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