While modern treatments have led to a dramatic improvement in
survival for pediatric malignancy, toxicities are high and a
significant proportion of patients remain resistant. Gene
transfer offers the prospect of highly specific therapies for
childhood cancer. &#8220;Corrective&#8221; genes may be transferred to
overcome the genetic abnormalities present in the precancerous
cell. Alternatively, genes can be introduced to render the
malignant cell sensitive to therapeutic drugs. The tumor can also
be attacked by decreasing its blood supply with genes that
inhibit vascular growth. Another possible approach is to modify
normal tissues with genes that make them more resistant to
conventional drugs and/or radiation, thereby increasing the
therapeutic index. Finally, it may be possible to attack the
tumor indirectly by using genes that modify the behavior of the
immune system, either by making the tumor more immunogenic, or by
rendering host effector cells more efficient. Several gene
therapy applications have already been reported for pediatric
cancer patients in preliminary Phase 1 studies. Although no major
clinical success has yet been achieved, improvements in gene
delivery technologies and a better understanding of mechanisms of
tumor progression and immune escape have opened new perspectives
for the cure of pediatric cancer by combining gene therapy with
standard therapeutic available treatments.

Ettore  Biagi

Catherine  Bollard

Raphael  Rousseau

Malcolm  Brenner

Gene Therapy for Pediatric Cancer: State of the Art and Future Perspectives

Malignant gliomas are the most common neoplasm in the central
nervous system. When treated with conventional treatments
including surgery, irradiation, and chemotherapy, the average
life expectancy of the most malignant type, glioblastoma
multiforme is usually less than 1 year. Therefore, gene therapy
is expected to be an effective and possibly curative treatment.
Many gene therapeutic approaches have demonstrated efficacy in
experimental animal models. However, the current clinical trials
are disappointing. This review focuses on current therapeutic
genes/vectors/delivery systems/targeting strategies in order to
introduce updated trends and hopefully indicate prospective gene
therapy for malignant gliomas.

Takao Kanzawa

Hideaki Ito

Yasuko Kondo

Seiji Kondo

Current and Future Gene Therapy for Malignant Gliomas

Nicol  Keith

Claude  Bagnis

Why a Special Issue on Gene Therapy&#63;

This review focuses on the prodrugs used in suicide gene therapy.
These prodrugs need to satisfy a number of criteria. They must be
efficient and selective substrates for the activating enzyme, and
be metabolized to potent cytotoxins preferably able to kill cells
at all stages of the cell cycle. Both prodrugs and their
activated species should have good distributive properties, so
that the resulting bystander effects can maximize the
effectiveness of the therapy, since gene transduction
efficiencies are generally low. A total of 42 prodrugs explored
for use in suicide gene therapy with 12 different enzymes are
discussed, particularly in terms of their physiocochemical
properties. An important parameter in determining bystander
effects generated by passive diffusion is the lipophilicity of
the activated form, a property conveniently compared by diffusion
coefficients (<mml:math alttext="$\mathrm{log} \mathrm{P}$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>log P</mml:mtext></mml:mrow></mml:math> for nonionizable compounds
and <mml:math alttext="$\mathrm{log}\mathrm{D}_7$" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mrow><mml:mtext>log D</mml:mtext></mml:mrow><mml:mn>7</mml:mn></mml:msub></mml:mrow></mml:math> for compounds containing an
ionizable centre). Many of the early antimetabolite-based
prodrugs provide very polar activated forms
that have limited abilities to diffuse across cell membranes, and
rely on gap junctions between cells for their bystander effects.
Several later studies have shown that more lipophilic, neutral
compounds have superior diffusion-based bystander effects.
Prodrugs of DNA alkylating agents, that are less cell cycle-specific than antimetabolites and more effective against noncycling tumor cells, appear in general to be more active
prodrugs, requiring less prolonged dosing schedules to be
effective. It is expected that continued studies to optimize the
bystander effects and other properties of prodrugs and the
activated species they generate will contribute to improvements
in the effectiveness of suicide gene therapy.

