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622 Chapter 12: Gene Therapy
INTRODUCTION
A potentially interesting treatment modality that could be applied as an adjuvant
therapy to acute leukemia is immunotherapy. Successful immunotherapy is based
on the generation of a specific antitumor immune response. 12
Initial efforts in
immunotherapy employed adoptive transfer of in vitro stimulated antitumor
lymphocytes into melanoma patients. These studies showed that a clinical
antitumor response could be achieved in approximately 30% of patients treated. 3
The logical extension of this work was to attempt in vivo lymphocyte stimulation
via the administration of tumor-cell vaccines. This strategy has been tested for
several malignancies but has shown only modest levels of success. 4
To further
enhance the immunogenicity of tumor-cell vaccines, several investigators have
employed gene transfer techniques as a means to introduce factors that may
augment T cell costimulation and/or immunomodulation. 5
' 6
Evidence supporting
the clinical utility of a gene transfer strategy for generation of leukemia vaccines
has previously been shown in animal model systems. Several groups have shown
that transduction of leukemic cells with genes such as CD80 and GM-CSF,
followed by administration of the genetically modified tumor, can induce a
significant and prolonged cytotoxic T lymphocyte (CTL)-specific antitumor
response. 78
Given the lack of CD80 expression on human leukemic tumors (C.T.J.,
unpublished observation), it appears likely that such a strategy would also be
worthy of clinical evaluation in leukemia.
While it has been feasible in laboratory studies to generate gene-modified tumor
cells, 9
it has proven much more difficult to develop a sufficiently easy and practical
means of transducing large numbers of primary human leukemic cells. Several
investigators have successfully employed retroviral vectors to infect murine cells;
however, to date retroviral transduction procedures have shown only low and
inconsistent levels of gene transfer for primary human hematopoietic cells. 10-12
An
alternative to retroviral gene transfer would be the use of adenoviral vectors. 13
' 14
Previously, we have shown that under the appropriate conditions, adenoviral
vectors can achieve limited gene transfer into primitive CD34 +
cells. 15
In contrast
to retroviral vehicles, adenoviruses can be easily generated in high concentrations
(>10 12
viral particles/mL) and typically express their transgenes very effectively.
Although adenoviral vectors do not integrate into the host cell genome, and are thus
only transiently maintained, it is likely that transient expression will be sufficient
for the purposes of inducing a vaccine response. While adenoviruses have been
reported to infect some types of malignant hematopoietic cells, 16-18
the efficiency
varies widely among differing cell types and patients. We believe that a more
efficient technology will be required to mediate general use of this approach.
Accordingly, we have developed a new type of vehicle that combines an adenoviral
vector with a synthetic polyamidoamine dendramer. 19
Preliminary studies have