Enhancing cancer immunotherapy using antiangiogenics: Opportunities and challenges

Nature Reviews Clinical Oncology

Volumn 15, Issue 5, 2018, Pages 325-340

  Fukumura, Dai ^a   Kloepper, Jonas ^b   Amoozgar, Zohreh ^a   Duda, Dan G ^a   Jain, Rakesh K ^a  

^a MASSACHUSETTS GENERAL HOSPITAL   (United States)

^b LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

AFLIBERCEPT; ANGIOGENESIS INHIBITOR; APATINIB; BEVACIZUMAB; CARBOPLATIN; CVX 060; FLUOROURACIL; FOLINIC ACID; IPILIMUMAB; IRINOTECAN; MONOCLONAL ANTIBODY DC101; NINTEDANIB; ORANTINIB; PACLITAXEL; REGORAFENIB; SORAFENIB; SUNITINIB; TREBANANIB; UNCLASSIFIED DRUG; VANUCIZUMAB; C11ORF2 PROTEIN, HUMAN; VASCULOTROPIN A; VEGFA PROTEIN, HUMAN; VESICULAR TRANSPORT PROTEIN;

ADVANCED CANCER; ANGIOGENESIS; BRAIN METASTASIS; CANCER GROWTH; CANCER IMMUNOTHERAPY; CANCER INCIDENCE; CANCER RECURRENCE; CANCER RESISTANCE; CARCINOGENESIS; CHEMORADIOTHERAPY; GLIOBLASTOMA; HUMAN; HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 POSITIVE BREAST CANCER; IMMUNOSUPPRESSIVE TREATMENT; LIVER CELL CARCINOMA; METASTATIC COLORECTAL CANCER; METASTATIC MELANOMA; NON SMALL CELL LUNG CANCER; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OVERALL SURVIVAL; PANCREAS CANCER; PRACTICE GUIDELINE; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; RENAL CELL CARCINOMA; REVIEW; RISK FACTOR; TUMOR ESCAPE; TUMOR MICROENVIRONMENT; UROGENITAL TRACT TUMOR; DRUG EFFECT; IMMUNOLOGY; IMMUNOTHERAPY; NEOPLASM; NEOVASCULARIZATION (PATHOLOGY); TRENDS;

ANGIOGENESIS INHIBITORS; HUMANS; IMMUNOTHERAPY; NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; TUMOR MICROENVIRONMENT; VASCULAR ENDOTHELIAL GROWTH FACTOR A; VESICULAR TRANSPORT PROTEINS;

EID: 85044610191     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2018.29     Document Type: Review

References (189)

1. Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480-489 (2011).
2. Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275-287 (2016).
3. Broderick, J. M. FDA approves pembrolizumab for microsatellite instability-high and mismatch repair deficient cancers. OncLive http://www. onclive. com/ web-exclusives/fda-approves-pembrolizumab-for-microsatellite-instabilityhigh-and-mismatch-repair-deficient-cancers (2017).
4. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321-330 (2017).
5. Nishino, M., Ramaiya, N. H., Hatabu, H. & Hodi, F. S. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol. 14, 655-668 (2017).
6. Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205-2218 (2013).
7. Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605-622 (2014).
8. Palucka, A. K. & Coussens, L. M. The basis of oncoimmunology. Cell 164, 1233-1247 (2016).
9. Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298-307 (2011).
10. Jain, R. K. et al. Leukocyte-endothelial adhesion and angiogenesis in tumors. Cancer Metastasis Rev. 15, 195-204 (1996).
11. Hoshida, T. et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: Therapeutic implications. Cancer Res. 66, 8065-8075 (2006).
12. Hiratsuka, S. et al. Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation. Proc. Natl Acad. Sci. USA 108, 3725-3730 (2011).
13. Chen, D. S. & Mellman, I. Oncology meets immunology: The cancer-immunity cycle. Immunity 39, 1-10 (2013).
14. Melder, R. J. et al. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat. Med. 2, 992-997 (1996).
15. Hendry, S. A. et al. The role of the tumor vasculature in the host immune response: implications for therapeutic strategies targeting the tumor microenvironment. Front. Immunol. 7, 621 (2016).
16. Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl Med. 9, eaak9670 (2017).
17. Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226-230 (2011).
18. Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31-44 (2011).
19. Chang, A. L. et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res. 76, 5671-5682 (2016).
20. Raman, D., Baugher, P. J., Thu, Y. M. & Richmond, A. Role of chemokines in tumor growth. Cancer Lett. 256, 137-165 (2007).
21. Huang, Y. H., Goel, S., Duda, D. G., Fukumura, D. & Jain, R. K. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 73, 2943-2948 (2013).
22. Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139-148 (2015).
23. Gabrilovich, D. et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92, 4150-4166 (1998).
24. Gabrilovich, D. I. et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 2, 1267 (1996).
25. Maenhout, S. K., Thielemans, K. & Aerts, J. L. Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells. Oncoimmunology 3, e956579 (2014).
26. Chaudhary, B. Khaled, Y. S., Ammori, B. J. & Elkord, E. Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol. Immunother. 63, 81-99 (2014).
27. Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561-17566 (2012).
28. Jain, R. K. Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307, 58-62 (2005).
29. Scholz, A. et al. Angiopoietin-2 promotes myeloid cell infiltration in a 2-integrin-dependent manner. Blood 118, 5050-5059 (2011).
30. Coffelt, S. B. et al. Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion. J. Immunol. 186, 4183-4190 (2011).
31. De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211-226 (2005).
32. Holopainen, T. et al. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis. J. Natl Cancer Inst. 104, 461-475 (2012).
33. Saharinen, P., Eklund, L. & Alitalo, K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat. Rev. Drug Discov. 16, 635-661 (2017).
34. Murdoch, C., Tazzyman, S., Webster, S. & Lewis, C. E. Expression of Tie-2 by human monocytes and their responses to angiopoietin-2. J. Immunol. 178, 7405-7411 (2007).
35. Kloepper, J. et al. Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc. Natl Acad. Sci. USA 113, 4476-4481 (2016).
36. Peterson, T. E. et al. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc. Natl Acad. Sci. USA 113, 4470-4475 (2016).
37. Rahbari, N. N. et al. Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci. Transl Med. 8, 360ra135 (2016).
38. Jung, K. et al. Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer. Proc. Natl Acad. Sci. USA 114, 10455-10460 (2017).
39. Jung, K. et al. Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy. J. Clin. Invest. 127, 3039-3051 (2017).
40. Chen, Y. et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology 61, 1591-1602 (2015).
41. Shojaei, F. et al. Tumor refractoriness to anti-VEGF treatment is mediated by CD11b+Gr1+ myeloid cells. Nat. Biotechnol. 25, 911-920 (2007).
42. Ilhan-Mutlu, A. et al. Bevacizumab prevents brain metastases formation in lung adenocarcinoma. Mol. Cancer Ther. 15, 702-710 (2016).
43. Kodack, D. P. et al. Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc. Natl Acad. Sci. USA 109, E3119-E3127 (2012).
44. Minami, T. et al. The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases. Cell Rep. 4, 709-723 (2013).
