Neurological Surgery 脳神経外科49巻3号

2021年05月発行

特集 グリオーマ—現在の常識と近未来のスタンダード Ⅳグリオーマ治療法update

—悪性神経膠腫に対するVEGFを中心とした—血管新生標的療法および免疫療法の効用と展望

著者： 石川栄一¹ 宮崎翼²³

所属機関： ¹筑波大学医学医療系脳神経外科 ²筑波大学大学院人間総合科学研究科脳神経外科学 ³セルメディシン株式会社

ページ範囲：P.597 - P.607

Point
・悪性神経膠腫において，豊富な新生血管を標的とした抗VEGF抗体療法は患者の急激な病態悪化の制御に有用である．
・VEGFおよびそのシグナル経路の関連分子は免疫抑制微小環境の形成を促進しており，これらの分子を標的とする療法はこの環境改善にも寄与すると期待される．
・悪性神経膠腫においても免疫チェックポイント阻害薬は最も注目される療法であるが，本療法自体は微小環境における免疫応答のブレーキの一部を解除する役割のため，アクセルすなわち獲得免疫を刺激するような免疫療法との併用，抗VEGF抗体療法や腫瘍関連マクロファージ（TAM）阻害薬など免疫抑制環境を抑制する治療法との併用が望ましい．

参考文献

1）Goldmann E：The growth of malignant disease in man and the lower animals, with special reference to the vascular system. Proc R Soc Med 1（Surg Sect）：1-13, 1908

2）Greenblatt M, Shubi P：Tumor angiogenesis：transfilter diffusion studies in the hamster by the transparent chamber technique. J Natl Cancer Inst 41：111-124, 1968

3）Senger DR, et al：Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219（4587）：983-985, 1983

4）Leung DW, et al：Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246（4935）：1306-1309, 1989

5）Keck PJ, et al：Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246（4935）：1309-1312, 1989

6）McLaren J, et al：Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest 98：482-489, 1996

7）Ferrara N, et al：The biology of VEGF and its receptors. Nat Med 9：669-676, 2003

8）Plate KH, et al：Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359（6398）：845-848, 1992

9）Fukumura D, et al：Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer Res 61：6020-6024, 2001

10）Chinot OL, et al：Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370：709-722, 2014

11）Gilbert MR, et al：A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370：699-708, 2014

12）Nagane M, et al：Phase Ⅱ study of single-agent bevacizumab in Japanese patients with recurrent malignant glioma. Jpn J Clin Oncol 42：887-895, 2012

13）Levin VA, et al：Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79：1487-1495, 2011

14）Taal W, et al：Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma（BELOB trial）：a randomised controlled phase 2 trial. Lancet Oncol 15：943-953, 2014

15）Wick W, et al：Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med 377：1954-1963, 2017

16）van den Bent MJ, et al：Bevacizumab and temozolomide in patients with first recurrence of WHO grade Ⅱ and Ⅲ glioma, without 1p/19q co-deletion（TAVAREC）：a randomised controlled phase 2 EORTC trial. Lancet Oncol 19：1170-1179, 2018

17）Montana V, Sontheimer H：Bradykinin promotes the chemotactic invasion of primary brain tumors. J Neurosci 31：4858-4867, 2011

18）Yadav VN, et al：CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis：a genetic knockdown study. Oncotarget 7：83701-83719, 2016

19）Uemae Y, et al：CXCL12 secreted from glioma stem cells regulates their proliferation. J Neurooncol 117：43-51, 2014

20）Kovalchuk B, et al：Nintedanib and a bi-specific anti-VEGF/Ang2 nanobody selectively prevent brain metastases of lung adenocarcinoma cells. Clin Exp Metastasis 37：637-648, 2020

21）Sharma I, et al：IL-8/CXCR1/2 signalling promotes tumor cell proliferation, invasion and vascular mimicry in glioblastoma. J Biomed Sci 25：62, 2018

