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TherMelVac- dendritic cell-targeted peptide vaccine against melanoma by ligand-modified nanoparticles

iMed.ULisboa/ FFULisboa Research Institute for Medicines/ Faculdade de Farmácia, Universidade de Lisboa
Project classification

Scientific area

3.1 Basic medicine

Discipline(s)

Immunology
Pharmacology and pharmacy

Project description

Project title

TherMelVac- dendritic cell-targeted peptide vaccine against melanoma by ligand-modified nanoparticles

Scientific Coordinator's name:

Helena F Florindo Roque Ferreira

Scientific Coordinator's e-mail:

hflorindo@ff.ul.pt

Principal R&D Unit:

iMed.UL/FFUL

Other R&D Units involved in the project:

Unité de Pharmacie Galénique, Industrielle et Officinale (FARG); Migal - Galilee Technology Center (Migal)

Project keyword(s)

Melanoma immunotherapy, Dendritic cell targeting, Melanoma antigens, Nanotechnology

Short abstract and comments

The extensive investigation and use for decades of chemotherapy, surgery and radiation have not been enough to defeat Cancer, being therefore the leading cause of death worldwide. Cancer cells are able to overcome the general body immune response and then the vaccine design aiming the induction of an integrated T-cell mediated immunity is one of the most used strategies for the last 20 years to improve cancer immunotherapy. Dendritic cells (DCs) are the most potent antigen presenting cells (APCs) in the human body for the stimulation of naive T-cells, playing a key role in the fight of the immune system against cancer cells. After recognizing, taking up and processing the antigen, DCs migrate into T-cell areas of secondary lymph nodes and present antigen to T cells. The interaction among B cells, T cells and mature DCs results in broaden and integrated immune response, crucial to get a cytotoxic effect that will lead to tumor rejection and regression. Effective immune responses are then dependent on the delivery of antigen to DCs and their presentation to T-cells, being these important factors to have in consideration when developing an effective vaccine. Antigen recognition and DCs migration are highly controlled and involves several mediators and their receptors. DC therapy is a complex approach as it involves the isolation, culture and stimulation of patient’s monocytes and macrophages ex vivo. As DC biology is not completely known, the in vivo direct targeting of these APCs with a specific antigen constitutes an important alternative and this in fact will be the basis of this project. An ideal vaccination strategy involves the administration of the most immunogenic tumor associated antigen (TAA) along with the most effective adjuvants, in order to prime the tumor specific T cells, induce tumor-specific antibodies and kill tumor cells by host immune effector mechanisms. Previous studies, some of our team, have shown that nanoparticles (NP) have important adjuvant properties to prevent infectious diseases, but these carriers are emerging as safe alternatives for the induction of anti-cancer immune responses in several tumor models. By encapsulating the TAA in NP it is possible to stimulate tumor-specific cytotoxic T lymphocytes (CTL) responses and direct the immune response towards the Th1 pathway, which are vital for tumor-protective immunity. Melanoma is the most dangerous type of skin cancer, mainly due to its great potential for metastasis. It has been resistant to the most available radiotherapy and chemotherapy treatments, urging the need of an alternative treatment modality for melanoma patients. A number of melanoma associated-antigens have been identified, being involved in melanocyte differentiation or melanin production, and extensively expressed both in human and murine melanoma. These immunogenic epitopes are important for the development of melanoma immunotherapeutic strategies and thus these peptides have been selected to be associated to NP. Our strategy aims to combine the antigen carry capacity of NP and the specific targeting and maturation of DC receptors in vivo, by developing an antigen-specific therapeutic melanoma cancer vaccine based on lipid and polymeric carriers able to target mannose receptors or Toll-like receptors (TLR) at DCs. This study will evaluate and characterize the in vitro lymph node distribution of ligand-modified and non-targeted NP, their transport mechanism and stimulus for DC maturation and T cell activation, and their in vivo role as adjuvants for melanoma peptide vaccination to improve the induction of an effective (cellular and humoral) anti-tumor immune response in a highly metastatic melanoma murine model.

Potential uses/indications

With this project, we intend not only to achieve a tumor-protective immunity, but also understand and correlate this anti-tumor effect with the role and interaction between DCs and these ligand-modified antigen delivery systems, providing an alternative to more empirical approaches to protein vaccines. Therefore, this approach will provide important insights into the design and rational development of cancer vaccines able to effectively eradicate cancer cells.

Status

Ongoing

Partner Status: Seeking Partners?

Yes

Grant number (QREN, FP7, Eureka, etc)

PTDC/SAU-FAR/119389/2010

Last edited on

2013-11-04 13:20:14

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