Summary of the project:
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 individualized
production of these vaccines. Recent evidence indicates that
these limitations may be overcome. In fact, distinct sets of
stereotyped immunoglobulins have been identified 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
lymphoproliferative disorders expressing molecularly
correlated idiotypes. A database of Id sequences expressed
by different B-NHL will be constructed to identify subgroups
of tumors expressing molecularly correlated Id proteins.
Selected Id proteins will be characterized 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 identified using innovative
approaches and dedicated assays for immunomonitoring will be
developed. Optimized 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 purified according to GMP standards and
included in new vaccine formulations for innovative trials
of “cross-reactive” immunotherapy.
Problem:
Non-Hodgkin’s lymphomas
(NHL) constitute a heterogeneous group of malignancies whose
incidence has significantly increased in recent decades. In
the year 2000, more than 145,000 cases of NHL were diagnosed
in developed countries, representing thus the sixth most
common cancer occurring among men and the eighth among
women. Low-grade B-cell NHLs, in particular, are incurable
diseases characterized 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 characterized 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 first relapse. These clinical
findings, coupled with the substantial toxicities of
standard treatments, have stimulated the search for novel
and more tumor-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 recognized as
tumor specific-antigens. Indeed, both protein- and dendritic
cell-based vaccines that use the patient-specific Id have
resulted in clinically significant tumor-specific 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-specific so that
the vaccine must be individually produced for each patient.
On these grounds, new strategies obviating the need to
produce customized vaccines would further simplify clinical
applications of idiotypic vaccines.
Aim:
The objective of VITAL is
the development and production of optimized recombinant
idiotypic vaccines for the treatment of subgroups of
lymphoproliferative 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.
Expected results:
- Establishment of a large database including sequences of
idiotypic VH and VL genes expressed by a variety of
lymphoproliferative disorders, including low grade B-NHL,
autoimmunity-associated lymphoproliferations, and chronic
lymphocytic leukemia. This will allow the identification of
candidate Id proteins for “cross-reactive” immunotherapy.
- Pre-clinical characterization of
the immunogenicity of selected natural Id proteins, with
particular regard to their ability to induce immune
responses against lymphoma cells expressing molecularly
correlated Id proteins. The characterization will include
the identification of B cell epitopes and HLA Class
I-restricted cytotoxic T cell epitopes using innovative
approaches and will allow the development of dedicated
assays for immunomonitoring.
- Design and validation of optimized
Id vaccines.
- Evaluation and validation of new
adjuvants and innovative delivery systems for improved Id
vaccine formulations and administration.
- “Clinical-grade” production and
purification of optimized Id proteins for patient
vaccination.
The SMEs are an integral part in the
project in making the new diagnostic and therapeutic tools
available, not only for Europe but also for the world
market. The close integration between clinical and research
activities at several university hospitals and Cancer
Centers with the SMEs will form new centres of excellence
where European SMEs will benefit from close collaboration at
the same time as new diagnostic and therapeutic products
will be developed to the benefit of patients with lymphoid
malignancies.
Potential
applications:
The results obtained in the present project will
allow the design and activation of phase I/II clinical
trials aimed at validating the use of optimized, pre-made
vaccines for the treatment of a relatively broad spectrum of
lymphoid malignancies. The proposed Id vaccination may be
beneficial also for patients with pre-neoplastic B-cell
lymphoproliferations, such as mixed cryoglobulinaemia. These
vaccines, in fact, may be used with the purpose to alleviate
the symptoms and, ultimately, to prevent the possible
evolution towards an overt B cell malignancy. Once validated
as drugs, the vaccines will have the advantage to be easily
distributed to all Hematology and Oncology Departments,
including those of peripheral Hospitals/Universities. Thus,
results obtained in the present project will have an
important strategic impact in solving, at least in part, the
dramatic social and health problem represented by NHL.
Project
Coordinator:
