NY‐ESO‐1 specific antibody and cellular responses in melanoma patients primed with NY‐ESO‐1 protein in ISCOMATRIX and boosted with recombinant NY‐ESO‐1 fowlpox virus

Abstract

Vaccination strategies based on repeated injections of NY-ESO-1 protein formulated in ISCOMATRIX particles (NY-ESO-1 ISCOMATRIX) have shown to elicit combined NY-ESO-1 specific antibody and T cell responses. However, it remains unclear whether heterologous prime-boost strategies based on the combination with NY-ESO-1 ISCOMATRIX with different NY-ESO-1 boosting reagents could be used to increase NY-ESO-1 CD8 1 or CD4 1 T cell responses. To address this question, we carried out a randomized clinical trial in 39 high-risk, resected melanoma patients vaccinated with NY-ESO-1 ISCOMATRIX, and then boosted with repeated injections of either recombinant fowlpox virus encoding full length NY-ESO-1 (rF-NY-ESO-1) (Arm A) or NY-ESO-1 ISCOMATRIX alone (Arm B). We have comprehensively analyzed NY-ESO-1 specific T cells and B cells response in all patients before and after vaccination for a total of seven time points per patient. NY-ESO-1 ISCOMATRIX alone elicited a strong NY-ESO-1 specific CD4 1 T cell and antibody response, which was maintained by both regiments at similar levels. Current vaccination strategies based on the use of recombinant viruses are failing to elicit specific T-cell responses similar to those generated by natural infections. The limited success of recombinant viruses as delivery vectors for T cell vaccines is mainly due to their high immunogenicity, resulting in an overwhelming immune response focused on the viral-vector proteins rather than on the desired recombinant protein antigens. 1 However, it remains unclear whether recombinant viruses can be used to boost the magnitude of immune responses elicited by the prior injection of recombinant immunogenic proteins.The cancer-testis antigen NY-ESO-1 is an attractive target antigen for cancer therapy, as it is expressed in many cancer types, but not normal tissues, except testis.2 Although promising results in various NY-ESO-1 formulations have been reported in recent cancer vaccine studies, 3-6 the optimal strategy for generating integrated antibody and T cell responses to control tumor growth has yet to be determined.ISCOMATRIX adjuvant is comprised of saponin, cholesterol and phospholipid and is capable of associating with proteins to form ISCOMATRIX vaccines.7 Recombinant

Saponin-based adjuvants induce cross-presentation in dendritic cells by intracellular lipid body formation

“…Nevertheless, vaccinations with single injections of SBA-peptide compositions yielded only modest survival benefit for patients with established tumours56. Interestingly, when these vaccines were combined with TLR ligands like CpG-ODN5758, or followed up by a boosting regimen59, beneficial correlates of immunological protection could greatly be improved. We have previously shown that in situ tumour ablation can provide a source of (neo)-antigens for the generation of anti-tumour immune responses, provided that additional immune stimulation is given33.…”

Melanoma: tumor microenvironment and new treatments

“…97-99 By using reinforcements with repeated injections of recombinant Fowlpox virus encoded with NY-ESO-1 in its entirety, the results obtained were even better. 101 Other research has demonstrated effective inhibition of tumorigenesis and melanoma growth by using a novel NY-ESO-1 based vaccine and an aluminum-polysaccharide-HH2 adjuvant. 102 Finally, a Brazilian study that promoted the blockade of CTLA4 and effected the vaccination with attenuated protozoa of Trypanosoma cruzi, expressing NY-ESO-1, was able to induce both the effector function of CD8+ lymphocytes and memory.…”

Cytosolic Delivery of Liposomal Vaccines by Means of the Concomitant Photosensitization of Phagosomes

“…By the same token, phagosomolytic proteins such as listeriolysin and perfringolysin can be recombinantly integrated in antigens or in vaccine particles in order to facilitate cytosolic escape of antigen by lysis of the phagosomal membrane [29][30][31] . Another antigen delivery system that has been shown to stimulate CTLs is ISCOMs or ISCOMATRIX®, which is composed of nano-sized micelles of saponin, cholesterol, and phospholipids, and whose adjuvancy is in part mediated by its fast and efficient draining to lymph nodes [32][33][34] .As viruses naturally infect the cytosol of cells, cytosolic targeting with viral vehicles such as adeno and Vaccinia (MVA) viruses has been widely used 35,36 . Finally, the success of subunit vaccine developments is hardly thinkable without the inclusion of immuneresponse modifiers or adjuvants that provide pathogen-associated (PAMP) and danger-associated (DAMP) molecular patterns and signals activating the innate immune system [37][38][39][40] 6 hypothesized that a photosensitiser with affinity to cell membrane would translocate to the endosomal membrane upon its endocytosis and uptake in APCs.…”