The present era of anti-angiogenic treatment for cancer research started in with the publishing of Folkman's creative hypothesis [ 47 ], although it would take 33 years for the FDA to authorize the first drug produced as a blocker of angiogenesis.

Bevacizumab, a humanized monoclonal antibody targeted against VEGF, was coupled with standard chemotherapy in a randomly selected phase 3 study of first-line therapy of metastatic colorectal cancer CRC [ 48 ].

When utilized in conjunction with conventional chemotherapy, bevacizumab therapy improved overall survival OS in the first-line treatments of advanced non—small-cell lung cancer NSCLC [ 49 ]. The FDA of the United States has authorized a variety of angiogenesis inhibitors for the treatment of cancer.

Most of them are targeted treatments created to target VEGF, its receptor, or other angiogenesis-related molecules.

Bevacizumab, axitinib, everolimus, cabozantinib, lenalidomide, lenvatinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, thalidomide, Ziv-aflibercept and vandetanib are most famous accepted angiogenesis inhibitors, which have been approved for human advanced tumors [ 50 ].

As the first VEGF-targeted agent approved by FDA, bevacizumab, is used since February , for the treatment of patients suffering from metastatic m CRC in combination with the standard chemotherapy treatment as first-line treatment [ 51 ].

In June , it was approved with fluorouracil 5-FU -based therapy for second-line mCRC. Also, it has been indicated for NSCLC plus chemotherapy , breast cancer, glioblastoma, ovarian cancer plus chemotherapy , and also cervical cancer [ 51 ]. Another well-known angiogenesis inhibitor, axitinib, has gained approval from FDA for use as a treatment for renal cell carcinoma RCC since January and also has shown promising outcomes in pancreatic cancer plus gemcitabine [ 52 , 53 ].

Moreover, since , it is used for neuroendocrine tumors NET of gastrointestinal GI or lung origin with unresectable, locally advanced, or metastatic disease [ 55 ].

In November , cabozantinib, a small molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, was approved for thyroid cancer [ 56 ] and also in April was accepted as second-line treatment for RCC [ 57 ].

Lenalidomide, a 4-amino-glutamyl analogue of thalidomide, is used to treat multiple myeloma MM [ 58 ] and myelodysplastic syndromes MDS [ 59 ], and also lenvatinib, which acts as a multiple kinase inhibitor against the VEGFR1, VEGFR2, and VEGFR3 kinases, is applied for the treatment of thyroid cancer [ 60 ].

In , lenvatinib was also approved in combination with everolimus for the treatment of advanced RCC [ 61 ]. Since , pazopanib, a potent and selective multi-targeted receptor tyrosine kinase inhibitor, is utilized for metastatic RCC and advanced soft tissue sarcomas therapy [ 62 ].

Besides, since April , the ramucirumab, a direct VEGFR2 antagonist, is indicated as a single-agent treatment for advanced gastric cancer or gastro-esophageal junction GEJ adenocarcinoma after treatment with fluoropyrimidine- or platinum-containing chemotherapy [ 63 ]. Further, ramucirumab in combination with docetaxel has gained approval for treatment of metastatic NSCLC [ 64 ].

Ramucirumab also is used for mCRC since [ 65 ] and HCC since [ 66 ] therapy. Also, regorafenib, an orally-administered inhibitor of multiple kinases, has been indicated for the treatment of patients with advanced HCC who were previously treated with sorafenib [ 67 ].

Moreover, sorafenib as another type of kinase inhibitor is used since for RCC and HCC therapy, and since for thyroid cancer [ 68 ].

Multi-targeted receptor tyrosine kinase inhibitor sunitinib also is applied for gastrointestinal stromal tumor GIST and RCC therapy [ 69 ]. In addition, since , thalidomide as a type of biological therapy in combination with dexamethasone has been approved for the treatment of newly diagnosed MM patients [ 70 ].

Also, Ziv-aflibercept in combination with 5-fluorouracil, leucovorin, irinotecan FOLFIRI are used to treat patients with metastatic CRC [ 71 ]. Finally, tyrosine kinase inhibitor vandetanib is employed to treat medullary thyroid cancer in adults who are ineligible for surgery [ 72 , 73 ].

Despite their total tumor growth reduction, therapeutic anti-angiogenic agents were linked to enhanced local invasiveness as well as distant metastasis.

These events seem to be significant factors to resistance to anti-angiogenesis treatments. They were originally reported in various preclinical models by Paez-Ribes and coworkers [ 74 ]. Based on the literature, anti-angiogenic treatment may increase tumor invasiveness.

RCC cells, for example, showed increased proliferation and an invasive character after being treated with bevacizumab [ 75 ]. Likewise, glioblastoma cells in mice models were more invasive after VEGF suppression [ 74 ]. Sunitinib treatment also has been found to cause vascular alterations such as decreased adherens junction protein expression, reduced basement membrane, pericyte coverage, and increased leakiness [ 76 , 77 ].

These phenotypic alterations were found in both normal and tumor organ arteries, indicating that they promote tumor cell local intravasation and extravasation, culminating in metastatic colonization [ 78 ].

Angiogenesis blockade therapy may lead to vascular regression and resultant intra-tumoral hypoxia. Various investigations have been fulfilled to assess an enhancement in hypoxic areas in primary tumors upon angiogenesis blockade therapy [ 76 , 79 ].

Further investigation also exposed an attendant augmentation in HIF-1a expression during treatment. HIF-1a and hypoxia are recognized drivers of epithelial-mesenchymal transition EMT , a process that induced tumor metastasis. Significant improvement in the expression and activities of EMT-related genes e.

Moreover, loss of the epithelial marker, E-cadherin, and the stimulation of the mesenchymal marker, vimentin, has been evidenced following anti-angiogenic treatment [ 80 ].

Hypoxic milieu also largely promotes VEGF expression by the upstream transcription factor HIF-1a [ 81 ]. HIF-1, in turn, inspires tumors to achieve more angiogenic and invasive competencies, culminating in metastasis [ 82 ].

