Prognostic and Therapeutic Implications of IFNAR1 Signaling on CAR T Cell Therapy for Cancer

抗肿瘤细胞疗法（ACT）已经彻底改变了某些恶性肿瘤的治疗和反应 在用表达嵌合抗体受体（CAR）的T细胞治疗的难治性B细胞肿瘤中， 非常出色然而，即使在这些特别敏感的癌症中，ACT也不总是有疗效， 强调迫切需要创新的方法来改善这种强大的治疗方法。I型 通过I型干扰素受体（IFNAR）的干扰素（IFN）信号传导在激活中发挥关键作用， T细胞的分化和功能。重要的是，I型干扰素受体链亚基的降解 1（IFNAR1）在抗肿瘤T细胞中的表达有利于肿瘤进展，而其遗传或药理学（通过p38 抑制）稳定化改善了小鼠模型中的抗肿瘤T细胞活性。虽然啮齿类动物的研究 尽管对CAR T细胞的临床前研究有很多深入的了解，但它们无法准确预测临床安全性和有效性。然而，在这方面， 遗传上远系繁殖和免疫学上完整的犬癌症患者自发地发展肿瘤， 作为一个宝贵的临床前模型迅速获得牵引力。在令人兴奋的新的初步数据中，我们将CAR T 将用IFNAR 1稳定p38抑制剂ralimetinib处理的细胞移植到犬B细胞淋巴瘤患者中。 在治疗后，我们观察到与CAR T细胞介导的抗肿瘤活性相关的体征，这些体征在治疗后没有变化。 先前在用CAR T细胞治疗的犬患者中观察到。此外，在人类慢性 在淋巴细胞白血病患者中，活性I型IFN基因标记与改善的结果相关 CAR T细胞治疗后。总之，这些数据支持IFNAR1在细胞上的稳定化的假设。 CAR T细胞表面的修饰将提高其治疗B细胞恶性肿瘤的疗效。我们将 进行以下研究来验证这一点： 1.患有自发性弥漫性大B细胞淋巴瘤的犬癌症患者目前正在入组试验 试验将用于确定IFNAR1稳定的CART细胞的安全性和有效性。 2.将在体外和体内评价来自多个物种的CART细胞，以确定其机制 通过该方法，IFNAR1的遗传和药理学稳定增强了CART细胞的抗肿瘤活性。 3. IFNAR 1和下游信号在用于治疗的T细胞单采产物中的预后意义 将在患有B细胞恶性肿瘤的患者中评价制造的CAR T细胞和CAR T细胞本身。 我们预计IFNAR1稳定化将安全地增强CAR T细胞的活性。当做一个兽医 具有免疫学博士培训的肿瘤学家我有所需的知识和技能的坚实基础 进行这些研究。拟开展的应用CART细胞疗法治疗 B细胞瘤形成将在Ors的专家指导下进行。Fuchs和Mason，并代表了一个领域， 宾夕法尼亚大学在全球享有盛誉。

Adoptive cellular therapy (ACT) has revolutionized the treatment of certain malignancies and responses in refractory B cell tumors treated with chimeric antibody receptor (CAR)-expressing T cells have been remarkable. However, ACT is not consistently curative even in these particularly responsive cancers, highlighting the critical need for innovative approaches to improve this powerful therapeutic approach. Type I interferon (IFN) signaling through the type I interferon receptor (IFNAR) plays a key role in the activation, differentiation and function of T cells. Importantly, degradation of the type I interferon receptor chain subunit 1 (IFNAR1) in anti-tumor T cells favors tumor progression whereas its genetic or pharmacologic (by p38 inhibition) stabilization improves anti-tumor T cell activity in mouse models. While rodent studies have yielded much preclinical insight into CAR T cells, they fail to accurately predict clinical safety and efficacy. However, genetically outbred and immunologically intact canine cancer patients that develop tumors spontaneously are rapidly gaining traction as an invaluable preclinical model. In exciting new preliminary data, we infused CAR T cells treated with the IFNAR1 stabilizing p38 inhibitor ralimetinib into a canine B cell lymphoma patient. Following treatment, we observed signs associated with CAR T cell mediated anti-tumor activity that have not been previously observed in canine patients treated with CAR T cells. Furthermore, in human chronic lymphocytic leukemia patients, an active type I IFN gene signature was associated with improved outcomes following CAR T cell therapy. Together, these data support the hypothesis that stabilization of IFNAR1 on the surface of CAR T cells will improve their therapeutic efficacy for the treatment of B cell malignancies. We will perform the following studies to test this: 1. Canine cancer patients with spontaneous diffuse large B cell lymphoma currently being enrolled in a pilot trial will be used to determine the safety and efficacy of IFNAR1-stabilized CART cells. 2. CART cells derived from multiple species will be evaluated in vitro and in vivo to ascertain the mechanism by which genetic and pharmacologic IFNAR1 stabilization enhances the anti-tumor activity of CART cells. 3. The prognostic significance of IFNAR1 and downstream signaling in T cell apheresis products used to manufacture CAR T cells and CAR T cells themselves will be evaluated in patients with B cell malignancies. We anticipate that IFNAR1 stabilization will safely enhance the activity of CAR T cells. As a veterinary oncologist with doctoral training in immunology I have a solid foundation of the knowledge and skillsets required to undertake these studies. The proposed research on the application of CART cell therapy for the treatment of B cell neoplasia will be performed under the expert guidance of Ors. Fuchs and Mason and represents a field for which the University of Pennsylvania is globally renowned.