Monophosphoryl lipid a (MPL) as an adjuvant for anti-cancer vaccines: Clinical results

Abstract

Abstract As technological advances allow for the identification oftumor-associated antigens (TAAs) again st which adaptive immune responses can be raised , efforts to develop vaccines for the treatment ofcancer cont inue to gain momentum. Some ofthese vaccines target differentiation antigens that are expressed by tumors derived from one particular tissue (e.g., Melan -A/ MART-I , tyrosinase , gp 100). Some target antigens are specifically expressed in tumors ofdifferent 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 (H ER2 / neu, Ras, E7 HPV 16), tumor supp ressor genes (pS3 ) or tumor-specific post-translational modified proteins (underglycosylated Muc 1) can also be used as cancer vaccine candidates. In either case, th ese antigens tend to be poorly inmmunogenic by themselve s and vaccines containing them generally require the inclusion ofpotent immunological adjuvants in order to generate robust anti-tumor immune responses in humans. Man y 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 ofantigen to T-cells in draining lymph nodes. Lipid A, the biologically active portion of the gram-negative bacterial cell wall constitu ent lipopolysaccharide (LPS) , is known to possess strong immunostimulatory properti es and has been evaluated for more than two decades as an adjuvant for promoting immune respon ses to minimally immunogenic antigens, including TAAs. The relatively recent discovery ofTLRs and the identification ofTLR4 as the signaling receptor for lipid A have allowed for a better understanding ofhow this immunostimulant functions with regard to induction ofinnate and adaptive immune responses. Although several lipid A species,including LPS and synth etic analogs, have been developed and tested as monotherapeutics for the treatment of cancer, 1-8 only 3-0-desacyl-4'-monophosphoryllipid A (MPL) has been evaluated as a cancer vaccine adjuvant in published human clinical trials. MPL comprises the lipid A portion ofSalmonella minnesota LPS from which the (R)-3-hydroxytetrade canoyl group and the l -phosphate have been removed by successive acid and base hydrolysis9. LPS and MPL induce similar cytokine profiles, but MPL is at least 1OO-fold lesstoxic.9.10 MPL has been administered to more than 300 ,000 human subject s in studies ofnext-gen eration vaccines.11 In this chapter, published clinical trials conducted to evaluate the safety and/or efficacy of various cancer vaccines containing MPL, eith er alone or combined with other immunostirnulants, such as cell wall skeleton (CWS) of Mycobacterium pble;(in the adjuvant Detox™; Biomira, Inc.), the saponin QS-21 (in the adjuvants ASOIB and AS02B; GSK Biologicals) or with QS -21 and CpG oligonucleotides (in the adjuvant AS 15; 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. © 2009 Landes Bioscience and Springer Science+Business Media.