The quest to bring immunotherapy
into widespread clinical use against cancer and infectious diseases has made
great strides in recent years. For example, clinical trials of adoptive T cell
therapy are yielding highly promising results. The latest progress is being
reported at the Annual Meeting of the American Association for the Advancement
of Science (AAAS 2016) by three international leaders in the field: Prof. Dirk
Busch of the Technical University of Munich (TUM), Prof. Chiara Bonini of the
San Raffaele Scientific Institute, and Prof. Stanley Riddell of the Fred
Hutchinson Cancer Research Center and the University of Washington.
T
cell immunity has evolved to recognize and respond to health threats and provide
a lifelong memory that prevents recurrent disease. However, with chronic
diseases, reactive T cells often become inactive or even disappear. Recent
advances have brought the idea of fighting chronic infections, and even
cancers, by restoring protective T cell responses much closer to reality.
The main focus of the AAAS 2016 session "Fighting Cancer and
Chronic Infections with T Cell Therapy: Promise and Progress" is on
adoptive T
cell therapy, in which a patient receives "killer" immune cells
that target a disease-associated molecule. Several obstacles have stood in the
way of widespread clinical use: identifying or generating T cells that will be
most effective for each individual case, whether from the patient or from a
suitable donor; avoiding or countering potential side-effects; and finding ways
to shorten the path from bench to bedside. Progress is being reported on all
three fronts, including data from the first clinical trials.
Potent cells, with a safety mechanism
"There is a lot of scientific competition, of course, as well as
growing industry interest," says Prof. Dirk Busch. "What we bring
into the game is, first, the conviction that you have to select the right cells
to generate optimal cell products for therapy, together with superior
techniques to do it. Over the past years, we at TUM as well as Stan Riddell and
Chiara Bonini have worked on providing cell products that will upon tranfer to
patients expand to large numbers and stay active for a long time, potentially
life-long. We identified a subset of T cells with high regenerative potential,
where even low numbers of transferred cells -- in the extreme a single T cell
-- can confer therapeutic immune
responses." The use of such potent cells, he adds, requires the
implementation of safety mechanisms, and that too has now been demonstrated.
Within the TUM Institute for Advanced Study (TUM-IAS) Focus Group on
Clinical Cell Processing and Purification, Busch, Riddell, and colleagues have
pioneered methods to rapidly select defined T cell subsets for clinical
applications. Central memory T cells (TCMs) are of special interest: TCMs can
engraft, expand, and persist long-term, even at very low numbers of transferred
cells. Also, they can be genetically engineered to express novel
antigen-targeting receptors without affecting their in vivo behavior. The first
clinical trials using engineered T cells expressing so-called chimeric antigen
receptors that recognize an antigen on B cell leukemia (anti-CD19-CARs) have
provided outstanding results -- including cases of complete remission of
end-stage, blood-borne malignancies. Encouraging results have also been seen in
clinical trials of adoptive T
cell therapy against chronic infections.
At the same time, the researchers are exploring safeguards that would
allow, in the event of side-effects, selective elimination of the genetically
modified T cells used for therapy. One such safety mechanism has been tested
successfully in pre-clinical animal models and has already been transferred to
human patients. "We put a marker into the T cells, so that we can give an
antibody that binds to the cells that we have engineered but no others,"
Busch explains. "If an antibody binds to a cell, then other immune
mechanisms get activated that eliminate it. We call this antibody-mediated cell
toxicity."
The broader goal is to make sure the therapeutic cell products are so
well understood and defined -- and backed up by safety mechanisms -- that the
same approach can be confidently used to treat different patients, on an
individualized basis. "We believe the more defined our cell products are,
the more predictable the clinical outcome will be," Busch says.
Technology developed at TUM helped to launch a spin-off company called
STAGE Cell Therapeutics, which has merged with Seattle-based Juno Therapeutics.
The Munich-based Juno Therapeutics GmbH is the company's European arm.
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