Novel human Ab against vascular endothelial growth factor receptor 2 shows therapeutic potential for leukemia and prostate cancer

Vascular endothelial growth factor receptor 2 (VEGFR2) is highly expressed in tumor‐associated endothelial cells, where it modulates tumor‐promoting angiogenesis, and it is also found on the surface of tumor cells. Currently, there are no Ab therapeutics targeting VEGFR2 approved for the treatment of prostate cancer or leukemia. Therefore, development of novel efficacious anti‐VEGFR2 Abs will benefit cancer patients. We used the Institute of Cellular and Organismic Biology human Ab library and affinity maturation to develop a fully human Ab, anti‐VEGFR2‐AF, which shows excellent VEGFR2 binding activity. Anti‐VEGFR2‐AF bound Ig‐like domain 3 of VEGFR2 extracellular region to disrupt the interaction between VEGF‐A and VEGFR2, neutralizing downstream signaling of the receptor. Moreover, anti‐VEGFR2‐AF inhibited capillary structure formation and exerted Ab‐dependent cell‐mediated cytotoxicity and complement‐dependent cytotoxicity in vitro. We found that VEGFR2 is expressed in PC‐3 human prostate cancer cell line and associated with malignancy and metastasis of human prostate cancer. In a PC‐3 xenograft mouse model, treatment with anti‐VEGFR2‐AF repressed tumor growth and angiogenesis as effectively and safely as US FDA‐approved anti‐VEGFR2 therapeutic, ramucirumab. We also report for the first time that addition of anti‐VEGFR2 Ab can enhance the efficacy of docetaxel in the treatment of a prostate cancer mouse model. In HL‐60 human leukemia‐xenografted mice, anti‐VEGFR2‐AF showed better efficacy than ramucirumab with prolonged survival and reduced metastasis of leukemia cells to ovaries and lymph nodes. Our findings suggest that anti‐VEGFR2‐AF has strong potential as a cancer therapy that could directly target VEGFR2‐expressing tumor cells in addition to its anti‐angiogenic action.     

Everolimus (RAD001) in the Treatment of Advanced Renal Cell Carcinoma: A Review

Historically, there have been few treatment options for patients with advanced renal cell carcinoma (RCC) besides immunotherapy with interleukin‐2 and interferon (IFN)‐α. Targeted therapies have improved clinical outcomes over the past several years. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors sunitinib and sorafenib, which inhibit angiogenic signaling in endothelial cells and vascular pericytes predominantly through VEGFR and platelet‐derived growth factor receptor β. Also included is the anti‐VEGF monoclonal antibody bevacizumab used in combination with IFN‐α. These agents mediate their antitumor effects by interfering with the VEGF signaling pathway, thereby inhibiting angiogenesis and causing tumor shrinkage. However, ultimately, most patients develop resistance and experience disease progression during VEGF/VEGFR‐targeted therapy, and until the recent approval of the mammalian target of rapamycin (mTOR) inhibitor everolimus (RAD001), there were no agents available with proven activity in this setting. This review describes the clinical development of everolimus in advanced RCC and the rationale for the use of mTOR inhibitors after failure of VEGF/VEGFR inhibitors.     

Antitumor activities of synthetic and natural stilbenes through antiangiogenic action

We reported that the antitumor and antimetastatic actions of resveratrol might be due to the inhibition of tumor‐induced angiogenesis. To search for anticancer agents with stronger activity than resveratrol, we examined the antiangiogenic effects of 21 synthetic and/or natural stilbenes. Among these 21 stilbenes, 2,3‐, 3,4‐, and 4,4′‐dihydroxystilbene inhibited the pro‐matrix metalloproteinase (pro‐MMP)–9 production in colon 26 cells at 5–25 µM, vascular endothelial growth factor (VEGF)–induced human umbilical vein endothelial cell (HUVEC) migration at 10 and 25 µM, and VEGF‐induced angiogenesis at 5–50 µM. Resvertarol inhibited the pro‐MMP‐9 production and VEGF‐induced angiogenesis at 25 or 50 µM. Thus, the inhibition of pro‐MMP‐9 production in colon 26 cells and VEGF‐induced angiogenesis by three dihydroxystilbenes were greater than those of resveratrol. The three dihydroxystilbenes (8 mg/kg, intraperitoneal injection) inhibited the tumor‐induced neovascularization in colon 26–packed chamber‐bearing mice and the tumor growth in colon 26–bearing mice. Furthermore, the three dihydroxystilbenes inhibited VEGF‐induced VEGFR‐2 phosphorylation. On the other hand, the three dihydroxystilbenes had no effect on VEGFR‐1 and‐2 expression, and VEGF‐induced VEGFR‐1 phosphorylation in HUVECs. These findings suggest that the inhibition of tumor‐induced neovascularization by these three dihydroxystilbenes may be due to the inhibition of VEGF‐induced endothelial cell migration and VEGF‐induced angiogenesis through the inhibition of VEGF‐induced VEGFR‐2 phosphorylation in endothelial cells and pro‐MMP‐9 expression in colon 26 cells. (Cancer Sci 2008; 99: 2083–2096)     

