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Qiao T, Zhao J, Xin X, Xiong Y, Guo W, Meng F, Li H, Feng Y, Xu H, Shi C, Han Y. Combined pembrolizumab and bevacizumab therapy effectively inhibits non-small-cell lung cancer growth and prevents postoperative recurrence and metastasis in humanized mouse model. Cancer Immunol Immunother 2023; 72:1169-1181. [PMID: 36357599 PMCID: PMC10110651 DOI: 10.1007/s00262-022-03318-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 10/25/2022] [Indexed: 11/12/2022]
Abstract
Antibodies targeting the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) pathway have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, combination approaches are required to extend this benefit beyond a subset of patients. In addition, it is of equal interest whether these combination therapy can be applied to neoadjuvant therapy of early-stage NSCLC. In this study, we hypothesized that combining immunotherapy with anti-angiogenic therapy may have a synergistic effect in local tumor control and neoadjuvant therapy. To this end, the effect of combination of bevacizumab and pembrolizumab in humanized mouse models was evaluated. Furthermore, we innovatively constructed a neoadjuvant mouse model that can simulate postoperative recurrence and metastasis of NSCLC to perform neoadjuvant study. Tumor growth and changes in the tumor vasculature, along with the frequency and phenotype of tumor-infiltrating lymphocytes, were examined. Additionally, in vivo imaging system (IVIS) was used to observe the effect of neoadjuvant therapy. Results showed that combination therapy could inhibited tumor growth by transforming tumor with low immunoreactivity into inflamed ('hot') tumor, as demonstrated by increased CD8+granzyme B+ cytotoxic T cell infiltration. Subsequent studies revealed that this process is mediated by vascular normalization and endothelial cell activation. IVIS results showed that neoadjuvant therapy can effectively prevent postoperative recurrence and metastasis. Taken together, these preclinical studies demonstrated that the combination of bevacizumab and pembrolizumab had a synergistic effect in both advanced tumor therapy and neoadjuvant setting and therefore provide a theoretical basis for translating this basic research into clinical applications.
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Affiliation(s)
- Tianyun Qiao
- Department of Thoracic Surgery, Air Force Specialty Medical Center, Fourth Military Medical University, Xi'an, 710032, China
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Xiangbing Xin
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Yanlu Xiong
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Wenwen Guo
- Laboratory Animal Center, Fourth Military Medical University, Xi'an, 710032, China
| | - Fancheng Meng
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Hui Li
- Laboratory Animal Center, Fourth Military Medical University, Xi'an, 710032, China
| | - Yangbo Feng
- Department of Thoracic Surgery, Air Force Specialty Medical Center, Fourth Military Medical University, Xi'an, 710032, China
- Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Hui Xu
- School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China.
| | - Changhong Shi
- Laboratory Animal Center, Fourth Military Medical University, Xi'an, 710032, China.
| | - Yong Han
- Department of Thoracic Surgery, Air Force Specialty Medical Center, Fourth Military Medical University, Xi'an, 710032, China.
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Conde J, Oliva N, Zhang Y, Artzi N. Local triple-combination therapy results in tumour regression and prevents recurrence in a colon cancer model. NATURE MATERIALS 2016; 15:1128-38. [PMID: 27454043 PMCID: PMC6594055 DOI: 10.1038/nmat4707] [Citation(s) in RCA: 343] [Impact Index Per Article: 38.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 06/21/2016] [Indexed: 05/04/2023]
Abstract
Conventional cancer therapies involve the systemic delivery of anticancer agents that neither discriminate between cancer and normal cells nor eliminate the risk of cancer recurrence. Here, we demonstrate that the combination of gene, drug and phototherapy delivered through a prophylactic hydrogel patch leads, in a colon cancer mouse model, to complete tumour remission when applied to non-resected tumours and to the absence of tumour recurrence when applied following tumour resection. The adhesive hydrogel patch enhanced the stability and provided local delivery of embedded nanoparticles. Spherical gold nanoparticles were used as a first wave of treatment to deliver siRNAs against Kras, a key oncogene driver, and rod-shaped gold nanoparticles mediated the conversion of near-infrared radiation into heat, causing the release of a chemotherapeutic as well as thermally induced cell damage. This local, triple-combination therapy can be adapted to other cancer cell types and to molecular targets associated with disease progression.
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Affiliation(s)
- João Conde
- Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA
- School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK
- Correspondence and requests for materials should be addressed to J.C. or N.A. ;
| | - Nuria Oliva
- Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA
| | - Yi Zhang
- Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA
| | - Natalie Artzi
- Massachusetts Institute of Technology, Institute for Medical Engineering and Science, Cambridge, Massachusetts 02139, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
- Department of Medicine, Division of Biomedical Engineering, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
- Correspondence and requests for materials should be addressed to J.C. or N.A. ;
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Ferreira MA, Ferreira REA, Silva NS. Preoperative intravitreal bevacizumab and silicone oil tamponade for vitrectomy in diabetic retinopathy. World J Ophthalmol 2014; 4:75-81. [DOI: 10.5318/wjo.v4.i3.75] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 06/14/2014] [Accepted: 06/27/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the outcomes and complications of vitrectomy for diabetic retinopathy using preoperative bevacizumab and silicone oil (SO) tamponade.
