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

194 9 Dendritic Cells and Cancer: Prospects for Cancer Vaccination
9.10
Side Effects
Fortunately, adverse events have been limited. Minor discomfort at injection sites is
reported formally, together with minor febrile reactions hypotension (with infusions)
and myalgia. No definite treatment-related hematological hepatic or renal
toxicity has resulted. The greatest concern has been the possibility of life-threatening
or debilitating autoimmune reactions, which would undo the benefits of the
beneficial antitumor response. One view is that this problem has been minimal because
relatively weak immune responses have been generated. The alternative view
is that where patients have been at risk, the natural tolerance or regulating mechanisms
have prevented such detrimental self-reactivity. In the case of melanoma, vaccination
against melanoma differentiation antigens might lead to destruction of melanocyte-containing
tissue compartments such as the brain or the eye. To date, no serious
autoimmune-related events have been reported, although an allergic reaction to
exogenous protein has [165]. A few patients present with antinuclear antibodies or
antithyroid antibodies without evolving further. Interestingly, the use of melanoma
tumor lysates as antigens will induce widespread vitiligo in 43% of patients with
metastasizing melanoma (Nestle et al., submitted). These data demonstrate the
power of immune activation against self-antigens using DCs pulsed with tumor lysates
and emphasize that careful selection of target antigens will continue to be a
major issue.
Given the animal model predictions, the paucity of autoimmune problems is most
intriguing. As most TAAs generate low-affinity CTL responses, it is argued that this
may be protective [125]. An interesting experiment attempting to generate a deliberate
autoantigen response in vitro suggested that tolerance was preserved in the RNAloading
system used [120].
9.11
Monitoring Immune Responses
There is an urgent need to identify credible surrogate markers of an immune response
which will correlate with clinical responses. Until these techniques are identified
or validated, the encouraging results to date can only be progressed via careful
trial design, notably by selecting homogenous patient groups to study and documenting
their clinical response by well-accepted clinical monitoring using current
radiological or laboratory (tumor marker) methods. If and when surrogate immunological
markers are validated these may be used to test the multiplicity of variables
discussed, which have yet to be optimized. These can be incorporated into phase III
trials. At present, it is essential that DC vaccination studies are carried out in association
with laboratory facilities that can provide a full range of immunological laboratory
studies
It is assumed but not yet proven (given the limited phase I/II clinical data showing a
correlation) that DC vaccination should be optimized to produce maximal TAA-speci-