In fact, hypoxia and EMT bring about increased invasiveness and metastasis of tumors mainly caused by up-regulation of c-Met, Twist, and HIF-1a [ 83 , 84 ]. Conversely, semaphorin 3A Sema3A , a well-known endogenous anti-angiogenic molecule, is substantially down-regulated in tumors, ensuring provoked invasiveness and metastasis [ 85 ].

Ang-Tie signaling system is a vascular-specific receptor tyrosine kinases RTK pathway complicated in modifying the vascular permeability and blood vessel formation and remodeling by potent angiogenic growth factors, Ang-1 and Ang-2 [ 86 ].

Molecular analysis has confirmed that activation of the Ang-Tie pathway as a result of the connection between Ang-1 and Tie2 receptor on the M2 subpopulation of monocytes, hematopoietic stem cells HSCs , and endothelial cells ECs of blood and lymphatic vessels elicits maturation or stabilization of blood vessels [ 80 ].

Besides, Ang-2 suppresses this pathway, eventually sustaining remodeling or generation of vascular sprouts upon exposure to VEGF [ 87 ].

Ang-2 up-regulation has been noticed in multiple types of tumors and is likely involved in resistance versus anti-VEGF therapy [ 88 , 89 ]. For instance, there is clear evidence signifying that enhanced serum Ang-2 levels are in association with an undesired response to bevacizumab therapy in CRC patients [ 90 ].

Studies in lung adenocarcinoma patients revealed that elevated levels of VEGFA and Ang-2 is valued prognostic biomarkers and double targeting of VEGFA and Ang-2 can improve therapeutic outcome [ 91 ].

As well, up-regulation and compensatory mechanisms of other growth factors, in particular basic fibroblast growth factor bFGF , are thought to contribute to the stimulation of the resistance to VEGF targeted therapies.

Improved level of the bFGF has strongly been evidenced in the chronic inflammation area, after tissue injury, as well as human cancers bevacizumab [ 92 ].

Upon bevacizumab treatment in glioblastoma tumor models, Okamoto et al. showed the increased levels of the bFGF and PDGF expression in the endothelial cells, pericytes, and also tumor cells, in turn, caused robust resistance to bevacizumab [ 94 ]. Also, cancer patients with up-regulated bFGF in serum usually show no desired response to sunitinib, indicating the necessity of co-targeting VEGF and bFGF pathways concurrently [ 95 , 96 ].

Increased metastasis and invasiveness in response to anti-angiogenesis therapy vary according to treatment type, dosage, and schedule. Sunitinib and anti-VEGF antibody monotherapy showed varied effects on mice tumor models, according to Singh et al. reports [ 77 ]. While sunitinib therapy increased tumor cell aggressiveness, anti-VEGF antibody treatment did not [ 77 ].

Chung et al. also corroborated these findings by comparing the effectiveness of several RTK inhibitors and antibody treatments in mouse models [ 97 ]. Though imatinib, sorafenib, or sunitinib increased lung metastasis after 66c14 cell injection, employing an anti-VEGFR2 antibody reduced the development of lung nodules [ 97 ].

Overall, reports show that the increased metastasis and invasiveness caused by angiogenesis blockade therapy depend highly on the treatment type.

Anti-angiogenic drug dosage and delivery schedules may also potentially cause resistance. Sunitinib at high doses accelerated tumor development and facilitated metastasis to the lung and liver, resulting in decreased survival [ 74 , 98 ].

Although sorafenib had comparable outcomes, sunitinib produced conflicting findings in various trials. High-dose sunitinib therapy before systemic injection of tumor cells enhanced the metastatic potential of lung cancer cells, but not RCC cells.

Recently, scientists have concentrated on the role of immune checkpoint molecules, such as cytotoxic T-lymphocyte antigen-4 CTLA-4 and programmed cell death protein 1 PD-1 , largely participating in tumor cell escape from immune surveillance as their capacity to obstruct T cell activation [ 99 , ].

Hence, immune checkpoint inhibitors ICIs have been evolved for suppressing these immune checkpoint molecules [ ]. FDA-approved ICIs comprise the nivolumab, cemiplimab, and pembrolizumab, atezolizumab, avelumab, durvalumab, and also ipilimumab [ ]. Atezolizumab has been approved for use in combination with bevacizumab, paclitaxel, and carboplatin as the first-line treatment of patients with NSCLC [ ].

PD-L1 expression is regulated by various factors, such as inflammatory and oncogenic signaling, leading to the varied significances of PD-L1 positivity. Recent reports exhibited that combination therapy with anti-angiogenic agents and ICIs could elicit synergistic anti-tumor effects in preclinical models as well as humans Table 3.

Meanwhile, co-administration of anti-PD-1 and anti-VEGFR2 monoclonal antibodies mAbs in the Colon adenocarcinoma mice model gave rise to the potent inhibition of tumor growth synergistically without overt toxicity [ ].

VEGFR2 blockade therapy negatively regulated tumor neovascularization, as evidenced by the attenuated frequencies of microvessels, whereas PD-1 inhibition exerted no effect on tumor angiogenesis. PD-1 mAbs improved T cell infiltration into tumors and promoted local immune response, as documented via the improvement in various proinflammatory cytokine expressions.

Such events signified that concurrent suppression of PD-1 and VEGFR2 might inspire synergistic in vivo anti-tumor influences by dissimilar mechanisms [ ]. Further, in a mouse model of small-cell lung cancer SCLC , co-administration of anti-VEGF and anti-PD-L1 mAbs resulted in a more prominent therapeutic outcome than mono therapy with each agent [ ].

Notably, the depleted T-cell phenotype following anti-PD-L1 therapy was revoked through the addition of anti-VEGF blockade therapy. Analysis revealed that VEGFA expression improves the expression of the inhibitory receptor TIM-3 on T cells, representative of an immunosuppressive action of VEGF in patients with SCLC during PD-1 blockade therapy.

