Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model
Bevacizumab-mediated tumor vasculature remodelling improves tumor infiltration and antitumor efficacy of GD2-CAR T cells in a human neuroblastoma preclinical model
复制标题
DOI：
10.1080/2162402x.2017.1378843
复制
发表时间：
2018-01-01
期刊：
影响因子：
7.2
通讯作者：
Prigione, Ignazia
中科院分区：
文献类型：
--
作者：
Bocca, Paola;Di Carlo, Emma;Prigione, Ignazia
GD 2重定向的嵌合抗原受体（CAR）T淋巴细胞代表了神经母细胞瘤（NB）免疫治疗的一种有前途的治疗选择。然而，尽管在一些血液恶性肿瘤中观察到令人鼓舞的治疗效果，但CAR T细胞免疫疗法在实体瘤中的临床结果仍然是适度的。肿瘤驱动的新血管生成支持影响治疗反应的免疫抑制微环境，并且适合于用抗血管生成药物靶向。后一种药物通过瞬时重编程肿瘤血管系统促进淋巴细胞肿瘤浸润，并且可能代表与CAR T细胞免疫疗法的有效组合方法。鉴于这些考虑，我们研究了GD 2-CAR T细胞与贝伐单抗（BEV）组合在人NB的原位异种移植模型中的抗NB活性。肿瘤植入后两周，小鼠通过单次静脉内施用接受BEV或GD 2-CAR T细胞或两者。GD 2-CAR T细胞仅在与BEV组合时发挥显著的抗NB活性，即使在测试的最低浓度下，其本身不抑制肿瘤生长。当与BEV组合时，GD 2-CAR T细胞大量浸润肿瘤块，在那里它们产生干扰素-γ（IFN-γ），这反过来诱导NB细胞表达CXCL 10。IFN-γ和可能的其他细胞因子上调了NB细胞的PD-L1表达，而肿瘤浸润性GD 2-CAR T细胞表达PD-1。因此，PD-1/PD-L1轴可以限制GD 2-CAR T细胞/BEV联合的抗肿瘤功效。这项研究为在招募NB患者的临床试验中测试GD 2-CAR T细胞与BEV的组合提供了强有力的理论基础。PD-L1沉默或阻断策略可进一步增强此类组合的功效。
GD2-redirected chimeric antigen receptor (CAR) T lymphocytes represent a promising therapeutic option for immunotherapy of neuroblastoma (NB). However, despite the encouraging therapeutic effects observed in some hematological malignancies, clinical results of CAR T cell immunotherapy in solid tumors are still modest.Tumor driven neo-angiogenesis supports an immunosuppressive microenvironment that influences treatment responses and is amenable to targeting with antiangiogenic drugs. The latter agents promote lymphocyte tumor infiltration by transiently reprogramming tumor vasculature, and may represent a valid combinatorial approach with CAR T cell immunotherapy.In light of these considerations, we investigated the anti-NB activity of GD2-CAR T cells combined with bevacizumab (BEV) in an orthotopic xenograft model of human NB. Two weeks after tumor implantation, mice received BEV or GD2-CAR T cells or both by single intravenous administration. GD2-CAR T cells exerted a significant anti-NB activity only in combination with BEV, even at the lowest concentration tested, which per se did not inhibit tumor growth. When combined with BEV, GD2-CAR T cells massively infiltrated tumor mass where they produced interferon-gamma (IFN-gamma), which, in turn, induced expression of CXCL10 by NB cells. IFN-gamma, and possibly other cytokines, upregulated NB cell expression of PD-L1, while tumor infiltrating GD2-CAR T cells expressed PD-1. Thus, the PD-1/PD-L1 axis can limit the anti-tumor efficacy of the GD2-CAR T cell/BEV association.This study provides a strong rationale for testing the combination of GD2-CAR T cells with BEV in a clinical trial enrolling NB patients. PD-L1 silencing or blocking strategies may further enhance the efficacy of such combination.