Immunotherapy recruits: blocking the KIR2DL5/PVR immunosuppressive pathway to trigger NK cell-mediated anti-tumor immunity

The surface of immune cells is covered with receptors called "checkpoint" proteins that prevent immune cells from deviating from their normal targets — cells infected by pathogens and cancer cells
.
When checkpoint receptors on immune cells bind to proteins expressed by the body's own normal cells, this interaction blocks attacks that immune cells may initiate
.
Scary, most types of cancer cells express proteins that bind to checkpoint proteins, tricking immune cells into stopping attacking tumors
.
Immune checkpoint inhibitors are monoclonal antibodies designed to block tumor proteins or immune cell receptors that bind to tumor proteins, thereby shortening the immune cell/cancer cell interaction
.
Without braking, immune cells can attack and destroy cancer cells
.

Immune checkpoint inhibitors such as Keytruda and Opdivo attack tumor cells by releasing T cells
from the immune system.
Their introduction a decade ago marked a major advance in cancer treatment, but only 10 to 30 percent of patients treated experienced long-term improvement
.
In a paper published today in the online edition of the Journal of Clinical Investigation (JCI), scientists at the Albert Einstein School of Medicine present a finding
that may improve the effectiveness of immune checkpoint therapy.

Instead of summoning T cells to fight cancer, the Einstein School of Medicine research team looked at different human immune cells known as natural killer cells (NK), and achieved promising results
。 "We believe that the novel immunotherapies we have developed have great potential to enter clinical trials involving various types of cancer," said Xingxing Zang, Ph.
D.
, who led the study, the Louis Goldstein Swan Chair Professor of Cancer Research at the Einstein School of Medicine, a professor of microbiology and immunology, oncology, urology and medicine, and a member of
the Montefiore Einstein Cancer Center's Cancer Treatment Program.

A new focus for natural killer cells

The limited effects of checkpoint inhibitors prompted Dr.
Zang and other scientists to study checkpoint pathways
involving NK cells.
NK cells, like T cells, play an important role
in removing excess cells.
A cancer cell protein called PVR quickly caught their attention
.
"We realized that PVR could be a very important protein that human cancers use to thwart an attack by the immune system," Dr.
Zang said
.

PVR is a member of the mucin/mucin-like family that mediates cell adhesion, invasion and migration, and proliferation
.
PVR proteins are usually absent or very absent in normal tissue, but are overexpressed
in many types of tumors, including colorectal, ovarian, lung, esophageal, head and neck, stomach, pancreatic, and myeloid leukemia and melanoma.
PVR overexpression induces immune escape in tumor cells and is associated with
poor prognosis and accelerated tumor progression.
In addition to this, PVR appears to bind to the TIGIT checkpoint protein, an "inhibitory receptor T cell immune receptor with Ig and ITIM domains", to inhibit the activity of T cells and NK cells, prompting the use of monoclonal antibodies against TIGIT to interrupt the TIGIT/PVR pathway
.
There are currently more than 100 clinical trials underway for TIGIT worldwide
.
However, some clinical studies, including two large phase III clinical trials, have failed to improve cancer outcomes
.
Cancer immunotherapy targeting the TIGIT/PVR pathway is currently facing challenges
.

Recognize the role of a new receptor

Human killer cell immunoglobulin-like receptors (KIRs) modulate NK activity by recognizing their own HLA class I molecules, which enable NK cells to kill infected and tumor cells
through the "missing self" mechanism.
KIR2DL5, a member of the newly discovered human killer cell immunoglobulin-like receptor (KIR) family, has been identified as another binding partner
of PVR.
The biological and therapeutic potential of the KIR2DL5/PVR pathway is largely unknown
.

"We hypothesized that PVR inhibited NK cell activity not by binding to TIGIT, but by binding to the recently discovered KIR2DL5," Dr.
Zang said
。 To find out, he and his colleagues synthesized a monoclonal antibody against KIR2DL5 that recognized KIR2DL5 more efficiently than the commercial monoclonal antibody UP-R1, and determined that KIR2DL5 is mainly expressed on NK cells with mature phenotyping and cytolytic functions, and binds to PVR, and its binding site is different from the binding sites of the other 3 known PVR receptors DNAM-1, TIGIT, and CD96, and has no competition
relationship 。 KIR2DL5 acts as an inhibitory receptor for NK cells and mediates PVR + tumor immune resistance
.

In the JCI paper, Dr.
Zang and colleagues demonstrated that KIR2DL5 is a common checkpoint receptor on the surface of human NK cells, and that the PVR protein uses it to suppress immune attack
.
In studies involving humanized animal models of several human cancers, the researchers showed that their monoclonal antibody against KIR2DL5 — by blocking the KIR2DL5/PVR pathway — allowed NK cells to forcefully attack and shrink human tumors, prolonging animal survival
.
Dr.
Zang said: "These preclinical findings give us hope that targeting the KIR2DL5/PVR pathway is a good idea and that the monoclonal antibody we developed may be an effective immunotherapy
.
"

Einstein has filed a patent application for KIR2DL5/PVR immune checkpoints, including antibody drugs, and is interested in further developing and commercializing the technology
.
Dr.
Zang has previously developed and filed patents
for more than 10 immune checkpoint inhibitors.
One of these inhibitors is currently undergoing Phase 2 clinical trials in China involving hundreds of patients
with advanced solid cancer (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, melanoma, lymphoma) or relapsed/refractory blood cancer (acute myeloid leukemia, myelodysplastic syndrome).
Zang's other immune checkpoint inhibitor will be evaluated
in cancer clinical trials in the United States beginning next year.