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

240 11 Hybrid Cell Vaccination for Cancer Immune Therapy
The side effects seen in the trials were mild and all signs of vaccination-induced immune
responses. They included erythema at the sites of inoculation, some cases of
fever and others of strong but temporal perspiration. In some of the malignant melanoma
patients a locally restricted vitiligo occurred after vaccination which again is
indicative of the activity of cytotoxic T cells with specificity for public melanoma associated
antigens. No other signs of vaccination-induced autoimmune reactivity were
observed. Such low toxicity is, as discussed before, common to all vaccination therapy
trials reported so far.
11.5
Conclusion and Prospects
HCV has proven to be a feasible strategy for the treatment of cancer patients and
well-suited for individualized therapy, and the responses achieved so far in advanced-stage
cancer patients are encouraging. The hallmark of this approach is the
use of the patients own tumor cells, which is the broadest possible representation of
the antigen spectrum of the tumor and which also includes, besides shared TAAs,
the specific mutations private to the specific tumor cell clones of the patient. Other
vaccination strategies with this potential to address a broad spectrum of TAAs and to
induce a broad repertoire of tumor-specific T cells use heat shock proteins (gp96 or
HSP70; discussed in Chapter 12) or DCs pulsed with tumor lysates [174, 175], peptides
eluted from tumor cells [176, 177], or amplified total mRNA obtained from tumor
cell lines or micro-dissected tumor material [175, 178±180]. The latter three strategies
make use of the unique capacity of DCs to take up antigenic material and to
process it for presentation to T cells. The preparation of heat shock proteins, peptides
or lysates from tumor cells will require large tumor masses which in many cases
might be difficult to obtain from the patients. The HCV approach is burdened by the
same problem. It could be possible to use established tumor cell lines for the preparation
of the vaccines. However, such cultured cell lines might not express the
same antigens as the tumor in the patients. In fact, preliminary observations from
the initial HCV trials with melanoma patients indicate that autologous tumor cell
lines represent a different antigenicity than the original tumor and are less efficient
in the vaccine preparations [171]. Amplified mRNA of tumor cells might become a
promising solution for these problems if it becomes possible to ensure that the amplified
mRNA represents a sufficiently broad spectrum of the tumor antigens and
that these complex mixtures of RNA can be introduced into the DCs efficiently. The
best type and optimal maturation state of the APCs will depend on the vaccination
strategy and the mode of antigen transfer. The generation of hybrid cell vaccines will
certainly require mature DCs as most potent APCs and T cell stimulators [144]. For
those approaches that require active antigen processing, immature DCs might be
the better choice.
The repeated observation that patients who do not experience complete responses
can be treated with hybrid cell vaccines for prolonged times and stay in a stable disease
state throughout opens the option of vaccination therapy as a maintenance ther-