Abstract
The hallmarks of renal cell carcinoma (RCC) are angiogenesis and immunogenic tumor microenvironment. Over the past decades, treatment options for metastatic RCC (mRCC) have been expanding, from the inhibition of vessel formation via antiangiogenic agents (AAs) to the stimulation of immune system by immune checkpoint inhibitors (ICIs). Since 2005, the introduction of antiangiogenic agents targeting vascular endothelial growth factor (VEGF), its receptors (VEGFRs), and mammalian target of rapamycin (mTOR) pathway have experienced moderate success in the therapeutics of mRCC, but patient outcomes remain suboptimal. Recently, the development of ICIs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the programmed death-1/programmed death ligand 1 (PD-1/PD-L1) pathways has dramatically changed the treatment landscape of mRCC. Expressly, the combination of ipilimumab and nivolumab has been confirmed to improve clinical outcomes and approved as a standard care for intermediate- or poor-risk mRCC patients. Nevertheless, innate or adaptive drug resistance is observed within both treatment approaches, limiting overall clinical benefit. This phenomenon will underscore the urgent need for new combinational therapy strategies with different mechanisms of action, which can improve efficacy in an extended patient population without severe toxic effects. In 2019, as the results of two critical phase III trials came to light, FDA approved axitinib plus avelumab, or pembrolizumab as first-line standard management for mRCC, which cements the combination of AAs plus ICIs and advances the mRCC treatment field. This review summarizes current evidence on the interplay and synergies between AAs and immunomodulating drugs in mRCC, focusing on the theoretical background and the status of current clinical development.
Highlights
Kidney cancer is amid the ten most common cancers in both men and women, with more than 400,000 cases worldwide in 2018 [1]
This review summarizes current evidence on the interplay and synergies between Antiangiogenic Agent (AA) and immunomodulating drugs in metastatic RCC (mRCC), focusing on the theoretical background and the status of current clinical development
The strategy of combining immune checkpoint inhibitors (ICI) with AAs has a strong biological rationale, there is a lack of comparative studies juxtaposing novel combination front-line options, most of the available studies utilizing sunitinib monotherapy as a comparator arm
Summary
Kidney cancer is amid the ten most common cancers in both men and women, with more than 400,000 cases worldwide in 2018 [1]. A preclinical study in mice reported that tumor-associated VEGF enhanced expression of PD-1 and other inhibitory checkpoints involved in CD8+ T cell exhaustion, such as CTLA4, TIM-3, and LAG-3, and targeting VEGF reverted expression of inhibitory checkpoints [51] Another preclinical mice RCC model showed synergistic antitumor activity of the combination of suntinib plus a murine anti-PD-1 antibody, with greater numbers of tumor infiltrating lymphocytes than any other controls treated with each agent alone [52]. A small-scale study presented that pazopanib, but not sunitinib, sharply improved the antigen-presenting function of DCs, together with DC-maturation markers HLA-DR, CD40, and CCR7 upregulated, in RCC patients [61] This phenomenon may lie in the diversity of immune regulation effect and a similar pattern of receptor recognition displaying different affinities for VEGFR among agents [62]. Cabozantinib has been observed to increase intratumoral CD8+ T cell infiltration, as well as decrease the number and activity of MDSCs infiltration in several preclinical models which designed to explore the effects of cabozantinib on the immune cells function and immune microenvironment [67, 68]
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