LESERBREV
Opinion Clinically meaningful synergy through combined inhibition of VEGF and PD1/PD-L1 The advent of immune checkpoint blockade has revolutionized the understanding of tumor biology and cancer medicine. Still, existing approved immune checkpoint inhibitors, albeit rightfully honored with a Nobel Prize, are regarded as “low hanging fruits” heralding an even brighter future for cancer immunotherapy. An ever-increasing number of signal seeking and confirmatory immunotherapy combination trials are recruiting patients around the globe with the prospect of harnessing ever-increasing benefits. This article describes the emerging pre-clinical and clinical evidence of synergistic immune modulation through combined inhibition of VEGF and Anti-PD1/PD-L1. It is not a comprehensive review, but rather the personal opinion of the author.
CHRISTIAN KERSTEN Overlege, PhD Onkolog og koordinator Utprøvingsenheten ved onkologisk avdeling, Akershus Universitetssykehus Seniorforsker Sørlandet Sykehus
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he vascular endothelial growth factor (VEGF) receptor and their ligands have been widely recognized as having central roles in physiological and pathological angiogenesis. VEGF inhibitors which have been in clinical use for well over a decade, were developed to revert the ‘angiogenic switch’ which leads to the pathological blood supply in tumors. PRE-CLINICAL More recently, the immune modulating role of VEGF has gained widespread attention. In this regard, immune-evasion pathways, including overexpression of VEGF, have been linked to the development and progression of cancer. AntiVEGF therapies have in turn been shown to reduce VEGF-mediated immunosuppression within tumors and their microenvironment.1-3
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Furthermore, anti-VEGF therapies may also enhance anti–programmed death (PD)-1 and anti–PD-ligand 1 (PD-L1) efficacy by reversing VEGFmediated immunosuppression and promoting T-cell infiltration in tumors, see figure 1.4,5 In the following, drugs targeting PD1 or PD-L1 are collectively referred to as checkpoint inhibitor therapy (CIT). CLINICAL These intriguing pre-clinical findings have recently been supported through clinical trials combining anti-VEGF and CIT in multiple tumor types. RENAL CELL CARCINOMA Not surprisingly, renal cell carcinoma, a highly VEGF-dependent cancer, has lead the way to clinical evidence of synergy by combining anti-VEGF and
ONKONYTT • NR 2 // 2021
