Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

e linked to include multiple (including helper and cytotoxic) epitopes and different
structures investigated [112] to optimize delivery. Mouse models validate the role of
DCs in delivering effective antitumor responses (reviewed in [66]). Comparative data
in a mouse model suggests DC peptide administration is more effective than naked
DNA vaccination [113].
An alternative, which bypasses the need to consider HLA-restricting elements, is to
use recombinant proteins ± these can of course be engineered if necessary to remove
any potentially harmful epitopes. Cost is a consideration, but the quantities required
may be relatively small. Engineering targeting components as described for the GM-
CSF prostatic acid phosphatase fusion protein may be very effective [107].
New strategies have also seen a revival of the whole-cell vaccine approach in the form
of pulsing DC with apoptotic bodies. Necrotic material from tumors may be relevant
as it is likely that DC have sophisticated mechanisms to distinguish necrosis from
apoptosis, theoretically, with different outcomes. DC/tumor cell hybrids are also being
explored. The injection of DC/tumors hybrids in mice generated cure of advanced metastatic
disease [114]. Tumor fusions have now been generated with human cells and
hybrids produced in the presence of polyethylene glycol (PEG) yielded measurable
specific responses against breast cancer cells [115, 116]. Moreover, striking clinical responses
were reported with the use of electroporated hybrid preparations [117].
Further detailed studies on the quality of the cells injected and the nature of the immune
response generated are eagerly anticipated. A number of clinical trials using
both allogeneic and autologous DC are currently underway in various centers and the
initial results should emerge soon (P. Walden, personal communication).
Recombinant viruses DNA or RNA constructs may be used to deliver polytopes
(multiple peptide epitopes) or recombinant protein to DCs. This technique has been
very effective in mouse models. It is also capable of eliciting human cytotoxic T lymphocyte
(CTL)-specific responses in vitro [118±120]. Electroporated RNA may be
superior to DNA plasmid expression of RNA [121]. Clinical trials in patients with
prostate cancer using this technique are underway. Retrovirus vectors have been
used to deliver both class Iand IIepitopes [122]. Adeno [123] and canarypox [124]
viruses known to replicate poorly in humans have also been used.
Much excitement has been engendered by the use of RNA to deliver specific TAAs
and also total tumor RNA [118, 125]. Now alternatives are being considered including
delivering the antigens via DC surface antigen receptors [21] and by targeting
proteins using intracellular locations signals such as HIV tat [126].
9.7
Dose Delivery and Vaccination Schedule
9.7 Dose Deliveryand Vaccination Schedule
Dose-finding studies in DC vaccination has been difficult in the past because of
questionable endpoints. An endpoint such as induction of an immune response is
not necessarily correlated with clinical response. A potential but unsatisfactory way
is to titrate DC numbers injected against T cell response to a strong test immunogen
by measuring HLA/peptide tetramer (which bind specific T cell receptors) responses
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