Angiogenesis and immune checkpoint dual blockade in combination with radiotherapy for treatment of solid cancers: opportunities and challenges

Abstract

Several immune checkpoint blockades (ICBs) capable of overcoming the immunosuppressive roles of the tumor immune microenvironment have been approved by the US Food and Drug Administration as front-line treatments of various tumor types. However, due to the considerable heterogeneity of solid tumor cells, inhibiting one target will only influence a portion of the tumor cells. One way to enhance the tumor-killing efficiency is to develop a multiagent therapeutic strategy targeting different aspects of tumor biology and the microenvironment to provide the maximal clinical benefit for patients with late-stage disease. One such strategy is the administration of anti-PD1, an ICB, in combination with the humanized monoclonal antibody bevacizumab, an anti-angiogenic therapy, to patients with recurrent/metastatic malignancies, including hepatocellular carcinoma, metastatic renal cell carcinoma, non-small cell lung cancer, and uterine cancer. Radiotherapy (RT), a critical component of solid cancer management, has the capacity to prime the immune system for an adaptive antitumor response. Here, we present an overview of the most recent published data in preclinical and clinical studies elucidating that RT could further potentiate the antitumor effects of immune checkpoint and angiogenesis dual blockade. In addition, we explore opportunities of triple combinational treatment, as well as discuss the challenges of validating biomarkers and the management of associated toxicity.

Safety and Efficacy of Transarterial Chemoembolization Combined With Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma

“…Antiangiogenic treatment, such as TKIs, promotes the infiltration of effector lymphocyte cells into tumor microenvironment(TME) through “tumor vascular normalization”, meanwhile alleviates hypoxia and reduces immunosuppression, therefore enhances the efficacy of immunotherapy ( 16 ). ICIs may restore the immune-supportive TME through inhibiting immune checkpoints and promoting vascular normalization ( 17 ). Thus, TKIs plus ICIs develop a positive reinforcing feedback loop to deal with the hypoxic and immunosuppressive TME.…”

Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice

“…It is well accepted that neovascularization plays a critical role in tumor development, invasion, metastasis, and resistance to therapy ( Xu et al, 2022 ). Moreover, angiogenesis inhibitors combined with ICB show remarkable antitumor efficacy in non-small cell lung cancer, hepatocellular carcinoma, and CRC ( Schmittnaegel et al, 2017 ; Zhu et al, 2021 ). Therefore, our further study will focus on whether STS with angiogenesis inhibitors and ICB can be a more effective therapeutic strategy for CRC.…”

How to Improve SBRT Outcomes in NSCLC: From Pre-Clinical Modeling to Successful Clinical Translation

“…Due to considerable tumor and micro-environmental heterogeneity, multi-target multi-agent therapeutic strategies are currently being explored and are likely to yield promising results in the near future. One such example is the combination of anti-PD1 and anti-angiogenic agents aiming to alleviate immunosuppression with radiotherapy [ 140 ]. Similarly, dual immune-checkpoint blockade including established (anti-PD-1 and anti-CTLA-4) but also new combinations such as Relatlimab (anti LAG-3), as demonstrated in the RELATIVITY-047 (NCT03470922) study on the reinvigoration of T-cell activity, are awaited to be explored in combination with radiation therapy.…”