Thereby, it seems that VEGFA inhibition may entice T cell activation at higher levels, facilitating T cell-mediated anti-tumor immunity [ ].

Similarly, combination therapy with sunitinib and PD-L1 blocked therapy prolonged overall survival OS of treated RCC mice models in comparison to mono therapy with either drug [ ]. Besides, in the triple-negative breast cancer TNBC mice model, PD-L1 blocking was highly effective as an adjuvant monotherapy.

However, its co-administration with paclitaxel chemotherapy with or without VEGF blocked therapy showed superiority over neoadjuvant therapy [ ].

In , Schmittnaegel et al. also noticed that dual Ang-2 and VEGFA inhibition induced antitumor immunity that was promoted by PD-1 blockade therapy in breast cancer, pancreatic neuroendocrine tumor, and melanoma [ ].

They showed that Ang-2 and VEGFA blockade by a bispecific antibody A2V caused vascular regression, tumor necrosis along with improved antigen presentation by intratumoral phagocytes [ ].

Recent clinical trials have also shown that bevacizumab plus atezolizumab could induce synergistic influence on the median OS of patients with RCC [ ], and also in combination with nivolumab could elicit modest efficacy in ovarian cancer patients [ ].

Also, co-administration of PD-L1 inhibitor avelumab with axitinib resulted in improved objective response rate ORR in HCC [ ] and also RCC [ ] patients, with acceptable safety profile. Also, combination therapy with axitinib and pembrolizumab enhanced median progression-free survival PFS in sarcoma patients more evidently than axitinib or pembrolizumab monotherapy.

The most common treatment-related unwanted events were autoimmune colitis, pneumothorax, transaminitis, seizures, hemoptysis, and hypertriglyceridemia [ ].

Besides, co-administration of regorafenib plus nivolumab resulted in significant antitumor impacts in patients with gastric cancer and CRC [ ]. Moreover, co-administration of nivolumab plus sunitinib or pazopanib showed a significant anti-tumor effect in advanced RCC patients [ , ].

Conversely, other trials revealed that combined use of regorafenib plus nivolumab [ ] and also ramucirumab plus pembrolizumab [ ] had no remarkable therapeutic merits in CRC patients [ ] and patients with advanced biliary tract cancer BTC [ ], respectively.

Therapeutic cancer vaccines ease tumor regression, remove minimal residual disease MRD , entice durable antitumor memory, and also averts non-specific or adverse events [ , ]. Till, FDA has approved three cancer vaccines, comprising Bacillus Calmette-Guérin BCG lives, sipuleucel-T, and also talimogene laherparepvec T-VEC respectively for patients with early-stage bladder cancer, prostate cancer as well as melanoma [ ].

In the melanoma mice model, Bose and coworkers found that a treatment regimen comprising a 7-day course of axitinib 0. These desired outcomes are probably exerted by a decrease in myeloid-derived suppressor cells MDSC and Treg frequencies in the tumor concomitant with induction and recruitment of CTLs in TME [ ].

Also, addition of the axitinib to oncolytic herpes simplex virus oHSV expressing murine IL12 G47Δ-mIL12 triggered improved OS in both immunodeficient and immunocompetent orthotopic glioblastoma mice models than mice receiving monotherapy [ ].

Notably, the addition of the ICI did not promote efficacy in mice models [ ]. As well, combination therapy with sunitinib and vesicular stomatitis virus VSV brought about the eradication of prostate, breast, and kidney malignant tumors in mice, while monotherapy with VSV or sunitinib did not [ ].

Importantly, enhancement in median viral titers by fold following combination therapy indicated that this regimen could potentiate oncolytic virotherapy permitting the recovery of tumor-bearing animals.

In RCC and NSCLC mice model, co-injection of reovirus and sunitinib more potently attenuated tumor burden supporting improved OS, and also reduced the population of immune suppressor cells in tumors compared with monotherapy with reovirus [ ].

Thereby, it appears that this regimen can be a rational and effective strategy ready for clinical testing against RCC and NSCLC. Also, Tan and coworkers showed that the bevacizumab improved viral distribution and also tumor hypoxia and promoted the population of apoptotic cells and thus stimulated a synergistic antitumor impact when used in combination with oHSV in TNBC murine models [ ].

Combining bevacizumab with OHSV expressing vasculostatin RAMBO also demonstrated great anti-tumor capacities in glioma xenografts [ ]. Correspondingly, intratumorally administration of RAMBO 1 week after tumor inoculation, and intraperitoneally administration of bevacizumab twice a week reduced migration as well as invasion of glioma cells [ ].

Co-treated mice also experienced improved OS and dampened tumor invasion than those treated with bevacizumab alone [ ]. In another study, combining tumor antigen-loaded DCs vaccination and anti-angiogenic molecule lenalidomide synergistically potentiated antitumor immunity in the mice colon cancer model, largely provided by suppressing the establishment of immune suppressive cells and also activation of effector cells, such as natural killer NK cells [ ].

This regimen similarly caused a robust reduction in tumor growth and malignant cell spread in lymphoma [ ] and also myeloma [ ] xenografts by similar mechanisms. Further, lenalidomide in combination with a fusion DNA lymphoma vaccine reduced the systemic population of MDSC and Treg in tumor-bearing mice and also led to the decreased tumor burden [ ].

In addition, the combination therapy supported the incidence of the higher rates of the antitumor T cells, providing further rationale for clinical application [ ]. Currently, a clinical trial was conducted to address the safety and efficacy of combination therapy with sipuleucel-T as a cellular prostate cancer vaccine with bevacizumab in 22 prostate cancer patients [ ].

Combination therapy persuaded immune reactions and also alleviated prostate-specific antigen PSA in participants with biochemically recurrent prostate cancer [ ].

In contrast, co-administration of bevacizumab plus MA multi-peptide vaccine adjuvanted with poly-ICLC polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose did not show superiority over monotherapy with each agent in terms of alteration in OS and PFS in glioblastoma patients [ ].