Combination of low vascular endothelial growth factor A (VEGF‐A)/VEGF receptor 2 expression and high lymphocyte infiltration is a strong and independent favorable prognostic factor in patients with nonsmall cell lung cancer

BACKGROUND:

There seems to be a close interplay between angiogenesis and the immune system. The authors of this report investigated the prognostic role of angiogenic markers in coexpression with immune system markers in patients with nonsmall cell lung cancer (NSCLC).

METHODS:

Tumor resection samples from 335 patients with stage I to IIIA NSCLC were obtained, and tissue microarrays were constructed. Immunohistochemistry was used to evaluate the expression of vascular endothelial growth factor (VEGF) A (VEGF‐A), VEGF receptor 2 (VEGFR‐2), and lymphocytes that were positive for the cluster of differentiation 4 (CD4) and CD8 coreceptors.

RESULTS:

In univariate analysis, 5‐year survival rates were 87% for the combination of low tumor cell expression of VEGF‐A and VEGFR‐2 (↓VEGF‐A/↓VEGFR‐2) and high tumor cell expression of CD4 and CD8 (↑CD4/↑CD8) (n = 19), 58% for mixed combinations (n = 290), and 27% for the ↑VEGF‐A/↑VEGFR‐2 and ↓CD4/↓CD8 combination (n = 26). In multivariate analysis, the coexpression of ↑VEGF‐A/↑VEGFR‐2 and ↓CD4/↓CD8 was an independent negative prognostic factor (hazard ratio, 9.16; 95% confidence interval, 2.11‐39.8; P = .003).

CONCLUSIONS:

Low tumor cell VEGF‐A and VEGFR‐2 expression in combination with high adaptive immune cell expression in the tumor‐related stroma had a strong and independent favorable prognostic impact in patients with NSCLC. Cancer 2010. © 2010 American Cancer Society.     

Anti‐CD73 therapy impairs tumor angiogenesis

CD73 is an ecto‐nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti‐tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti‐CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor‐derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host‐derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro‐angiogeneic effects of CD73 relied on both enzymatic and non‐enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment.     

Combination of anti‐angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis

The clinical efficacy of anti‐angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti‐angiogenic therapies is. Here, we examined the impact of neutralizing tumor‐derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh‐VEGF) in osteotropic human MDA‐MB‐231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh‐VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock‐transfected (Sc‐VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor‐derived VEGF or the use of a VEGF‐neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti‐angiogenic monotherapies in metastatic breast cancer is relatively modest.     

Functional significance of VEGFR‐2 on ovarian cancer cells

Vascular endothelial growth factor receptor (VEGFR) has recently been discovered on ovarian cancer cells, but its functional significance is unknown and is the focus of this study. By protein analysis, A2780‐par and HeyA8 ovarian cancer cell lines expressed VEGFR‐1 and HeyA8 A2774, and SKOV3ip1 expressed VEGFR‐2. By in situ hybridization (ISH), 85% of human ovarian cancer specimens showed moderate to high VEGFR‐2 expression, whereas only 15% showed moderate to high VEGFR‐1 expression. By immunofluorescence, little or no VEGFR‐2 was detected in normal ovarian surface epithelial cells, whereas expression was detected in 75% of invasive ovarian cancer specimens. To differentiate between the effects of tumor versus host expression of VEGFR, nude mice were injected with SKOV3ip1 cells and treated with either human VEGFR‐2 specific antibody (1121B), murine VEGFR‐2 specific antibody (DC101) or the combination. Treatment with 1121B reduced SKOV3ip1 cell migration by 68% (p < 0.01) and invasion by 72% (p < 0.01), but exposure to VEGFR‐1 antibody had no effect. Treatment with 1121B effectively blocked VEGF‐induced phosphorylation of p130Cas. In vivo treatment with either DC101 or 1121B significantly reduced tumor growth alone and in combination in the SKOV3ip1 and A2774 models. Decreased tumor burden after treatment with DC101 or 1121B correlated with increased tumor cell apoptosis, decreased proliferative index, and decreased microvessel density. These effects were significantly greater in the combination group (p < 0.001). We show functionally active VEGFR‐2 is present on most ovarian cancer cells. The observed anti‐tumor activity of VEGF‐targeted therapies may be mediated by both anti‐angiogenic and direct anti‐tumor effects. © 2008 Wiley‐Liss, Inc.     

Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature.

PURPOSE: New strategies to detect tumor angiogenesis and monitor response of tumor vasculature to therapy are needed. Contrast ultrasound imaging using microbubbles targeted to tumor endothelium offers a noninvasive method for monitoring and quantifying vascular effects of antitumor therapy. We investigated the use of targeted microbubbles to follow vascular response of therapy in a mouse model of pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Microbubbles conjugated to monoclonal antibodies were used to image and quantify vascular effects of two different antitumor therapies in s.c. and orthotopic pancreatic tumors in mice. Tumor-bearing mice were treated with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies and/or gemcitabine, and the localization of microbubbles to endoglin (CD105), VEGF receptor 2 (VEGFR2), or VEGF-activated blood vessels (the VEGF-VEGFR complex) was monitored by contrast ultrasound. RESULTS: Targeted microbubbles showed significant enhancement of tumor vasculature when compared with untargeted or control IgG-targeted microbubbles. Video intensity from targeted microbubbles correlated with the level of expression of the target (CD105, VEGFR2, or the VEGF-VEGFR complex) and with microvessel density in tumors under antiangiogenic or cytotoxic therapy. CONCLUSIONS: We conclude that targeted microbubbles represent a novel and attractive tool for noninvasive, vascular-targeted molecular imaging of tumor angiogenesis and for monitoring vascular effects specific to antitumor therapy in vivo.     

Administration of VEGF receptor tyrosine kinase inhibitor increases VEGF production causing angiogenesis in human small-cell lung cancer xenografts

Angiogenesis is mediated mainly by vascular endothelial growth factor (VEGF), and VEGF causes rapid growth in cancers, including human small-cell lung cancer (SCLC). The anti-angiogenic strategy of treating cancer using VEGF receptor (VEGFR) inhibition is currently of great interest. We tested the effects of the VEGFR2 tyrosine kinase inhibitor (TKI) vandetanib on the proliferation of two kinds of SCLC cell lines: SBC-1 cells, with detectable VEGFR2 expression and MS-1-L cells, without detectable VEGFR2 expression. To evaluate the anti-tumor and anti-angiogenic effects of vandetanib in vivo, we grafted SBC-1 and MS-1-L cells into mice. After a 3-week treatment, we measured the tumor size and histologically evaluated necrosis and apoptosis using H&E and TUNEL staining, respectively. The microvessels in the xenografts were also quantified by immunostaining of CD31. Vandetanib did not affect the proliferation of SBC-1 cells, but stimulated the growth of MS-1-L cells. In the SCLC xenograft model, vandetanib inhibited growth and tumor angiogenesis in a dose-dependent manner in SBC-1 xenografts. Vandetanib inhibited the growth of MS-1-L xenografts at a low dose (<12.5 mg/kg/day), but it did not affect tumor size or change microvessel counts at a higher dose. Interestingly, secretion of VEGF increased significantly in the MS-1-L cell line in the presence of a high dose of vandetanib in vitro. The effects of vandetanib on tumor angiogenesis were different in SBC-1 and MS-1-L cell lines. Production of angiogenic factors such as VEGF by the tumor potentially stimulates tumor angiogenesis and results in the acquisition of resistance to VEGFR TKI.     

