Induction of immunity in hematologic malignancies mediated by NMD inhibition and potentiation of tumor-targeted co-stimulation
The main premise of this proposal is to develop a new therapeutic platform to favor the recognition and destruction of each tumor lesion by the immune system. Transiently modifying each tumor focus to increase antigenicity and immunogenicity in situ (Pastor et al Nature 2010 and Pastor et al Mol Ther 2011).
The aim is to combine NMD inhibition and potentiation of costimulatory signals in each tumor lesion. Although the strategy can be extrapolated to any type of cancer, this proposal focuses on hematological malignancies with MRP1 overexpression and therefore with poor prognosis due to the high resistance to chemotherapy that these tumors show.
In order to be successful in this project and to be able to transfer it to the clinic as quickly as possible, the following objectives are pursued:
A) Induction of immunity by inhibition of NMD in APCs (Antigen Presenting Cells) and tumor cells by using the CD40-aptamer/SMG1-siRNA chimera. The possibility of generating protective immunity against common antigens expressed after NMD inhibition will be explored.
B) Potentiation of immune system activation in contact with tumor cells by using biospecific anti-MRP1 aptamers/co-stimulatory ligands (CD28/4- 1BB/OX40).
C) Combination of target I and II in search of synergism. In this section we will study how the combination of both strategies enhances anti-tumor immunity by inducing tumor rejection and minimizing possible adverse effects.
D) Proof of concept to facilitate the transition to the clinic in a humanized murine model (Herrmann et al JCI 2014).
- Convocation: Health R&D Projects. AES 2014
- Duration: 3 years
- Start date: January 1, 2015
- End date: December 31, 2017
- Funder: Instituto de Salud Carlos III y cofinanciado por el Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”.
- Grant: 86.031€
- Nature of project: National