Conclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16... Show moreConclusions: This new study confirms that clinical efficacy of ISA101 vaccination is related to the strength of vaccine-induced HPV16-specific T-cell immunity and is an effective therapy for HPV16-induced high-grade VIN/VaIN. (C) 2016 AACR. Show less
Dendritic cells (DC) play a prominent role in the priming of CD8(+) T cells. Vaccination is a promising treatment to boost tumor-specific CD8(+) T cells which is crucially dependent on adequate... Show moreDendritic cells (DC) play a prominent role in the priming of CD8(+) T cells. Vaccination is a promising treatment to boost tumor-specific CD8(+) T cells which is crucially dependent on adequate delivery of the vaccine to DC. Upon subcutaneous (s.c.) injection, only a small fraction of the vaccine is delivered to DC whereas the majority is cleared by the body or engulfed by other immune cells. To overcome this, we studied vaccine delivery to DC via CD40-targeting using a multi-compound particulate vaccine with the aim to induce potent CD8(+) T cell responses. To this end, biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP) were formulated encapsulating a protein Ag, Pam3CSK4 and Poly(I:C) and coated with an agonistic αCD40-mAb (NP-CD40). Targeting NP to CD40 led to very efficient and selective delivery to DC in vivo upon s.c. injection and improved priming of CD8(+) T cells against two independent tumor associated Ag. Therapeutic application of NP-CD40 enhanced tumor control and prolonged survival of tumor-bearing mice. We conclude that CD40-mediated delivery to DC of NP-vaccines, co-encapsulating Ag and adjuvants, efficiently drives specific T cell responses, and therefore, is an attractive method to improve the efficacy of protein based cancer vaccines undergoing clinical testing in the clinic. Show less
Rosalia, R.A.; Cruz, L.J.; Duikeren, S. van; Tromp, A.T.; Silva, A.L.; Jiskoot, W.; ... ; Ossendorp, F. 2015
Overlapping synthetic long peptides (SLPs) hold great promise for immunotherapy of cancer. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are being developed as delivery systems to... Show moreOverlapping synthetic long peptides (SLPs) hold great promise for immunotherapy of cancer. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) are being developed as delivery systems to improve the potency of peptide-based therapeutic cancer vaccines. Our aim was to optimize PLGA NP for SLP delivery with respect to encapsulation and release, using OVA24, a 24-residue long synthetic antigenic peptide covering a CTL epitope of ovalbumin (SIINFEKL), as a model antigen. Peptide-loaded PLGA NPs were prepared by a double emulsion/solvent evaporation technique. Using standard conditions (acidic inner aqueous phase), we observed that either encapsulation was very low (1-30%), or burst release extremely high (>70%) upon resuspension of NP in physiological buffers. By adjusting formulation and process parameters, we uncovered that the pH of the first emulsion was critical to efficient encapsulation and controlled release. In particular, an alkaline inner aqueous phase resulted in circa 330nm sized NP with approximately 40% encapsulation efficiency and low (<10%) burst release. These NP showed enhanced MHC class I restricted T cell activation in vitro when compared to high-burst releasing NP and soluble OVA24, proving that efficient entrapment of the antigen is crucial to induce a potent cellular immune response. Show less
Steenwijk, P.J.D. van; Ramwadhdoebe, T.H.; Lowik, M.J.G.; Minne, C.E. van der; Berends-van der Meer, D.M.A.; Fathers, L.M.; ... ; Burg, S.H. van der 2012
CD4(+) T cell responses against the E6 oncoprotein of human papillomavirus (HPV) type 16 and 5 closely related members of clade A9 (HPV31, 33, 35, 52, and 58) were charted in peripheral blood... Show moreCD4(+) T cell responses against the E6 oncoprotein of human papillomavirus (HPV) type 16 and 5 closely related members of clade A9 (HPV31, 33, 35, 52, and 58) were charted in peripheral blood mononuclear cell cultures from healthy subjects and patients who underwent HPV16 E6/E7-specific vaccination. Initial analyses with overlapping peptide arrays showed that approximately one-half of the responding subjects displayed reactivity against corresponding E6 peptides from >= 2 HPV types. This suggested immunological cross-reactivity and complicated retrospective evaluation of the infection history of the healthy subjects. Importantly, further dissection of the response by means of enriched and clonal T cell cultures (with protein antigen instead of peptides) revealed that CD4(+) T cells that are capable of efficiently reacting against E6 antigen from multiple HPV types are rare and only occur when epitope sequences are highly conserved. Our data indicate that natural and vaccine-induced HPV16 E6-specific CD4(+) T cell responses are unlikely to mediate efficient cross-protection against other clade A9 members. Show less