22）Le Joncour V, et al：Vulnerability of invasive glioblastoma cells to lysosomal membrane destabilization. EMBO Mol Med 11：e9034, 2019

23）Auf G, et al：Inositol-requiring enzyme 1α is a key regulator of angiogenesis and invasion in malignant glioma. Proc Natl Acad Sci U S A 107：15553-15558, 2010

24）Krusche B, et al：EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells. Elife 5：e14845, 2016

25）Griveau A, et al：A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell 33：874-889.e7, 2018

26）Chen DS, Mellman I：Elements of cancer immunity and the cancer-immune set point. Nature 541（7637）：321-330, 2017

27）Miyazaki T, et al：Assessment of PD-1 positive cells on initial and secondary resected tumor specimens of newly diagnosed glioblastoma and its implications on patient outcome. J Neurooncol 133：277-285, 2017

28）Reardon DA, et al：Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma：the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol 6：1003-1010, 2020

29）Cloughesy TF, et al：Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 25：477-486, 2019

30）Zhao J, et al：Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat Med 25：462-469, 2019

31）Weller M, et al；ACT Ⅳ trial investigators：Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvⅢ-expressing glioblastoma（ACT Ⅳ）：a randomised, double-blind, international phase 3 trial. Lancet Oncol 18：1373-1385, 2017

32）Hashimoto N, et al：Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma：safety and impact on immunological response. Cancer Immunol Immunother 64：707-716, 2015

33）Akasaki Y, et al：Phase Ⅰ/Ⅱ trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma. Cancer Immunol Immunother 65：1499-1509, 2016

34）Johanns TM, et al：Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma. Oncoimmunology 8：e1561106, 2019

T-lymphocyte counts. CNS Oncol 7：CNS22, 2018

36）Ishikawa E, et al：Phase Ⅰ/Ⅱa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma. J Neurosurg 121：543-553, 2014

37）Akhavan D, et al：CAR T cells for brain tumors：lessons learned and road ahead. Immunol Rev 290：60-84, 2019

38）Huang H, et al：VEGF suppresses T-lymphocyte infiltration in the tumor microenvironment through inhibition of NF-κB-induced endothelial activation. FASEB J 29：227-238, 2015

39）Gabrilovich DI, et al：Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2：1096-1103, 1996

40）Huang Y, et al：Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73：2943-2948, 2013

41）Tamura R, et al：Bevacizumab for malignant gliomas：current indications, mechanisms of action and resistance, and markers of response. Brain Tumor Pathol 34：62-77, 2017

42）Tamura R, et al：The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment：perspectives for therapeutic implications. Med Oncol 37：2, 2019

T cells in tumors. J Exp Med 212：139-148, 2015

44）Tamura R, et al：Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab. Cancer Sci 110：499-508, 2019

45）Friebel E, et al：Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes. Cell 181：1626-1642.e20, 2020

46）Miyazaki T, et al：Therapeutic strategies for overcoming immunotherapy resistance mediated by immunosuppressive factors of the glioblastoma microenvironment. Cancers（Basel）12：1960, 2020

47）Kaneda MM, et al：PI3Kγ is a molecular switch that controls immune suppression. Nature 539（7629）：437-442, 2016

48）Takenaka MC, et al：Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39. Nat Neurosci 22：729-740, 2019

49）Pyonteck SM, et al：CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med 19：1264-1272, 2013

50）Miyazaki T, et al：Infiltration of CD163-positive macrophages in glioma tissues after treatment with anti-PD-L1 antibody and role of PI3Kγ inhibitor as a combination therapy with anti-PD-L1 antibody in in vivo model using temozolomide-resistant murine glioma-initiating cells. Brain Tumor Pathol 37：41-49, 2020

51）Ishikawa E, et al：Prospect of immunotherapy for glioblastoma：tumor vaccine, immune checkpoint inhibitors and combination therapy. Neurol Med Chir（Tokyo）57：321-330, 2017