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

11.3
Vaccination Strategies for Cancer Immune Therapy
11.3 Vaccination Strategies for Cancer Immune Therapy
Both the concept of therapeutic vaccination for immune therapy in general as well
as that of tumor vaccination have a long history dating back to the 19th century.
A systematic exploration of vaccination approaches to cancer therapy is, however, a
relatively recent development based on the rapidly expanding knowledge of tumor
antigenicity and the regulatory requirements of the induction of tumor-specific immune
responses. A number of different strategies have been developed during the
past 20 or so years, each reflecting the current understanding of tumor immunology.
Earlier attempts have focused on the induction of antibody responses against tumor
cell surface antigens using the tumor cells themselves or tumor lysates. This work
has been extended to the development of diagnostic tools, and of therapeutic agents
such as immunotoxins and immunocytokines, which are discussed elsewhere in this
volume (see Chapter 17).
With increasing appreciation of the importance of MHC class I-restricted CD8 +
T cells in antitumor immunity, tumor cells have also been employed to stimulate
specific antitumor cytotoxic T cell responses [110]. A number of modifications were
introduced to enhance the immunogenicity of the tumor cells: allogenic tumor cells
[111, 112], allogenic, MHC class I-matched tumor cells [113, 114] or tumor cell lysates
[115], haptenized tumor cells [116±119] or gene technologically altered tumor
cells that were transfected with genes coding for allogenic MHC class II molecules
to activate helper T cells [120], granulocyte-macrophage colony-stimulating factor
(GM-CSF) to enhance antigen presentation and DC function [121±124], IFN-g to
support the differentiation of tumor-specific cytotoxic T cells [125±127], or factors
such as B7 to enhance co-stimulation of the cytotoxic T cells [120, 128].
Following the discovery of the first TAAs and Tcell epitopes, these antigens and synthetic
peptides were used as vaccines [129, 130]. In the earliest studies, neat peptides
or peptides in incomplete Freund's adjuvant (IFA) were injected into patients to induce
antitumor T cell responses [131±134]. The initial clinical trials with these protocols
have yielded some cases of clinical responses, but overall the response rates
were low. These experiences together with the emergence of new concepts and technologies
for the generation of vaccines have led to the design of new types of vaccines.
Peptides with epitopes for tumor-specific cytotoxic T cells were combined with
helper T cell epitopes and IFA [135], the genes coding for the entire TAAs were engineered
into plasmid vectors or into virus DNA and used for naked DNA [135, 137] or
virus vaccination [138, 139], thus making use of the strong immunogenicity of the
virus, in most cases adenovirus. With the development of techniques for large-scale
production of DCs and the discovery that DCs are uniquely capable of taking up and
processing peptides, protein antigens or polynucleic acids, this cell is being extensively
explored as an antigen carrier and adjuvant for the induction of antitumor
T cell responses (see Chapter 9). DCs have been loaded with synthetic peptides [140±
144], antigen-coding DNA or RNA [145±147], tumor lysates [143], exosomes or apoptotic
bodies from tumor cells [148] or heat shock proteins extracted from tumor cells
(see Chapter 12), or have been fused to the tumor cells [149±159], all to generate a
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