Anti‐VEGF antibody therapy induces tumor hypoxia and stanniocalcin 2 expression and potentiates growth of human colon cancer xenografts

Tumor angiogenesis plays a critical role in colorectal cancer progression. Recent randomized clinical trials have revealed the additive effect of bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)‐A, to conventional chemotherapy in the improved survival of patients with metastatic colorectal cancer. However, a number of preclinical reports indicate the development of resistance to anti‐angiogenic therapy. In this study, we addressed the effects of anti‐VEGF antibodies on the growth and malignant behavior of colorectal cancer cells. TK‐4, a solid tumor strain derived from a colon cancer patient, was subcutaneously or orthotopically implanted into nude mice. Short‐term administration of anti‐VEGF antibodies inhibited the growth of cecal tumors at day 14 by suppressing mitosis, but prolonged treatment resulted in the recovery of cellular proliferation and suppression of apoptosis at day 35. Intratumoral hypoxia induced by anti‐VEGF antibody treatment resulted in activation of hypoxia inducible factor‐1α protein and an increased number of aldehyde dehydrogenase 1‐positive tumor cells. In microarray analysis, stanniocalcin 2 (STC2) was the most highly upregulated gene in anti‐VEGF antibody‐treated tumors. In vitro analyses showed that the growth and migration of SW480 colon cancer cells under hypoxic conditions were significantly inhibited by knockdown of STC2. In vivo serial transplantation of TK‐4 revealed that long‐term administration of anti‐VEGF antibodies increased the tumorigenicity of colon cancers and accelerated tumor growth when transplanted into secondary recipient mice. Our data provide a potential molecular explanation for the limited clinical effectiveness of anti‐VEGF antibodies.     

Selective inhibition of vascular endothelial growth factor (VEGF) receptor 2 (KDR/Flk-1) activity by a monoclonal anti-VEGF antibody blocks tumor growth in mice

Vascular endothelial growth factor (VEGF) is a multifunctional angiogenic growth factor that is a primary stimulant of the development and maintenance of a vascular network in embryogenesis and the vascularization of solid tumors. At the present time there are two well-characterized receptors for VEGF that are selectively expressed on endothelium. VEGF receptor 2 [VEGFR2 (KDR/Flk-1)] mediates endothelial cell mitogenesis and permeability increases, whereas the role of VEGF receptor 1 [VEGFR1 (Flt-1)] has not been clearly defined. In the present study, a monoclonal antibody, 2C3, is shown to block the interaction of VEGF with VEGFR2 but not with VEGFR1 through ELISA, receptor binding assays, and receptor activation assays. 2C3 blocks the VEGF-induced vascular permeability increase in guinea pig skin. 2C3 has potent antitumor activity, inhibiting the growth of newly injected and established human tumor xenografts in mice. These findings demonstrate the usefulness of 2C3 in dissecting the pathways that are activated by VEGF in cells that express both VEGFR1 and VEGFR2, as well as highlighting the dominant role of VEGFR2 in mediating VEGF-induced vascular permeability increase and tumor angiogenesis.     

MT95‐4, a fully humanized antibody raised against aminopeptidase N,reduces tumor progression in a mouse model

Aminopeptidase N (APN/CD13) is involved in tumor cell invasion and tumor angiogenesis and is considered a promising therapeutic target in the treatment of cancer. To develop a novel monoclonal antibody‐based cancer therapy targeting APN/CD13, we established a fully humanized anti‐APN/CD13 monoclonal antibody, MT95‐4. In vitro, MT95‐4 inhibited APN/CD13 enzymatic activity on the tumor cell surface and blocked tumor cell invasion. B16 mouse melanoma cells stably expressing human APN/CD13 were also established and were inoculated s.c. or injected i.v. into nude mice. We found that expression of human APN/CD13 in murine melanoma cells increased the size of subcutaneous tumors, extent of lung metastasis and degree of angiogenesis in the subcutaneous tumors; these tumor‐promoting and angiogenesis‐promoting characteristics were reduced by the i.p. administration of MT95‐4. To further verify the specificity of MT95‐4 for neutralization of APN/CD13 activity, MT95‐4 was administered into NOD/SCID mice inoculated s.c. with H1299 or PC14 cells, which exhibit high expression of APN/CD13, or with A549 cells, which exhibit weak expression of APN/CD13. MT95‐4 reduced tumor growth and angiogenesis in mice bearing H1299‐derived and PC14‐derived tumors, but not in mice bearing A549‐derived tumors. These results suggested that the antitumor and anti‐angiogenic effects of MT95‐4 were dependent on APN/CD13 expression in tumor cells. Given that MT95‐4 is the first fully humanized monoclonal antibody against APN/CD13, MT95‐4 should be recognized as a promising candidate for monoclonal antibody therapy against tumors expressing APN/CD13.     

