As technological advances allow for the identification of
tumor-associated
antigens (TAAs) against which adaptive immune responses can be raised, efforts to develop
vaccines for the treatment of
cancer continue to gain momentum. Some of these
vaccines target
differentiation antigens that are expressed by
tumors derived from one particular tissue (e. g.,
Melan-A/ MART-1,
tyrosinase, gp 100). Some target
antigens are specifically expressed in
tumors of different types but not in normal tissues (e. g., MAGE-3), while other possible targets are
antigens that are expressed at low level in normal tissues and are over-expressed in
tumors of different types (e. g., HER2, Muc 1). Oncogenes (HER2/neu, Ras, E7 HPV 16), tumor suppressor genes (pS3) or
tumor-specific post-translational modified
proteins (under glycosylated Muc 1) can also be used as
cancer vaccine candidates. In either case, these
antigens tend to be poorly inmmunogenic by themselves and
vaccines containing them generally require the inclusion of potent
immunological adjuvants in order to generate robust anti-
tumor immune responses in humans. Many adjuvants currently under evaluation for use in
cancer vaccines activate relevant antigen presenting cells, such as dendritic cells and macrophages, via
toll-like receptors (TLRs) and promote effective uptake, processing and presentation of
antigen to T-cells in draining lymph nodes.Lipid A, the biologically active portion of the gram-negative bacterial cell wall constituent
lipopolysaccharide (LPS), is known to possess strong immunostimulatory properties and has been evaluated for more than two decades as an adjuvant for promoting immune responses to minimally immunogenic
antigens, including TAAs. The relatively recent discovery of TLRs and the identification of TLR4 as the signaling receptor for
lipid A have allowed for a better understanding of how this
immunostimulant functions with regard to induction of innate and adaptive immune responses.Although several
lipid A species, including LPS and synthetic analogs, have been developed and tested as monotherapeutics for the treatment of cancer,1-8 only 3-O-desacyl-4'-monophosphoryl
lipid A (MPL) has been evaluated as a
cancer vaccine adjuvant in published human clinical trials. MPL comprises the
lipid A portion of Salmonella minnesota LPS from which the (R)-3-hydroxytetrade canoyl group and the l-phosphare have been removed by successive
acid and base hydrolysis.9 LPS and MPL induce similar
cytokine profiles, but MPLis at least 1OO-fold less toxic.9,10 lOMPL has been administered to more than 300, 000 human subjects in studies of next-generation
vaccines.11 In this chapter, published clinical trials conducted to evaluate the safety and/or efficacy of various
cancer vaccines containing MPL, either alone or combined with other
immunostimulants, Such as
cell wall skeleton (CWS) of Mycobacterium phlei in the adjuvant Detox; Biomira, Inc.), the
saponin QS-21 (in the adjuvants AS01B and AS02B; GSK
Biologicals) or with
QS-21 and CpG
oligonucleotides (in the adjuvant AS15; GSK
Biologicals) will be summarized. Combining MPL with other
immunostimulants has been demonstrated to be advantageous in many cases and may be required to elicit the full
complement of activities necessary to achieve an effective immune response and overcome the ability of
tumors to evade attack by the immune system. In this chapter, information relating to
vaccines targeting specific
cancers will be presented in the first section, while information relating to
vaccines targeting multiple
tumor types by the induction of immune responses to shared TAAs is presented in the second section.