However, a phase II study evaluating the safety and efficacy of bevacizumab in combination with ERC, advanced immunotherapy based on freshly extracted tumor cells and lysates, revealed that this regimen could prolong the OS in patients who received ERC plus bevacizumab compared to bevacizumab monotherapy 12 months versus 7.

Besides, evaluation of the safety, tolerability, and anti-myeloma activity of the PVX, a novel tetra-peptide vaccine with 3 of the 4 antigens XBP1 [2 splice variants] and CD with or without lenalidomide was accomplished in MM patients by Nooka et al.

They showed that the PVX vaccine was well tolerated, accompanied by mild injection site reactions and constitutional symptoms. Meanwhile, 5 of 12 patients showed clinical response to combination therapy [ ]. Importantly, CRC patients presented complete pathological remission following treatment with bevacizumab, oxaliplatin plus leucovorin and 5-fluorouracil FOLFOX-4 , surgery, and the oncolytic virus Rigvir [ ].

In consistence with previous findings, it appears that angiogenesis blockade therapy could promote viral delivery through targeting the TME [ ]. Adoptive cell therapy ACT with using TILs or genetically-modified T cells expressing novel T cell receptors TCR or chimeric antigen receptors CAR T cells or CAR-NK cells is another plan to convince the immune system to stimulate recognition of the maligned cells and then their eradication [ , ].

Notwithstanding, tumor vasculature usually obstructs the tumor-specific T cells infiltration, averting anti-tumor immunity. In the B16 melanoma mice model, co-administration of anti-VEGF mAb to ACT abrogated tumor progress and improve OS [ ].

Similarly, anti-angiogenic therapy could also improve the antitumor functions of cytokine-induced killer cells CIK cells cells by normalizing tumor vasculature and alleviating the hypoxic TME, as shown in NSCLC xenografts [ ]. Meanwhile, Shi et al. evaluated the therapeutic benefits of combination therapy with recombinant human endostatin rh-endostatin and CIK cells in NSCLC murine model.

They exhibited that rh-endostatin normalized tumor vasculature and attenuated hypoxic regions in the TME [ ]. The rh-endostatin markedly potentiated the administrated CIK cells homing and also reduced immune suppressive cells frequency in the tumor tissue. On the other hand, the used regimen instigated a higher level of TILs in tumor tissue [ ].

Further, GD2-redirected CAR T cells plus bevacizumab displayed a remarkable anti-tumor effect in an orthotopic xenograft model of human neuroblastoma [ ]. Co-administration of bevacizumab or ganglioside GD2-CAR T cells or both by single systemic injection supported higher rates of CAR T cells infiltration into tumor tissue accompanied with improved IFN-γ levels in TME.

Additionally, the analysis presented that PD-L1 blockade therapy might augment the efficacy of this regimen [ ]. Likewise, epithelial cell adhesion molecule EpCAM redirected CAR NK cells injection resulted in CRC cell regression in animal models, which was potentiated when used in combination with regorafenib [ ].

These findings delivered a novel plan for the treatment of CRC and also other solid tumors. Anti-angiogenic agents as noticed can transiently stimulate a functional normalization of the disorganized labyrinth of vessels, sustaining the therapeutic efficacy of coadministered chemotherapeutic agents.

Notwithstanding, durable angiogenesis suppression usually fences tumor uptake of chemotherapeutic drugs, and so accomplishment of further studies in this context are urgently required [ ]. Correspondingly, designing intermittent treatment schedules is of paramount significance [ ].

A study in 9L glioma cell-bearing rats showed that coadministration of axitinib with metronomic cyclophosphamide potently suppressed tumor progress, whereas multiple treatment cycles were needed by monotherapy with metronomic cyclophosphamide to abrogate tumor growth [ ].

Unfortunately, the abridged tumor infiltration of 4-OH-CPA resulted in a reduction in cyclophosphamide-mediated 9L cell elimination [ ]. Such events in turn underlined lacking tumor complete regression by applied combined regimen, reflecting the importance of the optimization of drug scheduling and dosages.

In another study, co-administration of the bevacizumab plus cisplatin and paclitaxel concurrently also induced reduced tumor growth as well as improved OS in ovarian cancer xenografts [ ]. Also, monotherapy with bevacizumab suppressed ascites formation, accompanied by the partial impact on tumor burden [ ].

TNP, an angiogenesis inhibitor, plus cisplatin inhibited the liver metastasis of human pancreatic carcinoma [ ]. Indeed, liver metastasis percentages reduced from While monotherapy with each agent did not modify tumor growth in vivo, the addition of TNP to cisplatin strikingly reduced tumor growth [ ].

Of course, it seems that TNP may entice a decrease in glioma tumor uptake of some chemotherapeutic drugs, such as temozolomide, by affecting the tumor vasculature as a result of its pharmacodynamic effect [ ].

As cited, more comprehensive studies are required to define how these combinations can efficiently be utilized. Another study also exhibited that the addition of the TNP to cisplatin chemotherapy reduced the microvascular density of bladder cancer in a murine model [ ]. Nonetheless, TNP has no significant influence on the cisplatin impact versus bladder cancer as determined by apoptosis and cell proliferation [ ].

Besides, Bow and coworkers demonstrated that local delivery of angiogenesis-inhibitor minocycline could potentiate the anti-tumor efficacy of radiotherapy RT and oral temozolomide, as evidenced by enhanced OS in a rodent glioma model [ ].

These findings offered further evidence for the idea that angiogenesis inhibitors in combination with conventional therapeutic modalities could promote OS in glioblastoma patients [ ].

Moreover, the addition of the novel anti-angiogenic agent, SU, to paclitaxel supported improved PFS accompanied with some mild to modest adverse events e. However, the regimen led to the occurrences of thromboembolic events and prophylactic anticoagulation, suggesting that careful consideration must be taken.