Norcantharidin inhibits tumor angiogenesis via blocking VEGFR2/MEK/ERK signaling pathways

Norcantharidin (NCTD), the demethylated form of Cantharidin, a reagent isolated from blister beetles, has been shown to be an anti‐tumor agent capable of inhibiting proliferation as well as inducing apoptosis in many cancer cell lines. However, little is known about the effect of NCTD in tumor angiogenesis. In this study, we demonstrated that NCTD inhibited vascular endothelial growth factor (VEGF)‐induced cell proliferation, migration, invasion, and capillary tube formation of primary human umbilical vein endothelial cells (HUVECs) in a dose‐dependent manner. Furthermore, we showed NCTD inhibited tumor growth and angiogenesis of colon cancer cells (LOVO) in vivo. We then mechanistically described that NCTD specifically abrogated the phosphorylation/activation of vascular endothelial growth factor receptor‐2 (VEGFR2)/MEK/ERK pathway kinases, with little effect on the phosphorylation of p38 MAPK and Akt, and on Cox‐2 expression. In summary, our results indicate that NCTD is a potential inhibitor of tumor angiogenesis by blocking VEGFR2/MEK/ERK signaling.     

Anti‐angiogenic therapies for gastric cancer

Tumor angiogenesis plays an important role in cancer cell proliferation and metastasis. In gastric cancer, among the numerous clinical trials investigating various anti‐angiogenic therapies, such as antivascular endothelial growth factor (VEGF) or anti‐VEGF receptor (VEGFR)‐2 monoclonal antibodies, VEGF‐Trap and VEGFR tyrosine kinase inhibitors, the anti‐VEGFR‐2 antibody ramucirumab was shown to prolong overall survival not only as a single agent but also in combination with paclitaxel as a second‐line chemotherapy. Additionally, apatinib, a selective VEGFR‐2 tyrosine kinase inhibitor, prolonged survival as a third‐line or later treatment option in patients with advanced gastric cancer. Preliminary results of studies investigating ramucirumab plus immune checkpoint inhibitors in gastric cancer were encouraging, and further investigations are ongoing. In China, apatinib in combination with cytotoxic agents is being investigated for systemic chemotherapy or maintenance therapy as an earlier treatment option. The clinical activity in gastric cancer of the multikinase inhibitor regorafenib was suggested in a randomized phase II study. A global phase III trial comparing regorafenib with placebo is currently ongoing. Further studies of anti‐angiogenic therapy combined with not only chemotherapy but also immune checkpoint inhibitors are also being pursued, providing hope for improved survival in patients with gastric cancer.     

Plumbagin inhibits tumorigenesis and angiogenesis of ovarian cancer cells in vivo

Angiogenesis is a hallmark of tumor development and metastatic progression, and anti‐angiogenic drugs targeting the VEGF pathway have shown to decrease the disease progression in cancer patients. In this study, we have analyzed the anti‐proliferative and anti‐angiogenic property of plumbagin in cisplatin sensitive, BRCA2 deficient, PEO‐1 and cisplatin resistant, BRCA2 proficient PEO‐4 ovarian cancer cells. Both PEO‐1 and PEO‐4 ovarian cancer cells are sensitive to plumbagin irrespective of BRCA2 status in both normoxia and hypoxia. Importantly, plumbagin treatment effectively inhibits VEGF‐A and Glut‐1 in PEO‐1 and PEO‐4 ovarian cancer cells. We have also analyzed the p53 mutant, cisplatin resistant, and BRCA2 proficient OVCAR‐5 cells. Plumbagin challenge also restricts the VEGF induced pro‐angiogenic signaling in HUVECs and subsequently endothelial cell proliferation. In addition, we observe a significant effect on tumor regression among OVCAR‐5 tumor‐bearing mice treated with plumbagin, which is associated with significant inhibition of Ki67 and vWF expressions. Plumbagin also significantly reduces CD31 expression in an ear angiogenesis assay. Collectively, our studies indicate that plumbagin, as an anti‐cancer agent disrupts growth of ovarian cancer cells through the inhibition of proliferation as well as angiogenesis.     