METHODS: Eighty-four eyes (64 patients) that underwent vitrectomy to treat severe proliferative diabetic retinopathy were enrolled in this retrospective, interventional, serial case study. All patients provided signed informed consent preoperatively and the off-label use of bevacizumab was discussed with the patients and confirmed in the signed consent forms. Bevacizumab injections and SO tamponades were used in all cases and intraoperative complications, postoperative complications and postoperative outcomes were analyzed. The primary outcome was the occurrence of intraoperative and postoperative bleeding during and after vitrectomy and SO removal. The secondary outcomes were other complications that occurred during the two surgeries, the surgical time and the postoperative best-corrected visual acuity (BCVA) in logMAR scale compared with the preoperative BCVA in logMAR. The statistical analysis was performed with GraphPad Prism 5 (GraphPad Software, La Jolla, CA) using a column analysis (column statistics and frequency distribution) for the noncomparative analysis and a paired t-test for the comparative study; P < 0.05 indicated statistical significance.
RESULTS: Eighty-four eyes of 64 patients were included in the study. Of the 88 eyes initially recruited, 4 eyes (0.45%) developed phthisis bulbi and were excluded from the statistical analysis. Bevacizumab was injected between 1 and 10 d before surgery, with a mean of 3.7 ± 2.2 d. Forty-six eyes (54.8%) had no complications during the surgery; 6 eyes (7.1%) had vitreous hemorrhage; 21 (25%) had a single retinal tear; 7 (8.3%) had two or more retinal tears, one of which was in the posterior pole, temporal to the fovea; 2 (2.4%) had retinal tears associated with hemorrhage; 1 (1.2%) had choroidal detachment; and 1 eye (1.2%) had dialysis in the temporal entrance of the trocar. After the surgery and SO removal, 60 eyes (71.4%) had no complications, 8 (9.5%) had vitreous hemorrhage, 2 (2.4%) had a macular hole, 2 (2.4%) had an epiretinal membrane, 7 (8.3%) had rhegmatogenous retinal detachment, 2 (2.4%) had neovascular glaucoma, 2 (2.4%) had a corneal trophic ulcer, and 1 (1.2%) had central venous occlusion. The surgical time ranged from 40 to 120 min, with a mean of 77.8 ± 20.7 min. The final status of the lens was 34 phakic eyes (40.5%) and 24 pseudophakic eyes (28.5%); in 26 eyes (31%), the lens was extracted via phacoemulsification combined with vitrectomy or SO removal. The preoperative BCVA in logMAR ranged from 0.1 to 3.0, with a mean of 1.6 ± 0.9; the postoperative BCVA in logMAR ranged from 0.0 to 3.0, with a mean of 0.9 ± 0.7; the preoperative and postoperative BCVA values were significantly different (P < 0.0001).
CONCLUSION: Bevacizumab may diminish intraoperative and postoperative bleeding, thus possibly facilitating intraoperative maneuvers, diminishing the complications and playing a role in the final outcomes of these eyes.
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Abstract
Human cancer has been one of the most difficult and tenacious problems that has defied many therapeutic regimens in the past. In recent years, there has been an explosive growth in our knowledge about molecular cell biology of cancer leading to the development of several molecularly targeted therapies. These therapeutic agents are used specifically for those tumors that are found to be susceptible to such a therapeutic approach. These therapies include a variety of monoclonal antibodies that target cell-surface receptors or, in some cases, their ligands. A second type of targeted therapies consists of small molecules that are designed to inhibit tyrosine kinase activity within the cancer cells. Despite initial optimism, this approach to cancer therapy is proven to be problematic because of inherent cancer heterogeneity and frequent development of drug resistance. The targeted therapies have improved survival time for many cancer patients but have not provided any definitive cures. The treating physicians constantly face the daunting challenge of balancing expected benefit with risk for complications, to achieve the most successful outcome. Still, the results often fall short of expectations. Personalized cancer treatment on the basis of targeted therapies is certainly an achievable goal, but more work is needed to make it a reality.
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Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proc Natl Acad Sci U S A 2013; 110:12018-23. [PMID: 23818623 DOI: 10.1073/pnas.1301331110] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.
