German Cancer Research Center: Scientists from the German Cancer Research Center (DKFZ) and the Helmholtz Zentrum München are exploring new ways to fight lymphoma. They have developed a new method that simulates a viral infection of cancer cells. The immune cells activated as a result are able to kill the cancer cells efficiently.
The medical term “non-Hodgkin lymphoma”
refers to a group of over 20 different cancers of the lymphatic system.
These cancers usually start in B lymphocytes that have undergone
malignant transformation. “The cure rate for lymphoma is about 70
percent today. In relapsing lymphomas, however, we are still lacking
better therapies to help patients,” says Professor Henri-Jacques
Delecluse of the DKFZ. “We are therefore trying to find new methods to
enhance the body's own immune system in fighting lymphoma cells.”
Delecluse's group, working together with Josef
Mautner and Regina Feederle from the Helmholtz Zentrum München, have
been searching for ways to label lymphoma cells in a special way that
makes them more visible to the immune system. To this end, the
researchers made use of antibodies that distinctively exhibit a piece of
viral protein.
These antibodies contained binding sites that
target specific molecules on the surface of the lymphoma cells. The
researchers had used genetic engineering methods to fuse protein pieces
of Epstein-Barr virus (EBV) to the “rear” end of the antibody protein.
Exposure to EBV is very common, so many people already have memory T
cells that can mount a rapid and powerful immune response upon a new
encounter with this pathogen.
The antibodies attach via their binding sites to
the cancerous B cells and are subsequently engulfed into the cell
interior. There, the antibody protein is degraded and the individual
fragments are presented by special molecules on the surface of the
cancer cells. As a result, the viral protein is also exhibited on the
cell surface, thus making it look like an EBV infection to the immune
system.
A viral infection is an alarm sign that T cells
cannot ignore. In a Petri dish, the researchers found that T cells
effectively killed the “infected” lymphoma cells. When the investigators
obtained blood cells from individuals who had been infected with
Epstein-Barr virus in the past, they succeeded in using the
antigen-armed antibodies to activate memory T cells. “This is a clear
indication that our antigen-armed antibodies can also induce an immune
response against lymphoma cells in a living organism,” explains
Delecluse.
Depending on one’s genetic makeup, the EBV protein
fragments presented on the cell surface can vary between individual
people. In order to activate the immune system in as many people as
possible, Delecluse and colleagues also inserted larger pieces of EBV
proteins into their antibodies. Depending on their genetic makeup, the
cells could then cut out various smaller protein segments and present
them on their surface.
“A problem with antibody-based cancer therapies is
that the tumor cells make the surface molecule targeted by the antibody
disappear from their surface,” says Delecluse. Explaining the benefits
of his treatment approach, he continues: “To prevent this situation, we
used a mixture of antibodies that target four different B cell surface
molecules.”
Antigen-armed antibodies were initially developed
as a vaccine to immunize people against pathogens. “We have now shown
for the first time that they can also be used as a tool in cancer
therapy, not only against B cell lymphoma but potentially also against
other types of cancer.”
Xiaojun Yu, Marta Ilecka, Emmalene J. Bartlett,
Viktor Schneidt, Rauf Bhat, Josef Mautner, Regina Feederle and
Henri-Jacques Delecluse: Antigen-armed antibodies targeting B lymphoma
cells effectively activate antigen-specific CD4+ T cells. Blood 2015,
DOI: 10.1182/blood-2014-07-591412