疫逃逸并增强 T 细胞反应，我们生成了一种包含 Fas 细胞外结合结构域与 4-1BB 共刺激结构域融合的免疫调节融合蛋白（IFP），而不是天然死亡结构域。将小鼠 T 细胞工程化表达 MSLN 特异性 TCR（TCR），单独或与 IFP 一起转染到 ID8 肿瘤荷瘤小鼠中，并评估其持久性、增殖、细胞因子产生和疗效。同样，将人类 T 细胞工程化表达 MSLN 特异性 TCR（TCR），单独或与截短的 Fas 受体或 Fas-4-1BB IFP 一起表达，并评估细胞因子产生和肿瘤溶解。
与仅表达 TCR 的小鼠 T 细胞相比，表达 TCR 和 Fas-4-1BB IFP 的 T 细胞在荷瘤小鼠的 TME 中更优先持续存在，T 细胞增殖和存活得到改善。此外，与仅表达 TCR 的 T 细胞相比，TCR/IFP T 细胞显著延长了荷瘤小鼠的存活时间。与仅表达 TCR 的细胞相比，表达 TCR 和 Fas-4-1BB IFP 的人 T 细胞表现出增强的功能活性和活力。
由于许多卵巢肿瘤过度表达 FasL，因此可以使用将 Fas 介导的死亡信号转化为促生存和增殖信号的 IFP 来增强用于患者的工程化过继 T 细胞治疗。
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