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

196 9 Dendritic Cells and Cancer: Prospects for Cancer Vaccination
tors, defects in tumor antigen-processing and antigen display may influence the
TAA tumors display ± whether this merits individualizing therapy at this juncture is
a mute point. However, loss of MHC antigens in advanced disease may reflect a
hopeless situation and some would argue that rational trial design would exclude
such cases rather than waste resources in uninformative cases.
There is clear consensus that the best results will be obtained in patients with minimal
residual disease. This not only minimizes the risk of tumor escape, but may provide
an optimal immune environment for DC initiation of an effective immune response.
Like chemotherapy protocols, the aim must be tumor eradication and not
just control. Careful study design is required for this population and integrating DC
immunotherapy into an overall treatment program involving other modalities (with
a functional immune system) is a problem. Common diseases susceptible to immunotherapy
without standard curative protocols, such as multiple myeloma and lowgrade
NHL, should be investigated early [103].
9.13
New Developments in DC Immunotherapy
Phase III studies of DC in multiple myeloma, prostate cancer and melanoma are underway.
The preliminary data in multiple myeloma and prostate cancer are encouraging.
Thus, we can anticipate more phase III studies. Given the low toxicity of DC
immunotherapy, these are likely to be initiated in earlier disease. However, a major
limitation remains the paucity of well-recognized TAAs apart from melanoma,
whereby the TAAs (Mart-1/Melan-A. gp100, Tyrosinase) are virtually standard. Additionally,
antigens, e. g. MAGE-1 and -3, have been key additions to the repertoire and
novel antigens, e. g. the recently described embryonic TAA [171], are likely.
One can anticipate a rapid standardization of DC preparations as a result of commercial
input and the new appropriate regulatory environment monitoring biological
therapies. Key questions remain as how to load DCs with antigen effectively. This
may involve modifying antigen (protein, peptide, DNA or RNA) targeting DC membrane
receptors such as the Toll receptor, DEC-205 and Langerin or targeting DC intracellular
pathways, e.g. with HIV tat [93].
Activating/differentiating DCs in an optimal fashion will also require careful experimentation.
CD40L is already in use, CpG [172] likewise ± other more potent compounds
are likely to energy. These will need to be assessed to ensure they do not
compromise DC migration.
Finally, to improve on DCs as the specialist APC, additional IL-12 or IL-2 may encourage
T lymphocyte expansion. Genetic manipulation of DCs to enhance T lymphocyte
recruitment has been suggested [173]. Equally, passive TAA-specific T lymphocytes
generated in vitro for infusion [174] might be boosted in vivo by DC vaccinations.
Although HLA-matched allogeneic DCs may themselves be effective, it is possible
that allografting an immune system in its entirety may be extended from hematological
malignancies to other cancers. Thus, allogeneic stem cell transplants are effec-