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The extracellular matrix glycoprotein elastin microfibril interface located protein 2: a dual role in the tumor microenvironment. Neoplasia 2010; 12:294-304. [PMID: 20360940 DOI: 10.1593/neo.91930] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2009] [Revised: 01/26/2010] [Accepted: 01/27/2010] [Indexed: 12/22/2022] Open
Abstract
We have recently reported that elastin microfibril interface located protein 2 (EMILIN2), an extracellular matrix (ECM) glycoprotein, triggers cell death through a direct binding to death receptors. EMILIN2 thus influences cell viability through a mechanism that is unique for an ECM molecule. In the present work, we report an additional function for this molecule. First, we identify the region responsible for the proapoptotic effects, a 90-amino acid residue-long coiled-coil fragment toward the N-terminus of the molecule. The fragment recapitulates EMILIN2 proapoptotic mechanisms. In addition, using either the full molecule or the active fragment, for the first time, we demonstrate a significant antitumoral effect in vivo, likely due to a decrease in tumor cell viability. Unexpectedly, tumors treated with EMILIN2 or the deletion mutant display a significant increase of tumor angiogenesis. In view of this novel finding, the cotreatment of the growing tumors with an antiangiogenic drug led, in most cases, to a complete regression of tumor growth. These results grant further support to recent findings that pinpoint the microenvironment as an important regulator of cell fate under both physiological and pathological conditions and disclose the possibility of using EMILIN2 fragments as potent antineoplastic tools for cancer treatment.
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Hsu CW, King TM, Lin CH, Wang HT, Ou WC, Wang JH. Shifting to first-line regimen after previous failure of irinotecan and oxaliplatin containing chemotherapies in unresectable metastatic colorectal cancer: a retrospective study of case analysis. Int J Colorectal Dis 2009; 24:377-83. [PMID: 19116722 DOI: 10.1007/s00384-008-0621-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2008] [Indexed: 02/04/2023]
Abstract
PURPOSE Conventional use of FOLFIRI-FOLFOX or the reverse sequence is the optional regimen in metastatic unresectable colorectal cancer (CRC). We present our experience in chemotherapy (C/T) shifting to first-line regimen after previous failure of irinotecan and oxaliplatin containing regimens. MATERIALS AND METHODS A total of 48 patients with metastatic unresectable CRC were examined retrospectively. All the patients had both failure of a first-line C/T and a second-line C/T. Of these patients, 13 patients received C/T shifting to first-line regimen. Data were collected retrospectively. RESULTS Rate of disease control of 38.4% was achieved (five in 13 patients). In the positive disease control group, metastatic sites were all extra-hepatic (five patients). In the negative disease control group, hepatic metastatic rate was 62.5% (five in eight patients, P=0.044). CONCLUSIONS Even after previous failure of irinotecan and oxaliplatin containing C/T, we observe positive disease control response and survival benefit in selected patients with C/T shifting to the first-line regimen especially in extra-hepatic metastasis. The preliminary results are proposed to gain insight into the need for further investigations and large-scale studies.
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Affiliation(s)
- Chao-Wen Hsu
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veteran General Hospital, Kaohsiung, Taiwan, Republic of China.
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Cao Y, Liu Q. Therapeutic Targets of Multiple Angiogenic Factors for the Treatment of Cancer and Metastasis. Adv Cancer Res 2007; 97:203-24. [PMID: 17419947 DOI: 10.1016/s0065-230x(06)97009-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Like any growing healthy tissues, tumors build up their blood vessels by three mechanisms: angiogenesis, vasculogenesis, and intersucception. Vascular endothelial growth factor-A (VEGF-A) is one of the key factors responsible for stimulation and maintenance of the disorganized, leaky, and torturous tumor vasculature. In addition to VEGF-A, tumors produce multiple other factors to stimulate blood vessel growth. These include members in the platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), VEGF-C, insulin-like growth factor (IGF), angiopoietin (Ang), and hepatocyte growth factor (HGF) families. Recent studies show that these angiogenic factors can also promote lymphangiogenesis and potentially lymphatic metastasis. Understanding the roles of individual and combined angiogenic factors in promoting tumor angiogenesis is crucial for defining therapeutic targets and antiangiogenic drug development for the treatment of cancer.
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Affiliation(s)
- Yihai Cao
- Laboratory of Angiogenesis Research, Microbiology and Tumor Biology Center, Karolinska Institutet, 171 77 Stockholm, Sweden
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Abstract
This review advances the hypothesis that the function of vascular endothelial growth factor (VEGF) in breast cancer is not limited to angiogenesis, and that VEGF signaling in breast carcinoma cells is important for the ability of these cells to evade apoptosis and progress towards invasive and metastatic disease. In other terms, VEGF signaling provides a selective advantage for the survival and dissemination of breast carcinoma cells that may be independent of angiogenesis. The key component of this hypothesis is that breast carcinoma cells express specific VEGF receptors and that these receptors respond to autocrine VEGF, resulting in the activation of signaling pathways that impede apoptosis and promote cell migration. A related hypothesis, which is developed in this review, is that the alpha6beta4 integrin, which has been implicated in the survival and motility of breast cancer cells, can stimulate the translation of VEGF mRNA and, consequently, autocrine VEGF signaling. These findings imply that VEGF and VEGF receptor-based therapeutics, in addition to targeting angiogenesis, may also target tumor cells directly.
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Affiliation(s)
- Arthur M Mercurio
- Department of Cancer Biology and the Cancer Center, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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