Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody Journal Article
| Authors: | Park, J. A.; Espinosa-Cotton, M.; Guo, H. F.; Monette, S.; Cheung, N. K. V. |
| Article Title: | Targeting tumor vasculature to improve antitumor activity of T cells armed ex vivo with T cell engaging bispecific antibody |
| Abstract: | Background Success of T cell immunotherapy hinges on the tumor microenvironment (TME), and abnormal tumor vasculature is a hallmark of most solid tumors and associated with immune evasion. The efficacy of T cell engaging bispecific antibody (BsAb) treatment relies on the successful trafficking and cytolytic activity of T cells in solid tumors. Normalization of tumor vasculature using vascular endothelial growth factor (VEGF) blockades could improve efficacy of BsAb-based T cell immunotherapy. Methods Anti-human VEGF (bevacizumab, BVZ) or anti-mouse VEGFR2 antibody (DC101) was used as VEGF blockade, and ex vivo armed T cells (EATs) carrying anti-GD2, anti-HER2, or anti-glypican3 (GPC3) IgG-(L)-scFv platformed BsAb were used. BsAb-driven intratumoral T cell infiltration and in vivo antitumor response were evaluated using cancer cell line-derived xenografts (CDXs) or patient-derived xenografts (PDXs) carried out in BALB-Rag2 -/- IL-2R- 3c-KO (BRG) mice. VEGF expression on human cancer cell lines was analyzed by flow cytometry, and VEGF levels in mouse serum were measured using VEGF Quantikine ELISA Kit. Tumor infiltrating lymphocytes (TILs) were evaluated using flow cytometry and by bioluminescence; both TILs and tumor vasculature were studied using immunohistochemistry. Results VEGF expression on cancer cell lines increased with seeding density in vitro. BVZ significantly reduced serum VEGF levels in mice. BVZ or DC101 increased high endothelial venules (HEVs) in the TME and substantially enhanced (2.1-8.1 fold) BsAb-driven T cell infiltration into neuroblastoma and osteosarcoma xenografts, which was preferential for CD8(+) TILs versus CD4(+) TILs, leading to superior antitumor effects in multiple CDX and PDX tumor models without added toxicities. Conclusions VEGF blockade using specific antibodies against VEGF or VEGFR2 increased HEVs in the TME and cytotoxic CD8(+) TILs, significantly improving the therapeutic efficacy of EAT strategies in preclinical models, supporting the clinical investigation of VEGF blockades to further enhance BsAb-based T cell immunotherapies. © 2023 Nader Navabi et al., published by Sciendo. |
| Keywords: | immunohistochemistry; osteosarcoma; vasculotropin; vascular endothelial growth factor a; human cell; bevacizumab; nonhuman; flow cytometry; sensitivity and specificity; cd8+ t lymphocyte; t lymphocyte; tumor associated leukocyte; lymphocytes, tumor-infiltrating; t-lymphocytes; mouse; animal; animals; mice; animal tissue; gene expression; cell infiltration; animal experiment; animal model; antineoplastic activity; immunofluorescence; in vitro study; tumor xenograft; angiogenesis; enzyme linked immunosorbent assay; immunotherapy; xenograft; neuroblastoma; vasculotropin a; high performance liquid chromatography; th1 cell; tumor growth; ex vivo study; tumor vascularization; antibodies, neoplasm; bioluminescence; immunotherapy, adoptive; tumor microenvironment; antibodies, bispecific; bispecific antibody; humans; human; article; column chromatography; glypican; glypicans; melanoma cell line; neovasularization, pathologic; gpc3 protein, human |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 11 |
| Issue: | 3 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2023-03-01 |
| Start Page: | e006680 |
| Language: | English |
| DOI: | 10.1136/jitc-2023-006680 |
| PUBMED: | 36990507 |
| PROVIDER: | scopus |
| PMCID: | PMC10069597 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- MSK corresponding author is Nai-King Cheung --Export Date: 1 May 2023 -- Source: Scopus |
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