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Research Progress of Dual-target Blocking Therapy of PD-L1 and VEGF |
ZHAO Meng-ze1,LI Feng-zhi2,WANG Peng-yin2,LI Jian2,XU Han-mei1,*() |
1 Life Science and Technology College, China Pharmaceutical University, Nanjing 211100, China 2 Tasly Biopharmaceuticals Co., Ltd., Shanghai 201203, China |
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Abstract Immune checkpoint inhibitor (immune checkpoint inhibitors,ICIs) activates host anti-tumor immune response by blocking negative regulatory immune signals. Clinical trials have shown that the treatment of ICIs can significantly cause tumor regression in some patients with advanced cancer. In clinical practice, one of the main problems in ICIs treatment is the low response rate. Although various predictive biomarkers such as PD-L1 expression, mismatch repair deficiency, and tumor-infiltrating lymphocyte status have been used to screen patients who respond to treatment, the resistance of ICIs monotherapy still exists. Recent studies have shown that combined anti-VEGF therapy can reduce the resistance of ICIs. VEGF can inhibit angiogenesis necessary for tumor growth and metastasis, while it can reprogram the tumor immune microenvironment and reduce the resistance of ICIs. Many clinical trials have been carried out for the combination therapy of these two targets, and exciting results have been obtained. The mechanism of action of anti-PD-L1 combined with anti-VEGF therapy and the clinical studies of PD-L1/VEGF combined blocking therapy were reviewed and summarized.
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Received: 10 May 2021
Published: 30 September 2021
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Corresponding Authors:
Han-mei XU
E-mail: 1037714870@qq.com
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|
[1] |
Lee A, Sun S, Sandler A, et al. Recent progress in therapeutic antibodies for cancer immunotherapy. Current Opinion in Chemical Biology, 2018, 44:56-65.
doi: 10.1016/j.cbpa.2018.05.006
|
|
|
[2] |
Ramjiawan R R, Griffioen A W, Dan G D D. Anti-angiogenesis for cancer revisited: is there a role for combinations with immunotherapy? Angiogenesis, 2017, 20(2):185-204.
doi: 10.1007/s10456-017-9552-y
pmid: 28361267
|
|
|
[3] |
万颖寒, 慈磊, 王珏. PD-L1基因敲除小鼠构建及初步表型验证. 中国生物工程杂志, 2019, 39(12):42-49.
|
|
|
[3] |
Wan Y H, Ci L, Wang J. Construction and preliminary phenotypic verification of PD-L1 knockout mice. China Biotechnology, 2019, 39(12):42-49.
|
|
|
[4] |
Duraiswamy J, Kaluza K M, Freeman G J, et al. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Research, 2013, 73(12):3591-3603.
doi: 10.1158/0008-5472.CAN-12-4100
pmid: 23633484
|
|
|
[5] |
Curiel T J, Coukos G, Zou L H, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Medicine, 2004, 10(9):942-949.
pmid: 15322536
|
|
|
[6] |
Falcon B L, O'Clair B, McClure D, et al. Development and characterization of a high-throughput in vitro cord formation model insensitive to VEGF inhibition. Journal of Hematology & Oncology, 2013, 6:31.
|
|
|
[7] |
Rohani N, Hao L L, Alexis M S, et al. Acidification of tumor at stromal boundaries drives transcriptome alterations associated with aggressive phenotypes. Cancer Research, 2019, 79(8):1952-1966.
doi: 10.1158/0008-5472.CAN-18-1604
|
|
|
[8] |
Leung D W, Cachianes G, Kuang W J, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science, 1989, 246(4935):1306-1309.
pmid: 2479986
|
|
|
[9] |
Bouzin C, Brouet A, De Vriese J, et al. Effects of vascular endothelial growth factor on the lymphocyte-endothelium interactions: identification of caveolin-1 and nitric oxide as control points of endothelial cell anergy. Journal of Immunology, 2007, 178(3):1505-1511.
doi: 10.4049/jimmunol.178.3.1505
|
|
|
[10] |
Borgström P, Hughes G K, Hansell P, et al. Leukocyte adhesion in angiogenic blood vessels. Role of E-selectin, P-selectin, and beta2 integrin in lymphotoxin-mediated leukocyte recruitment in tumor microvessels. Journal of Clinical Investigation, 1997, 99(9):2246-2253.
