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Oiseth et al. Cancer immunotherapy

short) technique is a much simpler and more efficient C, or by cancer, thereby allowing these agents to avoid
method of editing genes than previous methods, and detection and destruction by immune cells [35,56-59] .
was first reported in 2012 [49] . The acronym stands for
“Clustered Regularly Interspaced Short Palindromic More than twenty checkpoint molecule pairs, both co-
Repeats”, which refers to a method normally used by stimulatory and co-inhibitory, have been discovered,
bacteria and archaea for protection against the invading including TIGIT/CD155, LAG-3/MHCII, and TIM3/Gal-
nucleic acids of viruses and plasmids. In 2013, the 9, which are variably expressed not only by T-cells
method was adapted for use in eukaryotic cells [50] , and but also by other cells of both myeloid and lymphoid
in late 2016 a group at Szechuan University became derivation [56,60] . Some of these molecules are similar to
the first to use CRISPR-edited cells in humans [51] . Other more common or better-known membrane moieties but
similar trials are scheduled to start in 2017 in the United with important differences: for example, lymphocyte-
States. Prior vaccination with a cancer vaccine can also activated gene-3 (LAG-3) is structurally homologous to
be used, in an attempt to “prime” rare tumor-specific CD4 but has a higher binding affinity to MHC class II
T-cells [52] . Although ACT has produced remarkable antigens than CD4. Since these checkpoint molecules
results in clinical trials with melanoma and hematologic are upregulated in suppressed T-cells, they can also
malignancies as well as with solid cancers, some deaths be used as markers of “T-cell exhaustion”. The two
have occurred in the trial phases secondary to marked pairs of inhibitory receptor/ligands which have received
cytokine release (“cytokine storm”, or “cytokine release the most attention in recent years are cytotoxic T
syndrome”) and cerebral edema [53] . Researchers are still lymphocyte-associated antigen-4 (CTLA-4) receptor
studying other ways of modifying T-cells to treat cancer. with B7 ligand, and programmed cell death protein 1
Relapsed and refractory B-cell acute lymphoblastic (PD1) receptor with PD1-L1 ligand. The expression
leukemia in pediatric and young adult patients is the first of CTLA-4 receptors on activated effector T-cells and
disease to receive approval from the FDA for CAR T-cell regulatory T-cells was reported in 1987 [61] . CTLA-
therapy, outside of clinical trials [54] . 4 has very high homology to CD28, with a higher
competitive binding affinity to B7, causing inhibition
IMMUNE CHECKPOINTS of proliferation and IL-2 secretion by T-cells [62] . PD-1
was cloned in 1992 [63] , and its ligands PD-L1 and PD-
In order to ensure that an immune inflammatory L2, which are members of the B7 ligand family, were
response is not constantly activated once foreign or tumor later characterized [64-66] . Unlike CTLA-4, PD-1 does not
antigens have stimulated a response, multiple controls or interfere with costimulation, but generates signals that
“checkpoints” are in place or activated. These checkpoints prevent phosphorylation of key signaling intermediates
are mostly represented by T-cell receptor binding to in the T-cell, which reduces their activation [67] . While B7
ligands on cells in the surrounding microenvironment, ligands are expressed by professional APCs (includes
forming immunological synapses which then regulate dendritic cells, macrophages and B cells), PD-L1 can
the functions of the T-cell, which become specialized, be expressed on many cell types, including T-cells,
or “polarized”, to perform different activities. As epithelial cells, endothelial cells, and tumor cells after
noted earlier, initial T-cell activation involves antigen exposure to interferon-gamma, produced later in
presentation by the MHC molecules on the antigen- the immune response by activated T cells. PD-L2 is
presenting cells (APCs) to the corresponding T-cell primarily expressed on dendritic cells and monocytes,
receptor (TCR) on naive T-cells. The interaction of the but can be induced in a wide variety of other immune
costimulatory T-cell receptor CD28 with the B7 ligand cells and nonimmune cells [68] .
is required for full activation, which is tightly regulated
or suppressed by inhibitory checkpoint receptor/ligand Since the CTLA-4/B7 synapse acts earlier than the
pairs to avoid collateral damage from autoimmunity [35] . PD1/PDL-1 synapse in the immune response, CTLA-
4 is considered the “leader” of the immune checkpoint
This type of suppression or induced dysfunctionality inhibitors, because it stops potentially autoreactive
of T-cells is also referred to as “T-cell exhaustion” and T-cells at the initial or priming stage of naive T-cell
is different from anergy or senescence. Although it is activation, occurring chiefly within lymph nodes [62,69] . The
a mostly reversible physiologic protective mechanism PD-1/PD-L1 pathway functions during the later effector
against autoimmunity, the first observation of it was phase in the periphery and protects the cells found there
made in mice infected with a chronically persistent strain from T-cell attack, including tumor cells which express
of lymphocytic choriomeningitis virus [55] . This T-cell PD-L1 [70] . The PD1/PD-L1 pathway represents an
dysfunction was later discovered to exist in multiple adaptive immune resistance mechanism that is exerted
other conditions involving persistent antigen exposure by tumor cells in response to endogenous anti-tumor
by other viruses such as HIV, hepatitis B, and hepatitis activity [71] .
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