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Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?
Rakesh R Ramjiawan1,2, Arjan W Griffioen2, Dan G Duda3
1E. L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom St, Cox-734, Boston, MA, 02114, USA.
Abstract:
Angiogenesis is defined as the formation of new blood vessels from preexisting vessels and has been characterized as an essential process for tumor cell proliferation and viability. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve tumor of nutrients and oxygen, primarily through blockade of VEGF/VEGFR signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, alone or in combination with chemotherapy or other targeted therapies. But this success had only limited impact on overall survival of cancer patients and rarely resulted in durable responses. Given the recent success of immunotherapies, combinations of anti-angiogenics with immune checkpoint blockers have become an attractive strategy. However, implementing such combinations will require a better mechanistic understanding of their interaction. Due to overexpression of pro-angiogenic factors in tumors, their vasculature is often tortuous and disorganized, with excessively branched leaky vessels. This enhances vascular permeability, which in turn is associated with high interstitial fluid pressure, and a reduction in blood perfusion and oxygenation. Judicious dosing of anti-angiogenic treatment can transiently normalize the tumor vasculature by decreasing vascular permeability and improving tumor perfusion and blood flow, and synergize with immunotherapy in this time window. However, anti-angiogenics may also excessively prune tumor vessels in a dose and time-dependent manner, which induces hypoxia and immunosuppression, including increased expression of the immune checkpoint programmed death receptor ligand (PD-L1). This review focuses on revisiting the concept of anti-angiogenesis in combination with immunotherapy as a strategy for cancer treatment.
Insights
Combining anti-angiogenesis drugs with immunotherapy offers new cancer treatment strategies. Careful dosing can normalize tumor vasculature, enhancing immunotherapy, but excessive dosing may harm immune response.
Area of Science:
- Oncology
- Vascular Biology
- Immunotherapy
Background:
- Angiogenesis, the formation of new blood vessels, is crucial for tumor growth.
- Anti-angiogenic drugs targeting VEGF/VEGFR signaling have been approved but show limited survival benefits.
- Tumor vasculature is often abnormal, leading to poor perfusion and nutrient/oxygen supply.
Purpose of the Study:
- To review the role of anti-angiogenesis in combination with immunotherapy for cancer treatment.
- To explore the complex interactions between anti-angiogenic agents and the immune system.
- To understand how to optimize anti-angiogenic dosing for synergistic effects with immunotherapy.
Main Methods:
- Review of existing literature on angiogenesis, anti-angiogenic therapies, and immunotherapies.
- Analysis of the mechanisms by which anti-angiogenic drugs affect tumor vasculature and the tumor microenvironment.
- Examination of preclinical and clinical data on combination strategies.
Main Results:
- Anti-angiogenic therapy can transiently normalize tumor vasculature, improving perfusion and synergizing with immunotherapy.
- However, excessive anti-angiogenic dosing can lead to vessel pruning, hypoxia, and immunosuppression, including PD-L1 upregulation.
- The efficacy of combination therapy depends on careful dose and timing of anti-angiogenic agents.
Conclusions:
- Combination of anti-angiogenesis and immunotherapy is a promising strategy for cancer treatment.
- Optimizing anti-angiogenic dosing is critical to balance vascular normalization and avoid immunosuppression.
- Further research is needed to fully elucidate the mechanisms and guide clinical application.