pmid: 9151798
|
|
|
[11] |
Krock B L, Skuli N, Simon M C. Hypoxia-induced angiogenesis: good and evil. Genes & Cancer, 2011, 2(12):1117-1133.
|
|
|
[12] |
Tian L, Goldstein A, Wang H, et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature, 2017, 544(7649):250-254.
doi: 10.1038/nature21724
|
|
|
[13] |
Yasuda S, Sho M, Yamato I, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clinical and Experimental Immunology, 2013, 172(3):500-506.
doi: 10.1111/cei.12069
pmid: 23600839
|
|
|
[14] |
Allen E, Jabouille A, Rivera L B, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Science Translational Medicine, 2017, 9(385): eaak9679. DOI: 10.1126/scitranslmed.aak9679.
doi: 10.1126/scitranslmed.aak9679
|
|
|
[15] |
Wallin J J, Bendell J C, Funke R, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nature Communications, 2016, 7:12624.
doi: 10.1038/ncomms12624
|
|
|
[16] |
Lai Y S, Wahyuningtyas R, Aui S P, et al. Autocrine VEGF signalling on M2 macrophages regulates PD-L1 expression for immunomodulation of T cells. Journal of Cellular and Molecular Medicine, 2019, 23(2):1257-1267.
|
|
|
[17] |
Dong H D, Zhu G F, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine, 1999, 5(12):1365-1369.
pmid: 10581077
|
|
|
[18] |
Herbst R S, Soria J C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature, 2014, 515(7528):563-567.
doi: 10.1038/nature14011
|
|
|
[19] |
Alsaab H O, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcome. Frontiers in Pharmacology, 2017, 8:561.
doi: 10.3389/fphar.2017.00561
|
|
|
[20] |
Ostrand-Rosenberg S, Horn L A, Haile S T. The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. The Journal of Immunology, 2014, 193(8):3835-3841.
doi: 10.4049/jimmunol.1401572
|
|
|
[21] |
Dong H D, Strome S E, Salomao D R, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature Medicine, 2002, 8(8):793-800.
doi: 10.1038/nm730
|
|
|
[22] |
Hui E F, Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science, 2017, 355(6332):1428-1433.
doi: 10.1126/science.aaf1292
|
|
|
[23] |
Amarnath S, Mangus C W, Wang J C M, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Science Translational Medicine, 2011, 3(111): 111ra120.
|
|
|
[24] |
Azuma T, Yao S, Zhu G F, et al. B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood, 2008, 111(7):3635-3643.
doi: 10.1182/blood-2007-11-123141
|
|
|
[25] |
Black M, Barsoum I B, Truesdell P, et al. Activation of the PD-1/PD-L1 immune checkpoint confers tumor cell chemoresistance associated with increased metastasis. Oncotarget, 2016, 7(9):10557-10567.
doi: 10.18632/oncotarget.v7i9
|
|
|
[26] |
Ishibashi M, Tamura H, Sunakawa M, et al. Myeloma drug resistance induced by binding of myeloma B7-H1 (PD-L1) to PD-1. Cancer Immunology Research, 2016, 4(9):779-788.
doi: 10.1158/2326-6066.CIR-15-0296
pmid: 27440711
|
|
|
[27] |
Hattori K, Heissig B, Wu Y, et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1 + stem cells from bone-marrow microenvironment. Nature Medicine, 2002, 8(8):841-849.
pmid: 12091880
|
|
|
[28] |
Snuderl M, Batista A, Kirkpatrick N D, et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell, 2013, 152(5):1065-1076.
doi: 10.1016/j.cell.2013.01.036
pmid: 23452854
|
|
|
[29] |
Jain R K, Xu L. αPlGF: a new kid on the antiangiogenesis block. Cell, 2007, 131(3):443-445.
doi: 10.1016/j.cell.2007.10.023
|
|
|
[30] |
Goel H L, Mercurio A M. VEGF targets the tumour cell. Nature Reviews Cancer, 2013, 13(12):871-882.
doi: 10.1038/nrc3627
|
|
|
[31] |
Allen E, Jabouille A, Rivera L B, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Science Translational Medicine, 2017, 9(385): eaak9679. DOI: 10.1126/scitranslmed.aak9679.
doi: 10.1126/scitranslmed.aak9679
|
|
|
[32] |
Davis T A, Saini A A, Blair P J, et al. Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to dendritic cells: evidence for protein kinase C-mediated signaling. Journal of Immunology (Baltimore, Md: 1950), 1998, 160(8):3689-3697.