Besides, TSU when used plus carboplatin and paclitaxel showed a manageable safety profile in NSCLC patients [ ]. Furthermore, combining TNP and paclitaxel was well tolerated with no significant pharmacokinetic interaction between them in NSCLC patients [ ]. Further, several clinical trials have verified the efficacy of combination therapy with anti-angiogenic agent and conventional therapy in patients with ovarian cancer [ , ], CRC [ , ], NSCLC [ ], MCL [ ] and also MM [ ].

For instance combination therapy with bevacizumab and paclitaxel plus carboplatin prolonged the median OS in participants with platinum-sensitive recurrent ovarian cancer [ ].

Finally, axitinib combined with cisplatin and gemcitabine [ ] and also bevacizumab plus paclitaxel and carboplatin [ ] induced significant anti-tumor effect in NSCLC patients, as documented by improved OS and PFS. In addition, the Ziv-aflibercept in combination with 5-fluorouracil, leucovorin, and irinotecan FOLFIRI significantly promoted OS in a phase III study of patients with metastatic CRC previously treated with an oxaliplatin-based regimen [ ].

However, Ziv-aflibercept in combination with cisplatin and pemetrexed did not significantly affect OS and PFS in patients with previously untreated NSCLC cancer [ ].

A list of trials based on combination therapy with angiogenesis inhibitors plus chemotherapy or chemoradiotherapy has been offered Table 4. RT crucially contributes to the multimodality treatment of cancer. Current evolving in RT have chiefly complicated improvements in dose delivery [ ].

Upcoming developments in tumor therapeutics will probably include the combination of RT with targeted therapies. Meanwhile, preliminary results of anti-angiogenic agents in combination with RT have produced encouraging consequences [ ].

Further, there are clear proofs that suggest that well-vascularized and perfused tumors mainly exhibit desired response to RT [ , ]. Studies have shown that the addition of the angiogenesis-inhibitor minocycline to radiotherapy and oral temozolomide could result in prolonged OS in a murine glioma model [ ].

Anti-angiogenesis therapy using anginex in combination with RT also supported tumor control in squamous cell carcinoma SCC xenografts accompanied by reducing oxygen levels in tumor tissue [ ].

Observation showed that the applied regimen modified the amount of functional vasculature in tumors and also augmented radiation-elicited tumor eradication [ ].

Likewise, robust hindrance of tumor proliferation was achieved from the addition of the angiogenesis inhibitor TNP to RT in SCC xenografts more evidently than monotherapy with each approach [ ].

Also, it was speculated that exclusive investigation of each tumor neovascularization competence can be imperative before deciding the angiogenesis blockade treatment [ ]. In contrast, the addition of TNP to RT attenuated the tumor control probability in murine mammary carcinoma [ ].

Such unanticipated consequence could be ensured from the partial reserve of reoxygenation by TNP, as no remarkable alteration was shown between the RT plus TNP and RT alone under hypoxic conditions [ ].

A potent anti-angiogenesis agent, liposomal honokiol, also elicited significant anti-tumor influence by stimulating apoptosis and also suppressing angiogenesis when used plus RT in Lewis lung cancer LLC xenografts [ ].

Liposomal honokiol, in fact, could ameliorate tumor cell radiosensitivity in vivo, offering that RT plus liposomal honokiol can engender better anti-tumor efficacy in a myriad of tumors, such as lung cancer, SCC, and CRC [ , , ].

In , Yang et al. evaluated the safety and efficacy of that combination therapy with axitinib plus RT in advanced HCC patients. They exhibited that the regimen was well tolerated with an axitinib MTD of 3 mg twice daily [ ]. Besides, the addition of the bevacizumab to adjuvant radiotherapy was associated with the manageable safety profile in breast cancer patients [ ].

Likewise, erlotinib in combination with bevacizumab as well as capecitabine-based definitive chemoradiation CRT showed acceptable safety in unresectable pancreatic cancer patients [ ]. As well 2 of 9 participants showed complete response to intervention [ ]. Of course, large-scale trials on this newer therapeutic mean seem justified.

Albeit there are some reports which show that combining anti-angiogenic therapy with RT had no therapeutic advantages. For instance, in rectal carcinoma patients, combination therapy with bevacizumab and capecitabine plus RT revealed no merits in terms of improved PFS or OS in the short or long term during a phase 2 clinical trial NCT [ ].

As a result of some divergences results related to anti-angiogenic agents as well as their modest responses, we must determine and categorize a spectrum of biomarkers, screening the patients of possible responders [ ].

Additionally, such biomarkers are urgently required to can monitor disease development and angiogenic actions of tumors following exposure with treatment angiogenesis inhibitors. There are some reports showing that angiogenesis inhibitors could not support therapeutic effect in previously treated metastatic breast cancer [ ].

These undesired events are likely related to the secretion of pro-angiogenic factors from resistant malignant tissue [ ].

The finding outlines the importance of determining biomarkers to predict the efficacy of VEGF-targeted therapies. Much effort has been spent in this regard and resulted in the finding several biomarkers comprising dynamic measurements such as variations in systemic blood pressure , circulating markers such as VEGF serum levels , genotypic markers such as VEGF polymorphism , blood cells frequencies such as progenitor cells , tissue markers such as IFP and also imaging parameters [such as estimating capillary permeability employing magnetic resonance imaging MRI ] [ ].

Recent studies have revealed that there is a negative correlation between OS with serum lactate dehydrogenase LDH and neutrophil levels in CRC patients who received bevacizumab plus standard chemotherapy [ ].

Besides, enhanced IL-8 levels were associated with shorter PFS, while low Ang-2 serum levels were related to improved OS in tumor patients undergoing angiogenesis blockade therapy [ 90 ]. Circulating endothelial cells CEC also has been determined as a robust indicator for the outcome of treatment with bevacizumab.

