IMMUNOTHERAPY

Manipulating different arms of the immune system to orchestrate tumor-specific immunity and enhance tumor clearance

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 Obiettivo del progetto (Objective)

'Killing of cancer cells with an oncolytic adenovirus is an immunogenic phenomenon and can therefore be utilized for breaking the immunological tolerance of a tumor. Two complementary strategies can be used to enhance the T cell response towards the tumor: A) recruiting Dendritic Cells (DCs) to the tumor site to augment peptide loading onto MHC I; B) specific activation of DCs at the tumor site to increase their expression of co-stimulatory molecules for enhancement of cross-priming and T cell activation rather than cross-tolerance. As our first aim, we propose to generate three different capsid-modified oncolytic vectors expressing granulocyte-macrophage colony-stimulating factor (GM-CSF). The transgene will be driven by a replication-coupled adenoviral promoter to ensure GM-CSF production exclusively in tumor cells (an oncolytic virus replicates only in tumor cells). GM-CSF is a potent cytokine that enhances the function of antigen presenting cells (APCs) by the maturation, activation, and recruitment of DCs, macrophages and monocytes. All biologic responses crucial for DC functioning are influenced by signaling through the Toll-like receptors (TLRs), and TLR9 in particular is a key bridge between the innate and adaptive response. We propose, as our second aim, to generate an oncolytic vector containing CpG-stimulating sequences in its genome to combine oncolytic cell killing with effective delivery of CpG DNA to the endosome, where TLR9 is located. Finally, we will combine the two strategies described in aims 1 and 2, generating oncolytic vectors that are able to secrete GM-CSF for recruiting APCs to the tumor and at the same time to stimulate TLR9 in these cells. Overall we propose to capitalize on the entry biology of adenovirus for stimulation of TLR9 coupled with tumor specific secretion of immunomodulatory molecules to orchestrate immune rejection of the tumor.'

Introduzione (Teaser)

Immunotherapy has been in the spotlight of cancer treatment for many years. An EU research team is exploring the use of viruses to selectively kill tumour cells.

Descrizione progetto (Article)

Oncolytic adenoviruses are known to preferentially infect and destroy cancer cells while leaving normal cells unharmed. Despite what was initially envisaged, oncolytic viruses do not merely lyse tumour cells but they also induce host immune responses against cancer cells.

Scientists on the EU-funded IMMUNOTHERAPY project decided to exploit this feature for generating long-lasting anti-tumour immunity. To this end, they engineered adenoviruses to express the cytokine called granulocyte-macrophage colony-stimulating factor and attract antigen presenting cells at the tumour site. This approach essentially turns lysed tumour cells into a vaccine and induces systemic immunity against the tumour.

Administration of the virus in various preclinical models generated very promising results with respect to anti-cancer efficacy and also provided a long-term vaccine effect. Based on this data, researchers proceeded with testing this virus in a clinical trial in cancer patients who were refractory to standard therapy.

Modifications of the virus and co-administration with chemotherapy further improved the therapeutic outcome. This combinatorial approach was found to reduce the number of regulatory T cells that were present at the tumour site.

As an alternative strategy for enhancing immune responses, researchers explored the toll-like receptors (TLRs) that are known for their role in innate immunity. They successfully engineered a novel oncolytic adenovirus to stimulate TLR9 on dendritic cells and bring about T cell activation.

Engineering a 'super' virus is being considered as a long term plan for treating cancer. By combining TLR-mediated activation and immunomodulatory molecules, the IMMUNOTHERAPY strategy boasts enhanced tumour clearance.