45. Keskin, D. et al. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep. 10, 1066-1081 (2015).
46. Engblom, C., Pfirschke, C. & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447-462 (2016).
47. Mazzieri, R. et al. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell 19, 512-526 (2011).
48. Park, J. S. et al. Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment. Cancer Cell 30, 953-967 (2016).
49. Goel, S. et al. Effects of vascular-endothelial protein tyrosine phosphatase inhibition on breast cancer vasculature and metastatic progression. J. Natl Cancer Inst. 105, 1188-1201 (2013).
50. Rigamonti, N. et al. Role of angiopoietin-2 in adaptive tumor resistance to VEGF signaling blockade. Cell Rep. 8, 696-706 (2014).
51. Imanishi, Y. et al. Angiopoietin-2 stimulates breast cancer metastasis through the 51 integrin-mediated pathway. Cancer Res. 67, 4254-4263 (2007).
52. Sfiligoi, C. et al. Angiopoietin-2 expression in breast cancer correlates with lymph node invasion and short survival. Int. J. Cancer 103, 466-474 (2003).
53. Srivastava, K. et al. Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26, 880-895 (2014).
54. Kienast, Y. et al. Ang-2-VEGF-A CrossMab, a novel bispecific human IgG1 antibody blocking VEGF-A and Ang-2 functions simultaneously, mediates potent antitumor, antiangiogenic, and antimetastatic efficacy. Clin. Cancer Res. 19, 6730-6740 (2013).
55. Pezzella, F. & Gatter, K. Non-angiogenic tumours unveil a new chapter in cancer biology. J. Pathol. 235, 381-383 (2015).
56. Griveau, A. et al. A glial signature and Wnt7 signaling regulate glioma-vascular interactions and tumor microenvironment. Cancer Cell (in press).
57. Eggermont, A. M. et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol. 16, 522-530 (2015).
58. Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919-1929 (2017).
59. Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345-1356 (2017).
60. Jain, R. K., Martin, J. D. & Stylianopoulos, T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 16, 321-346 (2014).
61. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nat. Med. 7, 987-989 (2001).
62. Winkler, F. et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6, 553-563 (2004).
63. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83-95 (2007).
64. Willett, C. G. et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10, 145-147 (2004).
65. Amin, A. et al. Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J. Immunother. Cancer 3, 14 (2015).
66. Chae, S. S. et al. Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin. Cancer Res. 16, 3618-3627 (2010).
67. Batchelor, T. T. et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28, 2817-2823 (2010).
68. Wu, X. et al. Angiopoietin-2 as a biomarker and target for immune checkpoint therapy. Cancer Immunol. Res. 5, 17-28 (2017).
69. Tong, R. T. et al. Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res. 64, 3731-3736 (2004).
70. Van der Veldt, A. A. et al. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21, 82-91 (2012).
71. Heist, R. S. et al. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer. Proc. Natl Acad. Sci. USA 112, 1547-1552 (2015).
72. Yang, M. H. et al. Direct regulation of TWIST by HIF-1 promotes metastasis. Nat. Cell Biol. 10, 295-305 (2008).
73. Conley, S. J. et al. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl Acad. Sci. USA 109, 2784-2789 (2012).
74. Levin, V. A. et al. Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J. Neurooncol 122, 145-150 (2015).
75. Levin, V. A., Chan, J., Datta, M., Yee, J. L. & Jain, R. K. Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab. J. Neurooncol. 134, 325-330 (2017).
76. Lorgis, V. et al. Relation between bevacizumab dose intensity and high-grade glioma survival: A retrospective study in two large cohorts. J. Neurooncol 107, 351-358 (2012).
77. Lu-Emerson, C. et al. Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J. Clin. Oncol. 33, 1197-1213 (2015).
78. Tolaney, S. M. et al. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. Proc. Natl Acad. Sci. USA 112, 14325-14330 (2015).
79. Hegde, P. S. et al. Predictive impact of circulating vascular endothelial growth factor in four phase III trials evaluating bevacizumab. Clin. Cancer Res. 19, 929-937 (2013).
80. Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. Rev. Cancer 8, 592-603 (2008).
81. Moon, W. S. et al. Overexpression of VEGF and angiopoietin 2: A key to high vascularity of hepatocellular carcinoma Mod. Pathol. 16, 552-557 (2003).
82. Wang, H. L. et al. Expression of angiopoietin-2 is correlated with vascularization and tumor size in human colorectal adenocarcinoma. Tohoku J. Exp. Med. 213, 33-40 (2007).
83. Peeters, M. et al. A randomised, double-blind, placebo-controlled phase 2 study of trebananib (AMG 386) in combination with FOLFIRI in patients with previously treated metastatic colorectal carcinoma. Br. J. Cancer 108, 503-511 (2013).
