Tag: Prof. Cornelis Melief
Company News: Publication Demonstrates Superior Activity of ISA Pharmaceuticals´ SLP® Vaccines Compared to Whole Protein Vaccines
– Study published in European Journal of Immunology elucidates different, improved antigen presentation and T cell-inducing power of SLP® vaccines
ISA Pharmaceuticals B.V., a clinical-stage immunotherapy company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced the publication of a peer-reviewed paper in the European Journal of Immunology.[1] The article describes a previously unknown mechanism that explains the excellent efficacy of ISA’s Synthetic Long Peptide (SLP®) vaccines. The authors demonstrate that compared to whole protein antigens, SLP®s are processed much more rapidly and efficiently by dendritic cells (DCs), resulting in an increased antigen presentation to CD4+ and CD8+ T cells, and enhanced CD8+ T cell activation. The improved presentation relates to a distinct intracellular localization of SLP®s after uptake by DCs.
Cancer immune therapy requires the induction of potent CD4+ and CD8+ T cell responses to the malignant cells. This is accomplished by DCs, the major antigen-presenting cells of the immune system. So far it has been challenging to induce a sufficiently potent reaction by vaccinating with whole protein antigens. In a number of preclinical and clinical studies, ISA Pharmaceuticals has already observed improved efficacy of its SLP® vaccines as compared to whole protein vaccines.
To study the underlying mechanism, researchers used both mouse and human DCs. They found that after incubation with SLP® vaccines and subsequent uptake by the DCs, the SLP®s are located in the cell, but are largely outside the cells’ endosomes. In contrast, protein antigens are processed inside endosomes, resulting in a much slower and different processing route. In the study, SLP®s were processed far more efficiently and distinctly into both MHC class I and II antigen presentation pathways than whole protein antigens. This lead to a strong activation of both CD4+ and CD8+ T cells, resulting in potent and efficient immune responses to the antigen.
In previously published clinical studies, ISA had already demonstrated the superiority of SLP® vaccines over short peptide vaccines. Short peptide vaccines, which fit precisely into MHC class I molecules, often do not result in a sufficiently long antigen presentation, and also carry the risk of inducing a mix of favorable pro-immunogenic and detrimental tolerogenic signals. Moreover, short peptide vaccines do not instate efficient immunologic memory. ISA also demonstrated that these differences are caused by the highly selective uptake, processing and presentation of SLP®s by professional antigen-presenting cells, and by the presence of both CD4 and CD8 epitopes in the long peptides.
[1] Rosalia et al.; “Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T-cell activation”, DOI: 10.1002/eji.201343324
http://onlinelibrary.wiley.com/doi/10.1002/eji.201343324/abstract;jsessionid=F0FBA5A73F264503207C22EDF313FAB0.d04t03.
Company News: Novel AMPLIVANT™ Technology Introduced at AACR Annual Meeting 2013
– AMPLIVANT™ TLR-ligand adjuvant to improve immunotherapies –
ISA Pharmaceuticals B.V., a clinical-stage biopharmaceutical company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, announces that Cornelis Melief, Professor at Leiden University and Chief Scientific Officer of ISA, presented details on the company’s novel AMPLIVANT™ technology at the American Association for Cancer Research (AACR) 2013 Annual Meeting. AMPLIVANT™ is based on a powerful, proprietary toll-like receptor (TLR) ligand designed to improve immunotherapies. This promotes direct dendritic cell targeting of the antigen as well as antigen processing, resulting in long-term activation of dendritic cells and antigen presentation.
Toll-like receptors (TLRs) expressed by immune cells such as dendritic cells (DCs) or macrophages, play a key role in innate immunity by recognizing characteristic molecular structures present on the surface of bacteria and other microorganisms. Once these TLR ligands bind to the receptors, a signaling cascade is triggered which, among other effects, activates cells initiating immune responses. Thereby, they have the capacity to generate a robust acquired immune response.
Together with other scientists at Leiden University, the ISA team had observed that adding known strong TLR ligands to a vaccine consisting of synthetic long peptides resulted in a greatly improved immune response.
“Our rationale then was to link the peptide antigen chemically to the TLR ligands in order to obtain an even more efficient antigen delivery into the dendritic cells and additional activation stimuli from the TLR ligand,” said Melief. “In addition, we found that the AMPLIVANTTM-SLP conjugate is ingested more efficiently and leads to the creation of an antigen depot in the dendritic cells. This in turn results in long-lived antigen processing and presentation at the cell surface of the DCs.”
In tumor mouse models, conjugates of TLR ligands and synthetic long peptides resulted in much greater anti-tumor activity, long-term tumor protection and increased survival as compared to vaccines consisting of mixtures of peptides or peptides plus free TLR ligands.
To improve the TLR ligand performance further and to maximize clinical benefit, a synthetic TLR2-activating ligand was modified by rational molecular design, following a crystal structure analysis of the interaction between the ligand and its receptor.
“These efforts led to the AMPLIVANT™ technology, which had already yielded a number of proprietary agonists with enhanced receptor activation and DC maturation,” Melief added. “Our AMPLIVANTTM adjuvants are 100-fold more effective in terms of receptor stimulation than existing reference adjuvants, and we have also shown that they result in enhanced priming of CD8 T-cells in vivo.”
ISA is now planning a Phase I/II study to demonstrate safety and immunogenicity. “In this study, we will validate the AMPLIVANT™-SLP conjugate concept along the lines of our ISA101 vaccine, which has demonstrated clinical efficacy against pre-malignant disease,” said Gerard Platenburg, Managing Director of ISA Pharmaceuticals. “AMPLIVANT™ conjugates are based on two synthetic long peptides chosen from the 13 SLPs of the ISA101 vaccine. The trial in patients with HPV16-positive head and neck cancer is expected to start in early 2014.”
A Phase II trial of ISA101 in vulvar intra-epithelial neoplasia has established clinical proof-of-concept. In cervical cancer, ISA101 has completed a phase I/II trial and will enter into a randomized phase II trial later this year. ISA is also about to enter a phase I/II study in anal intra-epithelial neoplasia (AIN) with ISA101.
Company News: Prof. Cornelis Melief to Present Novel AMPLIVANT™ Platform at AACR Annual Meeting 2013
ISA Pharmaceuticals B.V., a clinical-stage biopharmaceutical company focusing on rationally designed therapeutic vaccines against cancer and persistent viral infections, today announced that Prof. Cornelis Melief, M.D., will present details on the novel AMPLIVANTTM platform at this year’s American Association for Cancer Research (AACR) Annual Meeting. AMPLIVANTTM is based on a powerful, proprietary toll-like receptor (TLR) ligand improving immunotherapies.
Presentation title: “Synthetic vaccine for immunotherapy of high risk HPV infections“
Symposium: SY27 “New Cancer Vaccines“
Abstract number: SY27-01
Date: April 9, 2013, at 10:40 a.m.
Location: Room 202 at the Washington Convention Center.
The abstract is available at the AACR website www.aacr.org.