Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice.
Anti-VEGF therapy improves EGFR-vIII-CAR-T cell delivery and efficacy in syngeneic glioblastoma models in mice.
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DOI：
10.1136/jitc-2022-005583
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发表时间：
2023-03
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
嵌合抗原受体（CAR）-T细胞已经彻底改变了多种类型血液恶性肿瘤的治疗，但在胶质母细胞瘤（GBM）或其他实体瘤患者中显示出有限的疗效。这可能在很大程度上是由于免疫抑制性肿瘤微环境（TME）损害了CAR-T细胞的递送和抗肿瘤活性。我们先前表明，阻断血管内皮生长因子（VEGF）信号传导可以使鼠和人肿瘤（包括GBM、乳腺癌、肝癌和直肠癌）中的肿瘤血管正常化。此外，我们证明了血管正常化可以改善小鼠乳腺癌模型中CD 8 + T细胞的递送和免疫治疗的功效。事实上，在过去的3年里，美国FDA（食品和药物管理局）已经批准了7种不同的抗VEGF药物和免疫检查点阻断剂的组合用于肝癌，肾癌，肺癌和子宫内膜癌。在这里，我们测试了抗VEGF治疗可以改善CAR-T细胞在携带原位GBM肿瘤的免疫活性小鼠中的递送和功效的假设。我们设计了两个同基因小鼠GBM细胞系（CT 2A和GSC 005）来表达EGFRvIII-人类GBM中最常见的新抗原之一-和CAR T细胞来识别EGFRvIII。我们发现，与单独的EGFRvIII-CAR-T细胞治疗相比，用抗小鼠VEGF抗体（B20）治疗改善了CAR-T细胞在整个GBM TME中的浸润和分布，延迟了肿瘤生长，并延长了携带GBM的小鼠的存活期。我们的研究结果提供了令人信服的数据和理由，用于GBM患者的抗VEGF药物与CAR T细胞的临床评价。
Chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of multiple types of hematological malignancies, but have shown limited efficacy in patients with glioblastoma (GBM) or other solid tumors. This may be largely due to the immunosuppressive tumor microenvironment (TME) that compromises CAR-T cells’ delivery and antitumor activity. We previously showed that blocking vascular endothelial growth factor (VEGF) signaling can normalize tumor vessels in murine and human tumors, including GBM, breast, liver, and rectal carcinomas. Moreover, we demonstrated that vascular normalization can improve the delivery of CD8+ T cells and the efficacy of immunotherapy in breast cancer models in mice. In fact, the US FDA (Food and drug administration) has approved seven different combinations of anti-VEGF drugs and immune checkpoint blockers for liver, kidney, lung and endometrial cancers in the past 3 years. Here, we tested the hypothesis that anti-VEGF therapy can improve the delivery and efficacy of CAR-T cells in immunocompetent mice bearing orthotopic GBM tumors. We engineered two syngeneic mouse GBM cell lines (CT2A and GSC005) to express EGFRvIII—one of the most common neoantigens in human GBM—and CAR T cells to recognize EGFRvIII. We found that treatment with the anti-mouse VEGF antibody (B20) improved CAR-T cell infiltration and distribution throughout the GBM TME, delayed tumor growth, and prolonged survival of GBM-bearing mice compared with EGFRvIII-CAR-T cell therapy alone. Our findings provide compelling data and a rationale for clinical evaluation of anti-VEGF agents with CAR T cells for GBM patients.
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影响因子：
11.2
作者：
Shrimali RK;Yu Z;Theoret MR;Chinnasamy D;Restifo NP;Rosenberg SA
通讯作者：
Rosenberg SA
巨噬细胞极化有助于通过免疫疗法和免疫检查点阻断来消除胶质母细胞瘤。
影响因子：
50.3
作者：
Saha D;Martuza RL;Rabkin SD
通讯作者：
Rabkin SD
影响因子：
50.3
作者：
Jain RK
通讯作者：
Jain RK
影响因子：
28.2
作者：
通讯作者：
--
影响因子：
64.5
作者：
Good CR;Aznar MA;Kuramitsu S;Samareh P;Agarwal S;Donahue G;Ishiyama K;Wellhausen N;Rennels AK;Ma Y;Tian L;Guedan S;Alexander KA;Zhang Z;Rommel PC;Singh N;Glastad KM;Richardson MW;Watanabe K;Tanyi JL;O'Hara MH;Ruella M;Lacey SF;Moon EK;Schuster SJ;Albelda SM;Lanier LL;Young RM;Berger SL;June CH
通讯作者：
June CH