2.Immune Checkpoint
The immune system consists of innate and acquired immunity, which, once
activated, clears infectious pathogens and tumor cells. There are
inhibitory pathways in antimicrobial or antitumor immune responses that
normally maintain autotolerance to avoid excessive damage and limit
associated tissue damage [17, 18]. These receptor and ligand
inhibitory pathways are known as ”Immune Checkpoint” and are used by
tumor cells to avoid Immune attack. The development of monoclonal
antibodies to inhibit these checkpoints, thereby removing the Inhibition
of immunocytes and enabling them to recognize and kill tumor cells, is
called ”Immune Checkpoint Inhibition”. These drugs are called ”Immune
Checkpoint Inhibitor” (ICI) [19, 20]. FDA-approved anti-CTLA-4 and
anti-PD-1 antibodies for cancer treatment led to the belief that
immunotherapy for cancer was realistic and further encouraged the
development of other new ICIs [21-23]. Immunotherapy is becoming an
important treatment for cancer patients [1, 12]. Immune checkpoint
blocking (ICB) based on monoclonal antibody (mAb) has also proved to be
a safe and effective treatment for hematologic malignancies in the past
decade [18, 23]. In oncology, checkpoints currently targeted by
inhibitors to amplify the reactivity of T cells, NK cells or bone marrow
cells include CTLA-4[24],PD-1,PD-L1(PD1 ligand
1/CD274),LAG-3(CD223),TIM3(T cell immunoglobulin-3),TIGIT(T cell
immunoglobulin and ITIM domain)[25],VISTA(V-domain immunoglobulin
suppressor of T cell activation)[26],B7/H3(CD276),KIR (killer cell
immunoglobulin-like
receptors),NKG2A,A2AR,CD39,CD73,CSF1R,CD47,etc.[18, 27, 28].(Figure
2)
Each member of the adenosine signaling pathway constitutes a different
drug target, meaning that it is possible for combined therapy with not
just only one drug to target this or complementary signaling
pathway[29]. Many of these combinations are currently in preclinical
and clinical trials, such as anti-CD73 and anti-A2aR combinations,
anti-CD73 and anti-PD-1 combinations, as well as anti-A2aR and
anti-TIGIT antibody combinations [17, 27, 30-32].(table 1)