Cancer Research - Europa

Keywords | Therapeutic vaccine | immunomonitoring | DC | CTL | CD4 | Treg | melanoma |
tumour escape | Ag processing |
CANCERIMMUNOTHERAPY
Cancer immunology and
immunotherapy
Summary
The first part of the project consists of clinical trials of vaccination,
to compare various vaccines, such as peptides and
RNA, with diff erent types of immunological adjuvants and
dendritic cells. Safety and clinical efficacy will be the primary
endpoints of these trials. A large eff ort will be devoted
to monitoring the anti-vaccine T-cell responses, as examining
the correlation between immunological and clinical
responses to the vaccines will be crucial to understanding
which factor(s) limit tumour regression. A second part of
the project,tightly connected to the clinical trials as it uses
biological material from the vaccinated patients, consists of
optimising tumour vaccines and combating immune evasion.
Foreseeable mechanisms of tumour escape will be
analysed and correlated with the clinical results. Improved
modalities of vaccination will be tested and new target antigens
will be identified. All these results will help to design
improved vaccines. Finally, considering the complexity of
mechanisms that may lead to or prevent tumour regression
in vaccinated patients, we propose to explore more fundamental
aspects of the anti-tumour immune response. This
includes the cross-presentation of tumour antigens by dendritic
cells, recruitment of cells of the innate immune system,
involvement of suppressor T-cells, and development of
murine models of inducible tumours. If new concepts
emerge from this work, they will also help in the design of
better vaccines.
Problem
Cancer is a major life-threatening disease and the second
greatest cause of mortality in Europe after cardio-vascular
diseases. Classical cancer treatment still relies on surgery,
chemotherapy and radiotherapy. Despite clear progress in
some cancer types, cancer therapy in general often fails to
prevent disease progression to metastatic disease. In addition,
these approaches are by themselves very toxic,
imposing a heavy burden of side eff ects on the patient.
There is clearly a need for new therapeutic approaches that
would be more efficient and less toxic.
TREATMENT
Aim
The ultimate objective of this Integrated Project is to develop
a therapeutic cancer vaccine with defined tumour antigens
that would provide a clinical benefit in at least 40 % of patients.
This threshold of 40 % of vaccinated patients showing an
objective tumour response, in the absence of unacceptable
toxicity, would definitely qualify immunotherapy as a standard
cancer treatment. Further improvements could come
from refining the vaccinations, and from combining tumour
vaccines with other modalities of cancer treatment.
Expected results
We believe that the principal objective of our project is
reachable, for the following reasons:
• the preliminary observation that vaccination with tumour
antigens can be associated with tumour regressions,
and in a few cases with sustained remissions, is encouraging,
as it indicates that the vaccines tested so far have
an anti-tumoural activity. Considering that vaccineinduced
immune responses and tumour regressions
seem to be correlated, and that the immune responses
that have been detected so far appear to be quantitatively
weak, it is reasonable to hypothesise that vaccines
with a greater immunogenicity, such as those we plan to
investigate, will also have a greater clinical efficacy;
• our project will build a close interaction between the
research laboratory and the clinic, which allows new ideas
emerging from observations made in either of these
two fields to be integrated rapidly into new projects;
• our consortium comprises groups with an excellent
record in clinical trials, T-cell immunology, dendritic cell
biology, and mechanisms of tumour resistance. Many of
these groups have a longstanding experience of collaborative
programmes with each other, both in the laboratory
and the clinical trial fields.
Potential applications
Development and validation of surrogate end-points is
a high priority in cancer vaccine research. The project will
contribute to this goal by promoting standardised assays
and methods for the immunomonitoring of clinical trials.
In practice, validation of these surrogate markers may prove
extremely useful for meaningful comparisons of various
immunisation modalities and as markers of consistency for
a given product.
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