VIRAL&IMMUNE THERAPY

Breaking Tolerance - Combination of Virotherapy and Immunotherapy for Cancer Treatment

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 Obiettivo del progetto (Objective)

'The aim of this project is to enhance the efficacy of a tumour killing virus and break tolerance within the tumour to induce an immune response against the primary tumour and metastatic deposits. The proposed strategy requires three steps. First, the tumour immunological microenvironment needs to be reset as tumours utilize a variety of mechanisms to escape host immune system. Here, we propose to use the chemotherapeutic agent cyclophosphamide to temporally deplete suppressor T cells and recruit new dentritic cell progenitors. Second, to kill cancer cells, we propose to systemically deliver the potent tumour-killing (oncolytic) adenovirus ICOVIR15, which replicates selectively in cancer cells with pRB pathway mutations. In order to favour anti-tumour immunity, the ICOVIR15 will be genetically engineered to express cytokines that have been shown to be useful to stimulate anti-tumour responses such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-g). Moreover, IFN-g has also been shown to kill tumour-associated vasculature. The host group has been awarded with three “non-commercial” clinical research grants from the “Fondo de Investigaciones Sanitarias” of the Ministry of Innovation and Science of Spain to test ICOVIR5 in clinical trials. ICOVIR5 is being produced under Good Manufacturing Practices. If the novel GM-CSF or IFNg armed viruses show promising results at preclinical level, the host group will apply for other non-commercial research grants to test it in clinical trials. This project is also aimed at further developing the skills of the applicant in genetic engineering, virotherapy, immunology and working in different tumour models. The applicant would move from the UK to Spain. The applicant hopes to establish herself as an expert in the multidisciplinary areas of cancer gene therapy such as immunotherapy, angiotherapy and virotherapy.'

Introduzione (Teaser)

An EU-funded project developed oncolytic adenoviruses with enhanced efficiency. The researchers combined the anti-tumour activity of the viruses with the ability to induce an immune response to cancer.

Descrizione progetto (Article)

Oncolytic, or tumour-killing, adenoviruses are genetically modified to selectively infect and replicate within cancer cells. As the infected cancer cells are destroyed by lysis they release new infectious virus particles to help destroy the remaining tumour. The aim of the 'Breaking tolerance - combination of virotherapy and immunotherapy for cancer treatment' (VIRAL&IMMUNE THERAPY) project was to increase the efficiency of oncolytic adenoviruses and induce an immune response against tumour cells.

Researchers genetically modified human adenovirus 5, which normally causes a common cold, to recognise the changes in the cell division that are typical of cancers. To achieve this, the key viral gene (E1A) was placed under the control of the promoter E2F1 that is active in cancer cells. In addition, the protein E1A was mutated to make it inactive in normal cells.

A binding site of a cell-surface protein, an integrin, which is over-expressed in some cancers, was inserted in the capsid of the virus. These modifications created the cancer-specific and highly potent oncolytic virus ICOVIR15K. The next project goal was further modification of the adenoviruses to combine their effect with the induction of an immune response against cancer.

Proteins and other molecules that can trigger an immune response are called antigens. Tumour-associated antigens are usually present in cancer cells but not in normal tissues. Researchers modified the virus ICOVIR15K to display small parts of tumour-associated antigens (called epitopes) within the viral capsid in order to trigger a strong anti-tumour response. Combinations of 10 different tumour-associated epitopes were used for capsid modifications.

Screening in an in vitro model identified the two most potent viruses containing two short epitopes of Wilms tumour (WT1) protein or a combination of survivin and WT1 epitopes. WT1 and survivin are common in many solid cancer types, such as melanoma and neuroblastoma. Evaluation of the immunogenic potency of these and other adenoviruses is currently underway in a murine model.

Genetic modifications of the adenoviral protein shell are extremely hard to obtain as they normally interfere with capsid structure and no viable viral particles are formed. However, specific immune response to the tumour-associated epitopes displayed by these viruses could be translated into better anti-tumour efficacy.