On the other hand, greater intra-tumoral expression of VEGFR-3 may predict better response, while overexpression of VEGFR1 mainly indicates poor survival [ ]. Other studies in RCC patients upon treatment with sorafenib also revealed that high baseline levels of VEGF were related to poor prognosis [ ], while serum levels of circulating neutrophil gelatinase-associated lipocalin NGAL and VEGF were powerfully supported prolonged PFS in RCC patients receiving sunitinib [ ].

In contrast to the classical hypothesis of vascular regression, the central aim of conventional anti-angiogenic treatments is tumor vascular normalization and maturity. This event, in turn, offered enhanced tumor access to chemotherapeutic drugs and underlays more efficient cancer immunotherapy.

As cited, survival benefits of angiogenesis blockade therapy are compromised by cancer resistance to theses agent, and thereby provoke interest in evolving more effective means to combine anti-angiogenic drugs with other conventional therapeutics.

To date, a large number of clinical trials have evaluated the safety and therapeutic merits of angiogenesis blockade therapy alone or in combination with other modalities in cancer panties Fig. Although combination therapy regimen mainly caused significant efficacy in cancer patients, intervention-related toxicities hurdle their application in clinic.

For instance, bevacizumab therapy could sustain ischemic heart disease. Indeed, CRC patients receiving bevacizumab may experience considerably augmented possibility of cardiac ischemia [ ]. In addition, it has been proved that combination therapy with angiogenesis inhibitors and chemotherapeutic agents may attenuate antitumor effects of chemotherapy.

Hence, further rigorous investigations are warranted to circumvent the cited problems. Moreover, determining the suitable dose and sequence is of paramount importance to optimize the effectiveness, toxicity, and tolerability of the combination therapy.

Thanks to the involvement of a myriad of cytokines and growth factors and the resultant interplay and compensation among them, co-targeting various growth factors is urgently required. The recognition and potent suppression of downstream kinases and strategic signaling biomolecules where several angiogenic pathways converge may defeat current difficulties motivated via the variety of angiogenic ligands and receptors and should be the emphasis of upcoming investigations.

For instance, dual EGFR inhibition erlotinib and cetuximab combined with bevacizumab is a safe and well-tolerated combination, demonstrating antitumor activity in patients with solid tumors [ ].

BQ13esides, continued treatment with conventional anti-angiogenic agents is related to toxicity and drug resistance. These conditions offer a robust justification for novel plans to improve the efficacy of mAbs targeting tumor vasculature, such as antibody—drug conjugates ADCs and peptide-drug conjugates PDCs , offering a new avenue to exert anti-angiogenic effects on cancerous cells.

Clinical trials based on cancer therapy by anti-angiogenic agents registered in ClinicalTrials. gov October The schematic exemplifies clinical trials utilizing anti-angiogenic agents depending on the study status A , study phase B , study location C , and condition D in cancer patients.

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Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Tumor cells can camouflage themselves in order to hide from immune cells, thus avoiding being discovered.

Numerous cellular and molecular mechanisms have been shown to be responsible for tumor evasion 28 , Immunosuppressive cells, such as T-regs, TAMs, and MDSCs frequently accumulate within the TME, which is associated with an unfavorable prognosis.

When there are a large number of immune cells in tumor tissues, such as T-regs, MDSCs, TAMs, and DCs, they can promote an immunosuppressive microenvironment and participate in immune escape. Figure 2 The role of anti-VEGF treatment in the tumor microenvironment TME.

Tumor angiogenesis creates a hypoxic tumor microenvironment, which impedes T-effector cells、NK cells and DC cells infiltration into tumor, mediates tumor cell de-differentiation into CSCs, promotes proliferation of immunosuppressive cells, including Tregs and MDSCs, and polarizes TAMs to the immune inhibitory M2-like phenotype.

After anti-VEGF treatment, the anti-tumor factors increase, and the pro-tumor factors are decreased. In summary, anti-VEGF treatment alleviate the immunosuppressive tumor microenvironment and improve cancer immunotherapy.

Additionally, primary drug resistance due to a lack of tumor-infiltrating lymphocytes in the tumor should not be ignored. Studies have shown that patients that receive immunotherapy with higher Ang-2 expression tend to have poorer clinical outcomes.

This suggests that the Ang-2 pathway is another cause of immunotherapy resistance 34 , Under normal circumstances, the immune system can recognize and eliminate tumor cells within the tumor microenvironment.

Immunotherapy has heralded a new era of oncotherapy and aims to either directly eliminate cancer cells or activate the host immune response.

It is mediated through anti-cancer cell vaccines and antibodies, cytokines, adoptive immune cell transfer and immune checkpoint blockers ICBs. Tumor immunotherapy includes monoclonal antibody immune checkpoint inhibitors 36 , therapeutic antibodies, cancer vaccines, cell therapy and small molecule inhibitors.

In recent years, cancer immunotherapy has continued to progress. At present, this treatment method has shown strong anti-tumor activity in the treatment of solid tumors such as melanoma, NSCLC, kidney cancer, and prostate cancer.

Furthermore, immunotherapy drugs have been approved by the US FDA Food and Drug Administration for clinical application Moreover, increasing evidence has shown that overexpression of vascular growth factors can activate immunosuppressive cells directly and suppress immune effector cells to alter the immunosuppressive microenvironment.

The relationship between angiogenesis and immune therapy is a complicated interplay. Anti-angiogenic agents can stimulate the immune system and improve the immunosuppressive environment, while immunotherapy can also have anti-angiogenesis effects.

Therefore, there is a synergistic relationship between the two treatment methods 38 , Tumor cells can evade T cell-mediated killing by up-regulating the interaction of PD-L1 with the inhibitory receptor PD-1, which is expressed on tumor-infiltrating T-cells.

Tumor cells can evade T cell-mediated killing by upregulating the interaction of ligands such as PD-L1 with the inhibitory receptor PD-1, CTLA-4, and LAG-3, which are expressed on tumor-infiltrating T-cells It is inevitable that patients will develop resistance to immune checkpoint inhibitors due to a lack of PD-L1 and the inhibitory effect in the TME.