William A. Denny

Prodrugs for Gene-Directed Enzyme-Prodrug Therapy (Suicide Gene Therapy)

The evaluation of quality, safety, and efficacy of medicinal
products by the European Medicines Evaluation Agency (EMEA) via
the centralized procedure is the only available regulatory
procedure for obtaining marketing authorization for gene therapy
(GT) medicinal products in the European Union. The
responsibility for the authorization of clinical trials remains
with the national competent authorities (NCA) acting in a
harmonized framework from the scientific viewpoint. With the
entry into force of a new directive on good clinical practice
implementation in clinical trials as of 1 May 2004, procedural
aspects will also be harmonized at EU level. Scientifically sound
development of medicinal products is the key for the successful
registration of dossiers and for contributing to the promotion
and protection of public health. The objective of this paper is
to introduce the EMEA regulatory processes and scientific
activities relevant to GT medicinal products.

Marisa  Papaluca Amati

Francesco  Pignatti

Alexis  Nolte

Nirosha  Amerasinghe

Daniel  Gustafsson

Isabelle  Moulon

Patrick  Le Courtois

EMEA and Gene Therapy Medicinal Products Development in the European Union

Gene therapy represents a promising novel treatment strategy for
colorectal cancer. Preclinical data has been encouraging and
several clinical trials are underway. Many phase 1 trials have
proven the safety of the reagents but have yet to demonstrate
significant therapeutic benefit. Ongoing efforts are being made
to improve the efficiency of gene delivery and accuracy of gene
targeting with the aim of enhancing antitumor potency. It is
envisaged that gene therapy will be used in combination with other
therapies including surgery, chemotherapy, and radiotherapy to
facilitate the improvements in cancer treatments in the future.

Daniel H. Palmer

Ming-Jen Chen

David J. Kerr

Taking Gene Therapy into the Clinic

The safety of retroviral-based systems and the possible
transmission of replication-competent virus to patients is a
major concern associated with using retroviral vectors for gene
therapy. While much effort has been put into the design of safe
retroviral production methods and effective in vitro monitoring
assays, there is little data evaluating the risks resulting from
retroviral vector instability at post-transduction stages
especially following in vivo gene delivery. Here, we briefly
describe and discuss our observations in an in vivo experimental
model based on the inoculation of retroviral vector-transduced
tumor cells in sheep. Our data indicates that the in vivo
generation of mosaic viruses is a dynamic process and that virus
variants, generated by retroviral vector-mediated recombination,
may be stored and persist in infected individuals prior to
selection at the level of replication. Recombination may not only
restore essential viral functions or provide selective advantages
in a changing environment but also reestablish or enhance the
pathogenic potential of the particular virus undergoing
recombination. These observations in sheep break new ground in
our understanding of how retroviral vectors may have an impact on
the course of a preestablished disease or reactivate dormant or
endogenous viruses. The in vivo aspects of vector stability raise
important biosafety issues for the future development of safe
retroviral vector-based gene therapy.

Anne Van den Broeke

Arsène Burny

Retroviral Vector Biosafety: Lessons from Sheep

Over the past ten years significant advances have been made in
the fields of gene therapy and tumour immunology, such that there
now exists a considerable body of evidence validating the proof
in the principle of gene therapy based cancer vaccines. While
clinical benefit has so far been marginal, data from preclinical
and early clinical trials of gene therapy combined with standard
therapies are strongly suggestive of additional benefit. Many
reasons have been proposed to explain the paucity of clinical
responses to single agent vaccination strategies including the
poor antigenicity of tumour cells and the development of
tolerance through down-regulation of MHC, costimulatory, signal
transduction, and other molecules essential for the generation of
strong immune responses. In addition, there is now evidence from
animal models that the growing tumour may actively inhibit the
host immune response. Removal of the primary tumour prior to T
cell transfer from the spleen of cancer bearing animals, led to
effective tumour cell line specific immunity in the recipient
mouse suggesting that there is an ongoing tumour-host
interaction. This model also illustrates the potential
difficulties of clinical vaccine trials in patients with advanced
stage disease.

Susy M. Scholl

Silke  Michaelis

Ray  McDermott

Gene Therapy Applications to Cancer Treatment

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