Outlining Novel Cellular Adjuvant Products for Therapeutic Vaccines Against Cancer

Josianne Nitcheu Tefit; Vincent Serra


Expert Rev Vaccines. 2011;10(8):1207-1220. 

In This Article

Vehicles: Adjuvant Emulsions & Liposomes

Adjuvant Emulsions

This class includes O/W or W/O emulsions such as free fatty acid, Montanide, adjuvant 65 and Lipovant.[97] Freund and colleagues developed and used water-in-oil (W/O) emulsions, in which antigen could be suspended in an aqueous phase, then slowly emulsified into oil. Early versions included paraffin oil, Arlacel A as emulsifier and dried Mycobacterium cells. Such emulsions are referred to as CFA.[105,106] CFA was found to be unacceptably reactogenic for use in human vaccines.

The mechanism of action of adjuvant emulsions includes the formation of a depot at the injection site, enabling the slow release of antigen and the stimulation of antibody-producing plasma cells.[107] Frequent side effects of emulsions include inflammatory reactions, granulomas and ulcers at the injection site. More recent W/O emulsions have included the introduction of purified, metabolizable oils and emulsifiers in order to find more stable, potent and less toxic formulations.

Montanide The most notable of the emulsion adjuvants are the Montanide adjuvants which are based on purified squalene and squalane,[108] emulsified with highly purified mannide mono-oleate.[109] There are several different types of Montanide, including ISA 50V, 51, 206 and 720. ISA 50V, 51 and 720 are W/O emulsions while ISA 206 is a W/O-in-water emulsion. ISA 206 and 50V have been used only in veterinary vaccine formulations, while the other two are under investigation for use in humans.[108] Emulsions of Montanide ISA 51 and 720 are composed of metabolizable squalene-based oil with a mannide mono-oleate emulsifier.[110,111]

In humans, Montanide has been used in Phase I and/or II trials for vaccines against various cancers.[110,111] In most cases, studies have reported efficacy, though safety results seem to be somewhat antigen- and antigen dose-dependent, with the incidence of adverse events and severe adverse events increasing with antigen dose and number of administrations. Trials with a Wilms' tumor protein vaccine against various malignancies and a melanoma vaccine containing either ISA 51 or 720 all showed strong CTL responses in humans.[112,113]

In addition, and as discussed earlier, emulsification in Montanide ISA 51 seems to increase immunogenicity of the CpG-containing vaccine formulation.[90]

O/W Emulsions MF59 and AS03™ (O/W Emulsions) Advances in stable emulsion technology have allowed the development of effective adjuvants containing small amounts of oil that do not form granulomatous depots upon injection, thus having superior safety profiles as compared with W/O emulsions. By far the most advanced O/W emulsion is MF59,[114] a component of licensed vaccines for both seasonal and pandemic influenza.[114] Overall, MF59 has an acceptable safety profile, and with several antigens, significantly increases antibody titers with reportedly more balanced Th1/Th2 responses than those obtained with alum. Other O/W emulsions are being developed, and include AS03,[115] AF03[116] and squalene-based O/W emulsions (Infectious Disease Research Institute, Seattle, USA).[46] These adjuvants have not yet been investigated in cancer immunotherapy.

Liposome Adjuvants

Liposomes are synthetic spheres consisting of lipid layers that can encapsulate antigens and act as both a vaccine delivery vehicle and adjuvant. In this section, we describe liposomes that are composed of nonviral lipids (i.e., lipids not obtained passively from host cells in viral budding processes).

For vaccine purposes, these particles are considered most useful for delivering antigens and adjuvants.[16,117] They enhance both humoral and cellular immunity to protein and polysaccharide antigens.[118,119] Liposomes help extend the half-life of antigens in blood, ensuring a higher antigen exposure to APCs after vaccination.[120] Liposomes have been used widely in experimental vaccines. An interesting preclinical study in mice conducted by Guan et al. revealed that liposome-associated MUC1 peptide produced a strong specific CTL response; however, an antibody response was only observed for the surface-associated BP25 formulation.[121]

Stimuvax, discussed earlier, uses a liposomal adjuvant. It is being developed by Merck and Biomira for treatment of NSCLC, and a Phase III clinical trial is currently underway. Additional liposomal vaccines that have been investigated in human cancer trials include one for prostate cancer[122] and were found to be safe and highly immunogenic. Stability, manufacturing and quality assurance problems seem to have been major factors behind the fact that as yet, no adjuvant based on liposomes has been registered for human use.


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