Facing a complex TME, the key strategy is to inhibit angiogenesis, and an effective immune response The formation of blood vessels in malignant tumors is largely caused by hypoxia and the excessive secretion of VEGF.

A case study of immune checkpoint inhibitors combined with anti-angiogenic drugs in the treatment of metastatic renal cell carcinoma demonstrated that antigen-specific T cell migration and expression of MHC-1 and PD-L1 were increased.

Furthermore, anti-tumor activity was enhanced with less toxicity Tumor blood vessels were found to be highly abnormal, with tumor vessels showing structural abnormalities, leading to hypoxia, acidity, and a high interstitial fluid pressure microenvironment.

These microenvironmental abnormalities can affect immune cell proliferation, infiltration, survival, and function Myeloid-derived suppressor cells MDSCs are one of the most important stromal cells of the TME, and protect tumor cells from the host immune system by suppressing T-cell function There is evidence to support the hypothesis that anti-angiogenic therapy and immunotherapy act synergistically GM-CSF, a potent cytokine promoting the differentiation of myeloid cells such as dendritic cells, macrophages and granulocytes, which elicits antitumor immunity by enhance tumor antigen presentation to T cells, has been proven to be effective across numerous clinical trials 46 — And Sylvie et al.

also included that human GFs in vitro actively inhibit the differentiation of monocyte-derived dendritic cells through the secretion of IL-6 and VEGF, limiting the immunotherapy of GM-CSF Furthermore, it also promotes proliferation of immunosuppressive cells, such as Tregs and MDSCs, and inhibits DC maturation, and restricts the development of T lymphocytes from the lymphoid progenitors 30 , 53 — A study 56 on three different NSCLC animal models demonstrated that combining adoptive transfer of cytokine-induced killer CIK cells with recombinant human endostatin significantly inhibited angiogenesis and tumor growth, whereas neither was effective when used alone.

Lydia Meder et al. conducted an experiment on five groups on the combined use of vehicle, IgG, VEGF inhibitor, PD-L1 inhibitor, VEGF inhibitor, and PD-L1 inhibitor in a mouse model of small cell lung cancer. The results indicate that treatment with VEGF, compared to any other treatment methods, the combination of inhibitor and PD-L1 inhibitor greatly improved PFS and OS in mice Yasuda et al.

reported that in a mouse model of colon cancer, the combined use of PD-1 inhibitors and VEGFR2 inhibitors demonstrated no obvious toxicity. Compared to the control group, the experimental group drugs were found to better inhibit tumor growth.

The author believes that the combined use of inhibitors can produce a synergistic anti-tumor effect in the body through a variety of mechanisms, including anti-VEGFR2 therapy resulted in a significant decrease of tumor micro vessels as well as reducing tumor vasculature and anti-PD-1 mAb treatment enhanced the infiltration of T cells into tumors.

And that the two drugs are not mutually exclusive Since immunotherapy has been proved to be effective against CSCs and the immunosuppressive TME, it is reasonable to surmise that a combination of anti-angiogenesis and immunotherapies would have a synergistic effect against recalcitrant tumors.

Indeed, studies have shown that 38 targeting the angiogenic factor VEGF, as well as its receptors, stimulates onco-immunity, since VEGF is known to be involved in the immune escape of tumors. The VEGF signaling pathway can abrogate the effects of anti-tumor therapy via various mechanisms.

Usually, is LFA1 that can interact on ICAM1. LFA1 is expressed on lymphocytes and it is a crucial for T cell entry into mammalian lymph nodes and tissues while ICAM1 on tumor target cells or endothelial cells Previous study showed that clustering of ICAM-1 was indeed prevented by VEGF and a reduced induction of ICAM-1 and VCAM-1 mRNA transcripts by TNF in the presence of VEGF Therefore, blocking VEGF and its receptor can help stimulate immune responses and improve immunotherapy outcomes.

Similarly, sunitinib inhibited the expansion of Tregs and MDSCs in patients with renal cell carcinoma 30 , 63 , In a mouse model of colon cancer, anti-PD-1 monoclonal antibodies and VEGFR2 resulted in significantly greater tumor inhibition compared to either monotherapy The relationship between angiogenesis and immune therapy has been suggested to be a complicated interplay Anti-angiogenic agents are known to stimulate the immune system and improve the immune suppression environment Furthermore, immunotherapy can also cause anti-angiogenesis effects, and there is a synergistic relationship between the two treatment methods Tumor cells can evade T cell-mediated killing by up-regulating the interaction of PD-L1 with the inhibitory receptor PD-1 that is expressed on tumor-infiltrating T cells.

Thus, it is inevitable that patients develop resistance to immune checkpoint inhibitors due to a lack of PD-L1 and the inhibitory effect in the tumor microenvironment. The therapy should inhibit angiogenesis, on the other hand trigger anti-tumor immunity The formation of blood vessels in malignant tumors is mainly caused by hypoxia and excessive secretion of vascular endothelial growth factor VEGF.

Recently, an accumulating number of clinical trials have been conducted to explore the efficacy of the combination of anti-angiogenesis and immunotherapy Table 1. Table 1 Principal clinical trials for the approval of antiangiogenic and or immunotherapy agents.

In a phase 3 clinical trial IMpower NCT , patients with metastatic non-squamous NSCLC ns-NSCLC were treated with a combination of Atezolizumab to Bevacizumab-based chemotherapy, including three groups: 1 Atezolizumab, Carboplatin, and Paclitaxel ACP ; 2 Atezolizumab, Bevacizumab, Carboplatin and Paclitaxel ABCP ; 3 Bevacizumab, Carboplatin and Paclitaxel BCP.

The results demonstrated that the ABCP group had significantly improved PFS and OS, with an average of 8. The median OS was not estimated in the ABCP, but it was In addition, patients with advanced NSCLC receiving treatment with a combination of Nivolumab and Bevacizumab were recruited for a phase 1 study NCT , which aimed to evaluate whether the combination therapy improves PFS and OS.

