Figure 1. Synergistic effect of immune checkpoint blockade and anti-angiogenesis as a rational for improved targeted therapies.
The resistance towards ICI could be alleviated by combination therapy with anti-angiogenesis treatment that not only prunes blood
vessel but also reprograms the tumor immune microenvironment. In this sequential and iterative immunity-angiogenesis cycle, the
complement interaction between ICI and anti-angiogenics transforms the immunosuppressive tumor microenvironment into
immunosupportive microenvironment. PD-1: anti-programmed death receptor 1; PD-L1: anti-programmed death receptor ligand 1;
CTLA-4: anti-cytotoxic T lymphocytes antigen-4; APC: antigen-presenting cell; VEGF: vascular endothelial growth factor; CAR:
Chimeric antigen receptor; TLR: toll-like receptors.
Kidney Cancer Journal 51
the RCC treatment algorithm and also highlight the
novel approaches being evaluated in ongoing clinical
trials.
Rationale for Selection of Immunotherapy
Given that RCC is considered immune-responsive in nature
with high numbers of immune cells present in the
tumor microenvironment, targeted immunotherapy was
explored as a potential therapy in RCC patients who
were non-responsive to conventional targeted therapies.7
One immune strategy involved the use of immune
checkpoint inhibitors (ICI).8 In particular, the use of sophisticated
ICIs, including anti-programmed death receptor
1 (PD-1), anti-programmed death receptor ligand
1 (PD-L1), and anti-cytotoxic T lymphocytes antigen 4
(CTLA-4), have been developed and studied in large international
phase III trials demonstrating significant and
clinically relevant improvements in efficacy. As such,
these new therapies have quickly been integrated into
the RCC landscape. PD-1 and PD-L1 antibody- based
novel ICIs have been approved by the FDA as the standard
second-line treatment for mRCC as well as in the
first-line for moderate to high-risk mRCC.9 Notably, the
footprints of ICI, expanded across the landscape of oncology
with the approval of nivolumab and ipilimumab
combination, especially in patients with intermediate to
poor-risk renal cell carcinoma (RCC).
Underlying Mechanisms of Action
In-depth understanding of T cell function and associated
immunosuppressive molecules have highlighted the central
role of the tumor micro-environment. During tumorigenesis,
a tumor may trigger certain immune- resis-
tant mechanisms including systemic dysfunction in T