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

α-galactosylceramide Analogs

The glycolipid α-galactosylceramide (αGalCer) and its analogs are a unique class of immunoenhancers which, when presented by the MHC class I-like molecule CD1d, are recognized by the αβ T-cell receptors of NK T cells (iNKT cells). αGalCer (also called KRN7000) is derived from marine sponges[131] and strongly stimulates mouse and human iNKT cells.[132] Naturally occurring glycolipid antigens include isoglobotrihexosylceramide (iGb3), an autologous mouse antigen, and GSL-1, a glycosphingolipid antigen from spingomonas bacteria that is structurally related to αGalCer.[133–135] The hallmark of iNKT-cell activation following T-cell receptor engagement is the rapid production of a high level of various immunoregulatory cytokines, including both Th1 and Th2 cytokines, unlike conventional CD4+ T-cell responses, which are usually polarized towards either Th1 or Th2 cytokine production.[136] Clinical trials with soluble αGalCer or αGalCer-pulsed DCs aimed towards in vivo reconstitution and activation of human iNKT cells have provided both promising and challenging results.[137–139] However, the use of αGalCer in cancer therapy has been limited since repeated injection of αGalCer induces long-term anergy of iNKT cells in mice.[140] Delivery of αGalCer on mature DCs or αGalCer loaded onto a recombinant soluble CD1d molecule (αGalCer/sCD1d) has proven effective at expanding iNKT cell numbers that correlate with antitumor responses in mice.[141,142] With regard to the prospect of using glycolipid agonists as immunotherapy to activate iNKT cells in vivo, repeated injections of weaker compounds might be a good candidate to avoid anergy. Owing to the fact that Th2 cytokines can antagonize the immunostimulatory properties of Th1 cytokines, a powerful treatment option is the use of agonists that shifts the response to Th1 type for antitumor therapy. Wittycell is developing neoglycolipds iNKT agonists with strong adjuvant activity, capable of stimulating both murine and human iNKT cells. In preclinical models, we found enhanced cellular responses to subunit vaccines incorporating protein antigens that induce crossprotection against different strains of influenza viruses in mouse and monkey models, with our leading candidate [Nitcheu Tefit J, Unpublished Data]. The anticancer efficacy was investigated against the B16-OVA melanoma mouse tumor model in both the prophylactic and treatment setting of vaccination with protein and adjuvant. We found complete tumor protection in mice treated with protein and adjuvant [Nitcheu Tefit J, Unpublished Data]. Preliminary toxicity studies in monkeys and mice demonstrated an excellent safety profile and Phase I/IIa clinical trial initiated by the company is underway with the objective to analyze the safety and biologic activity of the selected candidate.


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