One of the most prominent immunotherapies makes use of antibodies
that block PD-1, a regulatory “checkpoint” receptor found on the surface
of T cells. When this receptor is expressed in T cells, a protein
widespread in the tumor environment can attach to it, switching the T
cells into a state known as exhaustion. PD-1 antibodies prevent this
protein from attaching to T cells and repressing them, but many cancer
patients fail to respond to this treatment; in many others, the
effectiveness is short-lived.
To
develop a more effective immunotherapy, researchers from the
laboratories of Dr. Rony Dahan and Prof. Ido Amit in the immunology
department started by asking why existing treatments fall short. To
answer this question, they sampled T cells from two mouse models of
cancer that had undergone PD-1 antibody treatment.
“Using
advanced technologies such as single-cell DNA sequencing and big data
algorithms, we examined almost 130,000 T cells, some of which responded
to the treatment and some of which did not,” Amit explained.
“Surprisingly, the group of T cells that did respond to the treatment
expressed genes pointing toward an interaction with a rare population of
Such cells collect intelligence from across the body by gobbling up
molecules belonging to malignant cells.
The
researchers then present their findings to T cells, thereby warning
them about the cancerous growth and prompting them to take action. PD-1
antibodies are supposed to help with activating the T cells that fight
cancerous growths. However, when the researchers examined a cancer model
from a mouse lacking dendritic cells, they discovered that the antibody
treatment had lost its effectiveness entirely. In other words, they
revealed that dendritic cells are vital to the multiplication and
activation of specific T cells in the fight against cancer and are
therefore necessary for the treatment as a whole to be successful.
These
findings exposed a key weakness in existing treatments – the fact that
the relevant population of dendritic cells is rarely present in most
cancerous growths and in most patients currently being treated with PD-1
antibodies. Under these conditions, the interaction between these cells
and the T cells that they activate rarely occurs. This understanding
paved the way for the engineering of a new antibody called BiCE
(Bispecific DC-T Cell Engager), whose two arms were designed to connect
two different types of cells. One arm binds to T cells, inhibiting the
PD-1 receptor, just as existing treatments do; the other arm recruits
the dendritic cells from the rare population that is vital for
activating the T cells. The development of the new treatment was led by
doctoral research students Yuval Shapir Itai from Dahan’s laboratory and
Oren Barboy from Amit’s laboratory.
Having
created their antibody, the researchers studied its mechanism of
action. When they used fluorescent markers to label the antibody and the
immune cells of mice with skin cancer who had been given the new
treatment, they were able to observe how the antibody physically
connected the T cells to the dendritic cells, increasing the number of
such cellular pairs around the cancerous growth and in the adjacent
lymph nodes. They also discovered that the cellular pairs created by the
antibody were active and that they triggered an immune response against
the growth. Moreover, in the wake of the treatment, the dendritic cells
that had been adjacent to the cancerous growth migrated to the lymph
nodes and connected to the T cells there, in order to share intel and
activate them.
The
next stage of the study was to examine whether the new antibody also
manages to prevent the disease from returning. Many cancer patients
suffer such a recurrence even after the primary growth has been removed
and any known metastases have been treated. The main danger is the
existence of tiny remnants of the disease that escape detection and
start developing later, causing the tumor to recur.
BiCE,
unlike existing treatments, has been found to be effective in thwarting
the development of metastases in the lungs after the removal of the
primary tumor. This could be evidence that the antibody manages to
create a systemic immune response against the cancer throughout the
entire body, and that after treatment, it leaves behind immune cells
that remember how to identify the cancer and respond accordingly, the
team said.
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