84. Eatock, M. M. et al. Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. Ann. Oncol. 24, 710-718 (2013).
85. Rini, B. et al. AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney: A randomized, double-blind, placebo-controlled, phase 2 study. Cancer 118, 6152-6161 (2012).
86. Monk, B. J. et al. Final results of a phase 3 study of trebananib plus weekly paclitaxel in recurrent ovarian cancer (TRINOVA-1): long-term survival, impact of ascites, and progression-free survival-2. Gynecol. Oncol. 143, 27-34 (2016).
87. Marth, C. et al. ENGOT-ov-6/TRINOVA-2: Randomised, double-blind, phase 3 study of pegylated liposomal doxorubicin plus trebananib or placebo in women with recurrent partially platinum-sensitive or resistant ovarian cancer. Eur. J. Cancer 70, 111-121 (2017).
88. Reardon, D. A. et al. Phase 2 and biomarker study of trebananib, an angiopoietin-blocking peptibody, with and without bevacizumab for patients with recurrent glioblastoma. Cancer https://doi. org/10. 1002/ cncr. 31172 (2017).
89. Liu, C., Workman, C. J. & Vignali, D. A. Targeting regulatory T cells in tumors. FEBS J. 283, 2731-2748 (2016).
90. Wu, F. T. et al. Efficacy of cotargeting angiopoietin-2 and the VEGF pathway in the adjuvant postsurgical setting for early breast, colorectal, and renal cancers. Cancer Res. 76, 6988-7000 (2016).
91. Charles, N. A., Holland, E. C., Gilbertson, R., Glass, R. & Kettenmann, H. The brain tumor microenvironment. Glia 59, 1169-1180 (2011).
92. Kabbinavar, F. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/ leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J. Clin. Oncol. 21, 60-65 (2003).
93. Willett, C. G. et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J. Clin. Oncol. 23, 8136-8139 (2005).
94. Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).
95. Pinter, M. & Jain, R. K. Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy. Sci. Transl Med. 9, eaan5616 (2017).
96. Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171-6180 (2010).
97. Palazon, A. et al. An HIF-1/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32, 669-683. e5 (2017).
98. Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl Med. 9, eaak9679 (2017).
99. Reardon, D. A. et al. OS10. 3 Randomized phase 3 study evaluating the efficacy and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: CheckMate 143 [abstract]. Neuro-Oncol. 19 (Suppl. 3), iii21 (2017).
100. Martins, I. Opdivo fails to demonstrate survival benefit in phase 3 brain cancer trial. Immuno-Oncology News https://immuno-oncologynews. com/2017/04/18/ opdivo-fails-demonstrate-increased-survival-glioblastoma-multiforme-phase-3-study/ (2017).
101. D'Souza, N. M. et al. Combining radiation therapy with immune checkpoint blockade for central nervous system malignancies. Front. Oncol. 6, 212 (2016).
102. Zeng, J. et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int. J. Radiat. Oncol. Biol. Phys. 86, 343-349 (2013).
103. Sampson, J. H. et al. A randomized, phase 3, open-label study of nivolumab versus temozolomide (TMZ) in combination with radiotherapy (RT) in adult patients (pts) with newly diagnosed, O-6-methylguanine DNA methyltransferase (MGMT)-unmethylated glioblastoma (GBM): CheckMate-498 [abstract]. J. Clin. Oncol. 34 (Suppl.), TPS2079 (2016).
104. Weller, M. et al. A randomized phase 2, single-blind study of temozolomide (TMZ) and radiotherapy (RT) combined with nivolumab or placebo (PBO) in newly diagnosed adult patients (pts) with tumor O6-methylguanine DNA methyltransferase (MGMT)-methylated glioblastoma (GBM)-CheckMate-548 [abstract]. Ann. Oncol. 27 (Suppl. 6), 356TiP (2016).
105. Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250-254 (2017).
106. De Palma, M. & Jain, R. K. CD4+ T cell activation and vascular normalization: Two sides of the same coin Immunity 46, 773-775 (2017).
107. Zhu, X. et al. Severe cerebral edema following nivolumab treatment for pediatric glioblastoma: case report. J. Neurosurg. Pediatr. 19, 249-253 (2017).
108. Qin, L. et al. Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma. Neuroradiology 59, 135-145 (2017).
109. Kamoun, W. S. et al. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. J. Clin. Oncol. 27, 2542-2552 (2009).
110. Salmon, H. et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J. Clin. Invest. 122, 899-910 (2012).
111. Eroglu, Z. et al. High response rate to PD-1 blockade in desmoplastic melanomas. Nature 553, 347-350 (2018).
112. Liu, H. et al. Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clin. Cancer Res. 23, 5959-5969 (2017).
113. Stylianopoulos, T. & Jain, R. K. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc. Natl Acad. Sci. USA 110, 18632-18637 (2013).
114. Fukumura, D., Incio, J., Shankaraiah, R. C. & Jain, R. K. Obesity and cancer: An angiogenic and inflammatory link. Microcirculation 23, 191-206 (2016).
115. Mirsoian, A. & Murphy, W. J. Obesity and cancer immunotherapy toxicity. Immunotherapy 7, 319-322 (2015).
116. Izumi, Y., Xu, L., di Tomaso, E., Fukumura, D. & Jain, R. K. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416, 279-280 (2002).