The experimental results indicate that the combined treatment group had significant safety, and the incidence of grade 3 and above adverse reactions is low.

Therefore, it has shown excellent therapeutic effects compared to the single-agent treatment group The combined treatment group had a median PFS of Additionally, the median OS of the combined treatment group was In , results of the phase 1 study NCT were reported.

Among the total 27 enrolled patients with previously treated advanced NSCLC that received Ramucirumab plus Pembrolizumab, 8 patients achieved an objective response.

Another phase 1 study NCT indicated that the combination of Ramucirumab plus Durvalumab led to an enhancement of preliminary antitumor activity in heavy pre-treated NSCLC patients with a median PFS of 1.

A first randomized phase 2 IMmotion study NCT for patients with previously untreated mRCC treated with Atezolizumab combination Bevacizumab or single Atezolizumab or single sunitinib showed that the PFS of this combination group significantly improved within the population, whatever the PD-L1 status Immunotherapy with PD-1 and PD-L1 inhibitors or combined with antiangiogenic therapy i.

VEGF inhibitors or CTLA-4 antibodies has become a first line therapy for advanced RCC patients Another phase 3 study NCT validated that the combination of Avelumab plus axitinib enhanced the curative effect in patients with advanced RCC, leading to remarkable improvement in median PFS In , a pivotal phase 3 study NCT demonstrated that Avelumab or Pembrolizumab Plus axitinib were more efficacious than sunitinib, a previous standard of care.

This study recruited metastatic renal cell carcinoma mRCC patients with results showing an improvement in PFS, a high response rate, and a low rate of intrinsic resistance Phase 1 study NCT of the VEGFR2 inhibitor apatinib plus anti-PD1 antibody SHR in patients with advanced hepatocellular carcinoma HCC has demonstrated manageable toxicity and encouraged clinical activity at recommended single-agent doses of both drugs These cohort results suggest that Nivolumab, plus Ipilimumab, may provide an improved ORR and OS, especially in arm A lower dose Nivolumab and higher dose Ipilimumab , relative to anti-PD-L1 monotherapy The combination of lenvatinib plus Pembrolizumab for unresectable HCC uHCC patients in the Phase 1b trial NCT represented a promising antitumor activity with an ORR of Moreover, an ongoing double-blind randomized controlled phase 3 study NCT of lenvatinib plus Pembrolizumab treatment of uHCC is currently being undertaken Imbrave NCT , a randomized, multicenter phase 3 clinical study aims to evaluate the efficacy and safety of Atezolizumab plus Bevacizumab versus Sorafenib among patients with advanced HCC.

The results indicated that, among patients in the combination group and in the Sorafenib group with HCC, the combination group showed a remarkable improvement in median PFS and OS with tolerated and controllable toxicity, compared to the Sorafenib group The results from this study indicated that the treatment had an ORR of Preliminary results from the phase 1 clinical trial NCT showed that Ipilimumab CTLA-4 antibody plus Bevacizumab VEGF inhibitors in patients with metastatic melanoma MM had favorable clinical outcomes, for reasons of increasing tumor vascular expression of ICAM-1 and VCAM-1 and lymphocyte infiltration in tumors Another open-label phase 1b trial NCT validated the efficacy of axitinib in combination with Toripalimab among patients with advanced melanoma with an ORR of In addition, a phase 2 study NCT in mCRC patients also demonstrated that the addition of Atezolizumab to Bevacizumab, as well as capecitabine, improved the median PFS of 4.

The results demonstrated that the combination was generally well tolerated, with an acceptable toxicity profile without any unexpected findings Anti-tumor angiogenesis was found to be favorable to T-cell infiltration and drug delivery to the tumor, thereby enhancing the efficacy of immunotherapy.

Additionally, immunotherapy can also increase tumor vascular normalization and form positive feedback to anti-angiogenesis. Therefore, the combination of anti-angiogenic agents and immunotherapy provides a new therapeutic approach for tumor patients.

A large number of studies have demonstrated that the combination therapy has good clinical application prospects. However, the relationship between tumor angiogenesis and immune response is intricate, and some tough problems still need to be solved for future practical application.

Firstly, there is no way to identify tumor patients that can benefit from combination therapy 93 , and anti-angiogenesis therapy has a lack of biomarkers, as mentioned above. In order to address the problem, oncologists have to identify the biomarkers that can be associated with patient groups that would be advantaged with this therapy.

Secondly, the dose of each drug, the optimal sequence, and the time of the combination also remain significant. The high or low dose, simultaneous or sequential treatment, will have an effect on the efficacy of the combination therapy.

Furthermore, studies have demonstrated that high doses of anti-angiogenic drugs can directly damage tumor blood vessels, which results in more serious disturbances of tumor microenvironment, such as hypoxia and immunosuppression Therefore, it is necessary to choose the appropriate drug dosage, and optimize the schedule of tumor immunotherapy and anti-angiogenesis therapy in order to obtain improved anticancer efficacy.

Moreover, the most frequent side effect of anti-angiogenic is hypertension Therefore, primary or acquired resistance, including non-upregulation VEGF in tumors, changes in the TME, the presence of CSCs, and the patient with hypertension contribute to anti-angiogenesis failure Besides, resistance to immunotherapy, including lack of tumor-infiltrating lymphocytes in the tumor, accumulating immunosuppressive cells in the TME and secreting immunosuppressive cytokines in the tumor cells, contributes significantly to failure of immunotherapy.

FL and JH contributed to the study design. HH and YC were responsible for data collection. ST, YH, and SF drafted and prepared the manuscript. SW worked for the table and figures. All authors participated in the data interpretation and contributed to the manuscript writing with important intellectual input.

All authors approved the final version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Soria J-C, Mauguen A, Reck M, Sandler A, Saijo N, Johnson D, et al.

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