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

188 9 Dendritic Cells and Cancer: Prospects for Cancer Vaccination
or possibly delayed-type hypersensitivity (DTH) reactions in vivo. Empirical dosing
of DCs and schedules suggest a minimal cell number is required, currently accepted
as approximately 10 6 , but 10-fold less may suffice. The few dose-escalation studies
have not shown a clear cell dose effect [127], although there are suggestions that this
is a relevant variable [72].
The issue is further complicated by the choice of the DC injection site. One million
DCs injected into a lymph node will produce a different outcome to the same number
of DCs injected intradermally (i.d.) or intravenously (i.v.). Currently available migration
studies [94, 128] predict that about 1% of Mo-DCs injected into the skin will
reach a draining lymph node. Rapid migration of CD34 + DCs into lymph nodes occurred
following intralymphatic injection but DC administered i.v. located in lung
and liver and ultimately the spleen but not lymph nodes [129]. The consensus from
animal data is that of the conventional parenteral administrations; delivery via the
skin [i.d. rather than subcutaneous (s.c.)] is preferable to i.v. administration [130,
131]. The clinical data accrued to date now needs a formal comparison to direct the
next generation of trials. Migration is likely to differ accordingly to the type of DC
preparation, as they have different chemokine receptors and adhesion-mediating
properties. Intranodal injection under ultrasound guidance was used in the first melanoma
vaccination study [132]. A recent paper [133] compared T lymphocyte and
antibody responses to blood DCs loaded with recombinant mouse prostatic and
phosphatase injected i.v., i.d. or into cannulated lymphatics. Only the latter two
routes resulted in T lymphocyte IFN-g production (T proliferation occurred in each)
and the i.v. route resulted in more antibody responses.
Injection schedules to date are derived from experiences in animal models and human
vaccination studies in infectious diseases. Weekly injections with monthly
boosting or monthly injection schedules are currently being performed. Again, data
optimizing these is urgently required given suggestions that frequent administration
may be counter-productive [131]. Given DC are critical for priming responses, it may
be that alternative vehicles for revaccinating may be possible, improving the feasibility
of the procedure.
The cautionary data suggesting that DCs in certain forms may in certain circumstances
have a negative influence on anti-tumor responses [99, 134] will need to be
heeded.
9.8
Phase I/II Clinical Trials
A summary is provided in Tab. 9.1. The initial clinical trials involving four patients
in relapsed low-grade NHL fortunately produced encouraging results without side effects
[106]. The most encouraging feature was the first demonstration that patients
could be immunized to generate T lymphocyte responses to the idiotype protein
antigen. The excellent results in low-grade NHL patients with minimal residual disease
(MRD) using GM-GSF and keyhole limpet hemocyanin (KLH)-conjugated idiotype
indicate the potential in this disease [135]. Longer-term follow-up has shown a