117. Mpekris, F., Baish, J. W., Stylianopoulos, T. & Jain, R. K. Role of vascular normalization in benefit from metronomic chemotherapy. Proc. Natl Acad. Sci. USA 114, 1994-1999 (2017).
118. Jain, R. K. et al. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: role of vascular endothelial growth factor. Proc. Natl Acad. Sci. USA 95, 10820-10825 (1998).
119. Goel, S. et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471-475 (2017).
120. Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: The promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566-581 (2016).
121. Garg, A. D. et al. Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell-driven rejection of high-grade glioma. Sci. Transl Med. 8, 328ra27 (2016).
122. Roy, S. & Trinchieri, G. Microbiota: A key orchestrator of cancer therapy. Nat. Rev. Cancer 17, 271-285 (2017).
123. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97-103 (2018).
124. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91-97 (2018).
125. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104-108 (2018).
126. Jain, R. K. et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat. Rev. Clin. Oncol. 6, 327-338 (2009).
127. Goel, S. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 91, 1071-1121 (2011).
128. Batchelor, T. T. et al. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J. Clin. Oncol. 31, 3212-3218 (2013).
129. Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709-722 (2014).
130. Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699-708 (2014).
131. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335-2342 (2004).
132. Sandler, A. et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N. Engl. J. Med. 355, 2542-2550 (2006).
133. Tewari, K. S. et al. Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med. 370, 734-743 (2014).
134. Zalcman, G. et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): A randomised, controlled, open-label, phase 3 trial. Lancet 387, 1405-1414 (2016).
135. Goel, H. L. & Mercurio, A. M. VEGF targets the tumour cell. Nat. Rev. Cancer 13, 871-882 (2013).
136. Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219, 983-985 (1983).
137. Leung, D. W., Cachianes, G., Kuang, W. J., Goeddel, D. V. & Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246, 1306-1309 (1989).
138. Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435-439 (1996).
139. Ferrara, N. et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380, 439-442 (1996).
140. Fukumura, D. et al. Tumor induction of VEGF promoter activity in stromal cells. Cell 94, 715-725 (1998).
141. Simon, T., Gagliano, T. & Giamas, G. Direct effects of anti-angiogenic therapies on tumor cells: VEGF signaling. Trends Mol. Med. 23, 282-292 (2017).
142. Hamrah, P., Zhang, Q. & Dana, M. R. Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in the conjunctiva-a potential link between lymphangiogenesis and leukocyte trafficking on the ocular surface. Adv. Exp. Med. Biol. 506, 851-860 (2002).
143. Sawano, A. et al. Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97, 785-791 (2001).
144. Basu, A. et al. Cutting edge: Vascular endothelial growth factor-mediated signaling in human CD45RO+ CD4+ T cells promotes Akt and ERK activation and costimulates IFN-production. J. Immunol. 184, 545-549 (2010).
145. Gavalas, N. G. et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br. J. Cancer 107, 1869-1875 (2012).
146. Wada, J. et al. The contribution of vascular endothelial growth factor to the induction of regulatory T-cells in malignant effusions. Anticancer Res. 29, 881-888 (2009).
147. Lichtenberger, B. M. et al. Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140, 268-279 (2010).
148. Sundberg, C., Kowanetz, M., Brown, L. F., Detmar, M. & Dvorak, H. F. Stable expression of angiopoietin-1 and other markers by cultured pericytes: phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in vivo. Lab. Invest. 82, 387-401 (2002).
149. Gamble, J. R. et al. Angiopoietin-1 is an antipermeability and anti-inflammatory agent in vitro and targets cell junctions. Circ. Res. 87, 603-607 (2000).
150. McGuire, P. G., Rangasamy, S., Maestas, J. & Das, A. Pericyte-derived sphingosine 1-phosphate induces the expression of adhesion proteins and modulates the retinal endothelial cell barrier. Arterioscler. Thromb. Vasc. Biol. 31, e107-e115 (2011).
151. Metheny-Barlow, L. J. & Li, L. Y. The enigmatic role of angiopoietin-1 in tumor angiogenesis. Cell Res. 13, 309-317 (2003).
152. Franco, M., Roswall, P., Cortez, E., Hanahan, D. & Pietras, K. Pericytes promote endothelial cell survival through induction of autocrine VEGF-A signaling and Bcl-w expression. Blood 118, 2906-2917 (2011).
153. Daly, C. et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1). Genes Dev. 18, 1060-1071 (2004).
154. Hori, S., Ohtsuki, S., Hosoya, K., Nakashima, E. & Terasaki, T. A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J. Neurochem. 89, 503-513 (2004).
155. Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat. Med. 6, 460-463 (2000).
156. Fiedler, U. et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 103, 4150-4156 (2004).
157. Ziegler, T. et al. Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis. J. Clin. Invest. 123, 3436-3445 (2013).
158. Pichiule, P., Chavez, J. C. & LaManna, J. C. Hypoxic regulation of angiopoietin-2 expression in endothelial cells. J. Biol. Chem. 279, 12171-12180 (2004).
159. Detjen, K. M. et al. Angiopoietin-2 promotes disease progression of neuroendocrine tumors. Clin. Cancer Res. 16, 420-429 (2010).
160. Sallinen, H. et al. Preoperative angiopoietin-2 serum levels: A marker of malignant potential in ovarian neoplasms and poor prognosis in epithelial ovarian cancer. Int. J. Gynecol. Cancer 20, 1498-1505 (2010).
161. Helfrich, I. et al. Angiopoietin-2 levels are associated with disease progression in metastatic malignant melanoma. Clin. Cancer Res. 15, 1384-1392 (2009).
162. Gale, N. W. et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by angiopoietin-1. Dev. Cell 3, 411-423 (2002).
163. Maisonpierre, P. C. et al. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277, 55-60 (1997).
164. Daly, C. et al. Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition. Cancer Res. 73, 108-118 (2013).
165. Labussiere, M. et al. Angiopoietin-2 may be involved in the resistance to bevacizumab in recurrent glioblastoma. Cancer Invest. 34, 39-44 (2016).
166. Scholz, A. et al. Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma. EMBO Mol. Med. 8, 39-57 (2016).
167. Bauerschlag, D. O. et al. Evaluation of potentially predictive markers for anti-angiogenic therapy with sunitinib in recurrent ovarian cancer patients. Transl Oncol. 6, 305-310 (2013).
168. Wada, H. et al. Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma: importance of angiopoietin-2 and hypoxia-induced factor-1. Liver Int. 26, 414-423 (2006).
169. Schulz, P. et al. Angiopoietin-2 drives lymphatic metastasis of pancreatic cancer. FASEB J. 25, 3325-3335 (2011).
170. Hacker, U. T. et al. Evaluation of angiopoietin-2 as a biomarker in gastric cancer: results from the randomised phase III AVAGAST trial. Br. J. Cancer 114, 855-862 (2016).
171. Goede, V. et al. Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br. J. Cancer 103, 1407-1414 (2010).
172. Nagorsen, D. et al. Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J. Transl Med. 5, 62 (2007).
173. Renner, D. N. et al. Improved treatment efficacy of antiangiogenic therapy when combined with picornavirus vaccination in the GL261 glioma model. Neurotherapeutics 13, 226-236 (2016).
174. Manning, E. A. et al. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin. Cancer Res. 13, 3951-3959 (2007).
175. Li, B. et al. Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clin. Cancer Res. 12, 6808-6816 (2006).
176. Farsaci, B., Higgins, J. P. & Hodge, J. W. Consequence of dose scheduling of sunitinib on host immune response elements and vaccine combination therapy. Int. J. Cancer 130, 1948-1959 (2012).
177. Foy, K. C. et al. Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo. Oncoimmunology 1, 1048-1060 (2012).
178. Huang, X. J. et al. Combined therapy of local and metastatic 4T1 breast tumor in mice using SU6668, an inhibitor of angiogenic receptor tyrosine kinases, and the immunostimulator B7. 2-IgG fusion protein. Cancer Res. 62, 5727-5735 (2002).
179. Wang, W. et al. Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency. Gene Ther. 20, 970-978 (2013).
180. Gabrilovich, D. I., Ishida, T., Nadaf, S., Ohm, J. E. & Carbone, D. P. Antibodies to vascular endothelial growth factor enhance the efficacy of cancer immunotherapy by improving endogenous dendritic cell function. Clin. Cancer Res. 5, 2963-2970 (1999).
181. Yasuda, S. et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin. Exp. Immunol. 172, 500-506 (2013).
182. Suzuki, H. et al. Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer. J. Transl Med. 11, 97 (2013).
183. Hayashi, H. et al. Phase I trial of OTS11101, an anti-angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor. Cancer Sci. 104, 98-104 (2013).
184. Hodi, F. S. et al. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol. Res. 2, 632-642 (2014).
185. Ott, P. A., Hodi, F. S. & Buchbinder, E. I. Inhibition of immune checkpoints and vascular endothelial growth factor as combination therapy for metastatic melanoma: An overview of rationale, preclinical evidence, and initial clinical data. Front. Oncol. 5, 202 (2015).
186. Ko, J. S. et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin. Cancer Res. 15, 2148-2157 (2009).
187. Amin, A. et al. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC) [abstract]. J. Clin. Oncol. 32 (Suppl.), 5010 (2014).
188. Rini, B. I. et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J. Clin. Oncol. 28, 2137-2143 (2010).
189. Escudier, B. et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J. Clin. Oncol. 28, 2144-2150 (2010).