Checkpoint modulation: Blocking the tumour’s immune evasion strategies

“The network of blood vessels itself is an important regulator of immunity because it controls white blood cell traffic. By preventing the infiltration of white blood cells, the cancer is able to evade the host’s immune system,” said lead author Gabriele Bergers from VIB-KU Leuven, Belgium. In animal models for breast and pancreatic cancer, Bergers and co-workers provided evidence that therapy with checkpoint inhibitors, such as anti-PD-L1, can sensitise and prolong the efficacy of anti-angiogenic therapy, and, conversely, anti-angiogenic therapy can improve anti-PD-L1 treatment, specifically when intratumoral vessels are generated that facilitate enhanced white blood cell infiltration, activity and tumour cell destruction (Science Translational Medicine, doi: 10.1126/scitranslmed.aak9679).

Opening the gates for T cells

Combining anti-angiogenic and immune-stimulating therapies in the treatment of tumours provided T cells, which excreted the immune activating cytokine interferon-g, with gates through which they could infiltrate the tumour and its micro-environment. There, the PD-L1-checkpoint inhibitors reversed the paralysation of T-cells by tumour cells, which – as a reaction to incoming T cells – overexpress the PD-L1 protein that binds to the PD-1 receptor on T-cells, shutting down their immune activity.

“We observed that the combination of immune system-activating and anti-angiogenic antibodies caused a kind of positive feedback loop,” stressed study co-author Elizabeth Allen. “The result is the growth of specific blood vessels that deliver cancer-fighting immune cells into the tumour. These high endothelial venules (HEVs) are normally found in lymphoid organs, such as lymph nodes, where they help transport white blood cells. For the first time, we showed that the growth of such HEVs can be therapeutically induced in tumours.” In animal models for breast cancer and pancreatic neuroendocrine tumours, but not in glioblastoma (GBM), the anti-VEGFR2-antibody-triggered growth of HEVs in tumours led to cancer cell death and tumour shrinkage.

Boosting HEVs

The researchers found that HEVs promoted lymphocyte infiltration and
activity through activation of lymphotoxin b receptor (LTbR) signalling. Further activation of LTbbR signalling in tumour vessels using an agonistic antibody enhanced HEV formation, immunity, and subsequent apoptosis and necrosis in pancreatic and mammary tumours. Finally, LTbR agonists induced HEVs in recalcitrant GBM, enhanced cytotoxic T cell (CTL) activity and, thus, sensitised tumours to antiangiogenic/anti-PD-L1 therapy.

“Our preclinical studies provide evidence that anti-PD-L1 therapy can sensitize tumours to antiangiogenic therapy and prolong its efficacy, and, conversely, antiangiogenic therapy can improve anti-PD-L1 treatment, specifically when it generates intratumoral HEVs that facilitate enhanced CTL infiltration, activity, and tumour cell destruction,” the authors conclude.

Industry activities

In order to broaden patient populations that respond to cancer immunotherapies and anti-angiogenesis, Big Pharma companies such as Roche have already begun to test combinations of angiogenesis blockers and checkpoint modulators. Roche is in Phase I/II testing of a bispecific Ang2/VEGF-antibody dubbed vanucizumab (RG7221) with its CD40 agonist RG7876.

Innovative T cell approach

In May, German Merck KGaA and its partner Pfizer entered into a research collaboration with Swiss/German vaccine maker Vaximm. Under the agreement, the partners will combine Merck’s PD-L1 blocker avelumab with Vaximm’s VXM01, an oral attenuated Salmonella vaccine overexpressing the VEGF-receptor 2 (VEGFR2). The bacterial vector, which tends to accumulate into solid tumours on its own, is designed to activate T cells to attack the tumour vasculature. Two years ago, Vaximm reported preliminary hints of efficacy from a Phase I study carried out in pancreatic cancer patients (Oncoimmunology: e1001217). Under the terms of the agreement, Vaximm will be responsible for conducting two, non-blinded Phase I/II trials – one in glioblastoma and the other in metastatic colorectal cancer. According to Vaximm, VXM01 increased infiltration of various immune cells into the tumour in preclinical tests. Clinically, this was associated with improved patient survival.