抗VEGF嵌合抗体的生物学特性分析

目的：分析抗人血管内皮生长因子（VEGF）嵌合抗体VcD11的各种生物学特性,确定其人源性,特异性,中和VEGF的中和活性以及体内抑制肿瘤生长转移的抗肿瘤活性。方法：采用纯化的VcD11进行ELISA和Westerm blot实验,分析其人源性、特异性;采用抑制由VEGF刺激引起的内皮细胞增殖实验分析VcD11的中和活性;采用近交系小鼠T739的小鼠肺腺癌LA795实验动物肿瘤模型分析VcD11的抗肿瘤活性。结果VcD11在ELISA和Western blot实验中均呈阳性结果,并可抑制由VcD11的刺激引起的内皮细胞增殖,虽未能明显抑制小鼠肺腺癌LA795原发瘤的生长,但可显著抑制其肺转移灶的形成和工。结论,抗VEGF嵌合抗体VcD11具有人抗体的恒定区,可与人VEGF特异地结合,并具有良好的中和活性和抗肿瘤转移的活性。它可能在临床治疗肿瘤中有着重要、广泛的应用潜力。     

抗血管形成靶向药物的研究进展

肿瘤的生长和转移离不开肿瘤新生血管,这使得抗血管形成治疗成为肿瘤治疗的重要途径之一。血管内皮生长因子及其受体是抗肿瘤治疗的重要靶点之一。本文主要介绍了近年来抗血管形成治疗的一些最新药物研究成果——包括针对血管内皮生长因子的单克隆抗体——贝伐;针对血管内皮生长因子受体的酪氨酸激酶抑制剂——舒尼替尼、索拉非尼等;以及血管内皮生长因子受体的单克隆抗体IMC-1C11等。     

Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation.

The family of vascular endothelial growth factor (VEGF) proteins include potent and specific mitogens for vascular endothelial cells that function in the lation of angiogenesis Inhibition of VEGF-induced angiogenesis either by neutralizing antibodies or dominant-negative soluble receptor, blocks the growth of primary and metastatic experimental tumors Here we report that VEGF expression is induced in Lewis lung carcinomas (LLCs) both in vitro and vivo after exposure to ionizing radiation (IR) and in human tumor cell lines (Seg-1 esophageal adenocarcinoma, SQ20B squamous cell carcinoma, T98 and U87 glioblastomas, and U1 melanoma) in vitro. The biological significance of IR-induced VEGF production is supported by our finding that treatment of tumor-bearing mice (LLC, Seg-1, SQ20B, and U87) with a neutralizing antibody to VEGF-165 before irradiation is associated with a greater than additive antitumor effect. In vitro, the addition of VEGF decreases IR-induced killing of human umbilical vein endothelial cells, and the anti-VEGF treatment potentiates IR-induced lethality of human umbilical vein endothelial cells. Neither recombinant VEGF protein nor neutralizing antibody to VEGF affects the radiosensitivity of tumor cells These findings support a model in which induction of VEGF by IR contributes to the protection of tumor blood vessels from radiation-mediated cytotoxicity and thereby to tumor radioresistance.     

Blockade of TGF‐β enhances tumor vaccine efficacy mediated by CD8+ T cells

Though TGF‐β inhibition enhances antitumor immunity mediated by CD8⁺ T cells in several tumor models, it is not always sufficient for rejection of tumors. In this study, to maximize the antitumor effect of TGF‐β blockade, we tested the effect of anti‐TGF‐β combined with an irradiated tumor vaccine in a subcutaneous CT26 colon carcinoma tumor model. The irradiated tumor cell vaccine alone in prophylactic setting significantly delayed tumor growth, whereas anti‐TGF‐β antibodies alone did not show any antitumor effect. However, tumor growth was inhibited significantly more in vaccinated mice treated with anti‐TGF‐β antibodies compared to vaccinated mice without anti‐TGF‐β, suggesting that anti‐TGF‐β synergistically enhanced irradiated tumor vaccine efficacy. CD8⁺ T‐cell depletion completely abrogated the vaccine efficacy, and so protection required CD8⁺ T cells. Depletion of CD25⁺ T regulatory cells led to the almost complete rejection of tumors without the vaccine, whereas anti‐TGF‐β did not change the number of CD25⁺ T regulatory cells in unvaccinated and vaccinated mice. Though the abrogation of CD1d‐restricted NKT cells, which have been reported to induce TGF‐β production by MDSC through an IL‐13‐IL‐4R‐STAT6 pathway, partially enhanced antitumor immunity regardless of vaccination, abrogation of the NKT cell‐IL‐13‐IL‐4R‐STAT‐6 immunoregulatory pathway did not enhance vaccine efficacy. Taken together, these data indicated that anti‐TGF‐β enhances efficacy of a prophylactic vaccine in normal individuals despite their not having the elevated TGF‐β levels found in patients with cancer and that the effect is not dependent on TGF‐β solely from CD4⁺CD25⁺ T regulatory cells or the NKT cell‐IL‐13‐IL‐4R‐STAT‐6 immunoregulatory pathway.