|
|
|
[33] |
Caux C, Dezutter-Dambuyant C, Schmitt D, et al. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature, 1992, 360(6401):258-261.
doi: 10.1038/360258a0
|
|
|
[34] |
Gabrilovich D I, Chen H L, Girgis K R, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nature Medicine, 1996, 2(10):1096-1103.
pmid: 8837607
|
|
|
[35] |
Menetrier-Caux C, Montmain G, Dieu M C, et al. Inhibition of the differentiation of dendritic cells from CD34+ progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood, 1998, 92(12):4778-4791.
pmid: 9845545
|
|
|
[36] |
Curiel T J, Wei S, Dong H D, et al. Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nature Medicine, 2003, 9(5):562-567.
pmid: 12704383
|
|
|
[37] |
Wu X Q, Giobbie-Hurder A, Liao X Y, et al. Angiopoietin-2 as a biomarker and target for immune checkpoint therapy. Cancer Immunology Research, 2017, 5(1):17-28.
doi: 10.1158/2326-6066.CIR-16-0206
|
|
|
[38] |
Kuang D M, Zhao Q Y, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. Journal of Experimental Medicine, 2009, 206(6):1327-1337.
doi: 10.1084/jem.20082173
|
|
|
[39] |
Adams S, Diamond J R, Hamilton E, et al. Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up: a phase 1b clinical trial. JAMA Oncology, 2019, 5(3):334-342.
doi: 10.1001/jamaoncol.2018.5152
|
|
|
[40] |
Rini B I, Powles T, Atkins M B, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. The Lancet, 2019, 393(10189):2404-2415.
doi: 10.1016/S0140-6736(19)30723-8
|
|
|
[41] |
Grau J F, Farinas-Madrid L, Oaknin A. A randomized phase III trial of platinum chemotherapy plus paclitaxel with bevacizumab and atezolizumab versus platinum chemotherapy plus paclitaxel and bevacizumab in metastatic (stage IVB), persistent, or recurrent carcinoma of the cervix: the BEATcc study (ENGOT-Cx10/GEICO 68-C/JGOG1084/GOG-3030). International Journal of Gynecologic Cancer, 2020, 30(1):139-143.
doi: 10.1136/ijgc-2019-000880
|
|
|
[42] |
Atkins M B, Rini B I, Motzer R J, et al. Patient-reported outcomes from the phase III randomized IMmotion151 trial: atezolizumab + bevacizumab versus sunitinib in treatment-Naïve metastatic renal cell carcinoma. Clinical Cancer Research, 2020, 26(11):2506-2514.
|
|
|
[43] |
Socinski M A, Jotte R M, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. The New England Journal of Medicine, 2018, 378(24):2288-2301.
doi: 10.1056/NEJMoa1716948
pmid: 29863955
|
|
|
[44] |
Harter P, Pautier P, Van Nieuwenhuysen E, et al. Atezolizumab in combination with bevacizumab and chemotherapy versus bevacizumab and chemotherapy in recurrent ovarian cancer - a randomized phase III trial (AGO-OVAR 2.29/ENGOT-ov34). International Journal of Gynecological Cancer, 2020, 30(12):1997-2001.
doi: 10.1136/ijgc-2020-001572
|
|
|
[45] |
Hack S P, Spahn J, Chen M S, et al. IMbrave 050: a Phase III trial of atezolizumab plus bevacizumab in high-risk hepatocellular carcinoma after curative resection or ablation. Future Oncology (London, England), 2020, 16(15):975-989.
doi: 10.2217/fon-2020-0162
|
|
|
[46] |
Finn R S, Qin S K, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. The New England Journal of Medicine, 2020, 382(20):1894-1905.
doi: 10.1056/NEJMoa1915745
|
|
|
[47] |
Moore K N, Pignata S. Trials in progress: IMagyn050/GOG 3015/ENGOT-OV39. A Phase III, multicenter, randomized study of atezolizumab versus placebo administered in combination with paclitaxel, carboplatin, and bevacizumab to patients with newly-diagnosed stage III or stage IV ovarian, fallopian tube, or primary peritoneal cancer. International Journal of Gynecologic Cancer, 2019, 29(2):430-433.
doi: 10.1136/ijgc-2018-000071
|
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