**8. Synergy of anti-angiogenic agents with immunomodulatory therapy**

A series of pre-clinical studies have shown that the use of anti-angiogenic agents along with immune checkpoint inhibitors (ICI) as a combination therapy has a synergistic and enhanced effect on the tumour when compared to either ICI therapy or anti-angiogenic therapy alone. Immunotherapy has emerged as a promising treatment option for many cancer types, offering hope for patients with the demonstration of improved outcomes including durable responses in some. Unfortunately, there are still many patients that either have short lived responses to such therapies or none at all. To overcome resistance mechanisms, combinations of immunotherapy with other treatments including VEGF inhibitors are being explored.

Since 2013, pre-clinical investigations in mice with various tumours have indicated that the combination of ICI and anti-angiogenic agents results in prolonged overall survival [80]. It has been observed that the VEGF can cause the upregulation of immune checkpoint molecules such as PD-1 and as a result, the use of anti-VEGF agents has been seen to reduce the expression of PD-1 on cytotoxic T lymphocytes [81]. Thus, the combination of using both anti-VEGF agents as well as anti-PD-1 agents could have a synergistic effect on inhibiting further tumour development [81]. Through the encouraging findings of pre-clinical investigations, many clinical studies have recently or are still in the process of investigating this.

There are a multitude of clinical studies supporting the role of bevacizumab in the positive immune modulation of the tumour microenvironment and its beneficial effects when combined with the immune checkpoint PD1/PDL1 and

**49**

*DOI: http://dx.doi.org/10.5772/intechopen.89667*

and macrophages increased as well.

suppression [84].

clinical setting.

**9.1 Circulating biomarkers**

*Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

CTLA4 inhibitors. In a study investigating melanoma patients treated with ipilimumab plus bevacizumab versus ipilimumab alone, the results showed that the combination therapy increased circulating CD4+ and CD8+ T cells compared with ipilimumab monotherapy [82]. The investigation showed that there was a greater median overall survival in patients undergoing combination therapy (25.1 months) compared to those who underwent the ipilimumab alone treatment (10.1 months) [82]. Furthermore, a separate study of patients with RCC investigating the effect that bevacizumab plus atezolizumab had versus bevacizumab alone found that the combination therapy demonstrated a reduction in neovasulature-related gene expression and decreased microvascular density. The treatment was also associated with an increased tumour infiltration of CD8+ T cells as demonstrated by immunohistochemical staining of cells [83]. This study also demonstrated that MHC Class I is upregulated as a result of the treatment and that both intratumoural CD8+ T cells

In a phase II study involving patients with RCC, as compared with sunitinib monotherapy, atezolizumab and bevacizumab demonstrated improvements in PFS in patients with an immunosuppressive tumour microenvironment [84]. Whilst it was also discovered that the use of atezolizumab failed to generate an anti-tumour immune response (possibly due to myeloid-induced immune suppression), the addition of bevacizumab to atezolizumab was found to be able to overcome this

Both pre-clinical and clinical studies have shown that anti-angiogenic agents and immunomodulatory therapies have a synergistic affect in reducing tumour growth and a multitude of clinical trials are currently investigating this synergy further. Thus, there is promise in the use of a combination therapy with anti-angiogenic

In view of the variable outcomes seen in the clinic, there is a need for the development of validated predictive biomarkers of response for anti-angiogenic therapy. In this way, patients who will derive benefit from such agents could be appropriately selected, whilst those that will not derive benefit (either at the outset or during therapy) could be selected for alternative, more effective therapy. Such a strategy would not only improve clinical outcomes but would also reduce the unnecessary burden of (a) toxicity to the patient, and (b) cost to the economy. Despite extensive international research in this field, there is currently no biomarker which predicts benefit or resistance to anti-angiogenic agents that is approved for routine clinical practice. The following are amongst several which have been investigated in the

Circulating biomarkers are an attractive tool for patients and clinicians as 'liquid biopsies' are relatively non-invasive and easy to perform, as compared with tissue biopsies of tumour with associated risks and potential technical difficulties depending on tumour site. VEGF levels have been studied as a potential biomarker with high levels associated with poorer outcomes [85]. Findings regarding its utility as a predictive biomarker have been more inconsistent [85]. An analysis of four randomised phase 3 trials investigated circulating VEGF level as a prognostic and predictive biomarker in mCRC, lung cancer and RCC which included bevacizumab in the treatment regimen. Tumour specimens were also tested for VEGF level. This

agents and immunomodulatory agents to improve on patient prognosis.

**9. Potential predictive biomarkers for anti-angiogenic agents**

*DOI: http://dx.doi.org/10.5772/intechopen.89667 Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

CTLA4 inhibitors. In a study investigating melanoma patients treated with ipilimumab plus bevacizumab versus ipilimumab alone, the results showed that the combination therapy increased circulating CD4+ and CD8+ T cells compared with ipilimumab monotherapy [82]. The investigation showed that there was a greater median overall survival in patients undergoing combination therapy (25.1 months) compared to those who underwent the ipilimumab alone treatment (10.1 months) [82]. Furthermore, a separate study of patients with RCC investigating the effect that bevacizumab plus atezolizumab had versus bevacizumab alone found that the combination therapy demonstrated a reduction in neovasulature-related gene expression and decreased microvascular density. The treatment was also associated with an increased tumour infiltration of CD8+ T cells as demonstrated by immunohistochemical staining of cells [83]. This study also demonstrated that MHC Class I is upregulated as a result of the treatment and that both intratumoural CD8+ T cells and macrophages increased as well.

In a phase II study involving patients with RCC, as compared with sunitinib monotherapy, atezolizumab and bevacizumab demonstrated improvements in PFS in patients with an immunosuppressive tumour microenvironment [84]. Whilst it was also discovered that the use of atezolizumab failed to generate an anti-tumour immune response (possibly due to myeloid-induced immune suppression), the addition of bevacizumab to atezolizumab was found to be able to overcome this suppression [84].

Both pre-clinical and clinical studies have shown that anti-angiogenic agents and immunomodulatory therapies have a synergistic affect in reducing tumour growth and a multitude of clinical trials are currently investigating this synergy further. Thus, there is promise in the use of a combination therapy with anti-angiogenic agents and immunomodulatory agents to improve on patient prognosis.
