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

236 11 Hybrid Cell Vaccination for Cancer Immune Therapy
potent immune stimulator cell. All these different approaches to cancer vaccination
therapy are being tested in clinical trials ±some of which are discussed in different
chapters of this volume. The initial observations reported from these trials include a
number of clinical responses of varying degree in late-stage cancer. A thorough evaluation
of these attempts, however, will have to await the conclusion of these trials.
There is, however, an increasing appreciation of the antigenic complexity of tumor
cells and the need to address with the tumor vaccines as many specificities, i. e. tumor-associated
T cell epitopes, and as many T cells as possible to induce a strong
antitumor immune response and to minimize the selection for specific antigen-loss
variants of the tumor cells. Antigen loss as effect of antigen-specific immune selection
induced by antigen-specific vaccination might in fact be among the most serious
side effects of vaccination therapy. In addition to this, all these trials have shown that
vaccination therapy is remarkably well tolerated by the patients. Some cases of autoimmune
reactions seen (usually restricted vitiligo) have been reported from different
trials, but, so far, no case of vaccination-associated autoimmune disease has been
seen [160]. Other adverse effects are very limited and signs of vaccine-induced immune
responses.
11.4
HCV
11.4.1
Conceptual Basis
The HCV approach to cancer immune therapy attempts to render antigenic tumor
cells immunogenic by fusing them with potent APCs, activated B cells or DCs [35,
158, 161±163]. Using the tumor cell itself as source and carrier of the tumor antigens
should ensure the broadest possible representation of the tumor's antigenicity in the
vaccine, including tumor-specific mutations. Two different designs of the hybrid
cells have been tested. The one relies on the co-stimulatory capacity of the activated
B cell or DC alone and uses autologous fusion cell combinations [162], whereas the
other fuses autologous tumor cells with allogeneic APCs to recruit and activate
helper T cells to support the induction of tumor-specific cytotoxic T cells [161]. While
the majority of tumor cells express MHC class I molecules, constitutive expression
of MHC class II expression is limited to a few cell types of the immune system (see
Chapter 9). Accordingly, the probability for a tumor cell to simultaneously express
both MHC class I and II in conjunction with suitable tumor antigens that can address
the helper and precursor cytotoxic T cells of the patients at the same time is
low. The use of allogeneic MHC class II molecules for the induction of T cell help
eliminates the need for MHC class II-restricted TAAs for the activation of CD4 +
helper T cells and the reliably induced strong T cell responses against allogeneic
MHC class II molecules does not require prior priming of these T cells. Moreover, recent
reports suggest that the immune stimulatory function of DCs in cancer patients
might be impaired and that allogeneic DCs prepared from the peripheral blood of