肿瘤细胞治疗研究
英文原题：Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy.
免疫刺激性 LOAd703 疗法是一种有前景的策略，可诱导抗淋巴瘤免疫应答，并改善 CAR-T 细胞疗法在 B 细胞淋巴瘤中的疗效。
对 B 细胞淋巴瘤患者预先实施携带免疫刺激基因的溶瘤病毒治疗，可能使肿瘤病灶为后续嵌合抗原受体（CAR）T 细胞治疗做好准备，增强 CAR-T 功能并可能提高缓解率。LOAd703（delolimogene mupadenorepvec）是一种溶瘤腺病毒（血清型 5/35），编码 CD40L 和 4-1BBL 转基因，可激活抗原呈递细胞和 T 细胞。许多腺病毒未能在 B 细胞恶性肿瘤中显示疗效，而 LOAd703 经 CD46 感染细胞，因此可感染 B 细胞。本研究在人体 B 细胞淋巴瘤模型中评估 LOAd703 单药及其与 CAR-T 联用的治疗潜力。LOAd703 可感染并在多种 B 细胞淋巴瘤细胞系中复制，并整体增强免疫原性特征，上调共刺激分子 CD80、CD86、CD70、MHC 分子、死亡受体 Fas 和黏附分子 ICAM-1。经 LOAd703 感染的淋巴瘤细胞刺激后，CAR-T 功能增强，表现为 IFN-γ 和颗粒酶 B 释放增加、脱颗粒标志物 CD107a 表达增加、体外 PD-1⁺TIM-3⁺ CAR-T 细胞减少，并在体外及体内异种移植模型中增强淋巴瘤细胞杀伤。此外，LOAd703 感染的淋巴瘤细胞上调多种对免疫细胞归巢重要的趋化因子（CXCL10、CCL17、CCL22、CCL3、CCL4），促进 CAR-T 细胞迁移。综上，免疫刺激性 LOAd703 治疗有望诱导抗淋巴瘤免疫反应并改善 B 细胞淋巴瘤 CAR-T 治疗。
Pretreatment of B-cell lymphoma patients with immunostimulatory gene therapy using armed oncolytic viruses may prime tumor lesions for subsequent chimeric antigen receptor (CAR) T-cell therapy, thereby enhancing CAR T-cell functionality and possibly increasing response rates in patients. LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus (serotype 5/35) that encodes for the transgenes CD40L and 4-1BBL, which activate both antigen-presenting cells and T cells. Many adenoviruses failed to demonstrate efficacy in B-cell malignancies, but LOAd703 infect cells via CD46, which enables B cell infection. Herein, we investigated the therapeutic potential of LOAd703 in human B-cell lymphoma models, alone or in combination with CAR T-cell therapy. LOAd703 could infect and replicate in B-cell lymphoma cell lines (BC-3, Karpas422, Daudi, DG-75, U-698) and induced an overall enhanced immunogenic profile with upregulation of co-stimulatory molecules CD80, CD86, CD70, MHC molecules, death receptor Fas and adhesion molecule ICAM-1. Further, CAR T-cell functionality was boosted by stimulation with lymphoma cells infected with LOAd703. This was demonstrated by an augmented release of IFN- and granzyme B, increased expression of the degranulation marker CD107a, fewer PD-1 + TIM-3+ CAR T cells in vitro and enhanced lymphoma cell killing both in in vitro and in vivo xenograft models. In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.
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