Cancer Research - Europa

Keywords | Lymphoma | leukaemia | vaccine | idiotype | immunotherapy |
VITAL
Development of optimised recombinant
idiotypic vaccines for subset-specifi c
immunotherapy of B cell lymphomas
Summary
Therapeutic vaccines targeting B cell non-Hodgkin lymphoma
(NHL) idiotype (Id) represent a promising approach
against these malignancies. A broad use of Id-based vaccination,
however, is hampered by the complexity and costs due
to the individualised production of these vaccines. Recent
evidence indicates that these limitations may be overcome.
In fact, distinct sets of stereotyped immunoglobulins have
been identifi ed in various B-NHL, suggesting that patients
share Id with a higher frequency than appreciated previously.
Through the complementary and synergistic work of academic
partners and three SMEs, we plan to exploit the molecular features
of Id proteins of distinct B cell lymphomas/leukemias,
particularly those pathogenically associated with antigen stimulation
and/or selection, to develop pre-made, recombinant
Id proteins to vaccinate subgroups of lympho-proliferative
disorders expressing molecularly correlated idiotypes.
A database of Id sequences expressed by diff erent B-NHL
will be constructed to identify subgroups of tumours expressing
molecularly correlated Id proteins. Selected Id proteins
will be characterised for their immunogenicity and, particularly,
for the ability to induce cross-reactive immune responses
against related Id proteins. B and T cell epitopes will be identifi
ed using innovative approaches, and dedicated assays for
immunomonitoring will be developed. Optimised versions of
selected Id vaccines will be produced using new strategies
and validated in animal models. New adjuvants and delivery
systems for improved Id vaccine formulations and administration
will be also evaluated and validated. The most
promising Id proteins will be produced and purifi ed according
to GMP standards and included in new vaccine formulations
for innovative trials of ‘cross-reactive’ immunotherapy.
TREATMENT
Problem
Non-Hodgkin’s lymphomas (NHL) constitute a heterogeneous
group of malignancies whose incidence has signifi cantly
increased in recent decades. In the year 2000, more than
145 000 cases of NHL were diagnosed in developed countries,
representing the sixth most common cancer occurring
among men and the eighth among women. Low-grade B cell
NHLs, in particular, are incurable diseases characterised by
relatively slow growth and excellent initial responsiveness to
chemotherapy but also by continuous relapses. In particular,
for patients with follicular lymphoma, median overall survival
(7-10 years) has not improved over the past 30 years.
Although in the vast majority of patients complete or partial
remissions can be obtained with either single agents or
combination chemotherapy, the clinical course is characterised
by a high relapse rate. After relapse, both the response
rate and relapse-free survival after subsequent salvage
treatment regimens steadily decrease, resulting in a median
survival of only 4-5 years after the fi rst relapse. These
clinical fi ndings, coupled with the substantial toxicities of
standard treatments, have stimulated the search for novel
and more tumour-selective therapies. Therapeutic vaccines
targeting B cell lymphoma idiotype (Id) represent a promising
immunotherapeutic approach for a better clinical control
of these malignancies. This strategy is based on the observation
that immunoglobulins (Ig) expressed by neoplastic
B lymphocytes carry unique determinants in their variable
regions (idiotypes), which can be recognised as tumourspecifi
c antigens.
Indeed, both protein- and dendritic cell-based vaccines that
use the patient-specifi c Id have resulted in clinically signifi -
cant tumour-specifi c cellular responses with very little toxicity.
A broad use of Id-based vaccination for B cell lymphomas,
however, is hampered by the fact that these approaches are
patient-specifi c, so that the vaccine must be individually produced
for each patient. On these grounds, new strategies
obviating the need to produce customised vaccines would
further simplify clinical applications of idiotypic vaccines.
Aim
The objective of VITAL is the development and production of
optimised recombinant idiotypic vaccines for the treatment of
subgroups of lym phoproliferative disorders expressing molecularly
correlated idiotypes. These vaccines will be included in
new formulations for innovative trials of immunotherapy
potentially targeting a large fraction of lymphoma/leukemia
patients.
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