Combination cytotoxic immune effector cell and oncolytic virus therapy for cancer therapy

Lead Research Organisation: University of Leeds
Department Name: Leeds Institute of Molecular Medicine

Abstract

Certain viruses have been shown, in the laboratory, to be able to kill cancer cells. These viruses are not normally damaging to humans and don‘t generally cause significant illnesses. Some cancer cells have lost the ability to eradicate viruses in the way that healthy cells can, so that these viruses can be used to target and selectively kill cancer cells in patients. We are trying to improve the effectiveness of this approach by studying different viruses, and by combining the viruses with cells from the body‘s own immune system which themselves can attack cancer.
Combining cell and viral therapy for cancer is an exciting new approach to cancer therapy. Critically, this research is focused on testing cells and viruses using human reagents, including tumour cells freshly resected from patients; this ensures that our work is of maximum relevance to the disease as seen in patients, and helps rapid translation of our findings into early clinical trials. We‘re specifically looking at melanoma; an aggressive form of skin cancer that kills thousands of people, particularly young people, each year, and for which there is little effective treatment. We hope our research will also benefit other cancers too.

Technical Summary

Oncolytic viruses (OV) are being investigated both for their ability to directly kill cancer cells, and for their role as immunogens, stimulating bystander innate and adaptive anti tumour immune responses. Reovirus (RV) and measles virus (MV) can cause immunogenic tumour cell death, and are already in early clinical trials. Cytotoxic immune effector cells (LAK, NK, CIK, CTL) may potentiate viral therapy, by combining direct cell-mediated killing with an ability to carry (hitchhike) OV, and hand them off to target tumour cells. My aim is to study the combination of immune effector cells and OV as a novel human anti-cancer therapy suitable for clinical translation. I will study the direct innate cytotoxicity of immune effector cells, and direct killing by RV and MV against melanoma, using both cell lines and autologous systems of freshly resected tumour. Combined OV hitchhiked on immune effector cells will then be tested for direct cytotoxicity and activation of anti-tumour immunity. Finally, the effect of cell carriage on protection of OV from neutralising anti-viral antibodies, potentially enhancing in vivo efficacy, will be explored.

Publications

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Alonso-Camino V (2014) The profile of tumor antigens which can be targeted by immunotherapy depends upon the tumor's anatomical site. in Molecular therapy : the journal of the American Society of Gene Therapy

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Donnelly O (2013) Live viruses to treat cancer. in Journal of the Royal Society of Medicine

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Donnelly O (2012) The hitchhiker's guide to virotherapy. in Oncotarget

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Donnelly OG (2012) Recent clinical experience with oncolytic viruses. in Current pharmaceutical biotechnology

 
Description Ellison Cliffe Travelling Fellowship
Amount £15,000 (GBP)
Organisation Royal Society of Medicine 
Sector Learned Society
Country United Kingdom
Start 04/2011 
End 04/2012
 
Description Oncolytic Virus Conference Travel Award
Amount £400 (GBP)
Organisation Mayo Foundation for Medical Education and Research (MFMER) 
Sector Charity/Non Profit
Country United States
Start 02/2011 
End 02/2011
 
Description Immunogenicity of Radiotherapy 
Organisation Mayo Clinic
Department Department of Molecular Medicine
Country United States 
Sector Charity/Non Profit 
PI Contribution During 12 months spent at the Mayo Clinic I worked with Prof Richard Vile on preclinical models of the immune effects of radiotherapy, and with clinicians in the radiation oncology department to develop a translational clinical study of the immune consequences of SBRT for patients with oligometastatic melanoma
Collaborator Contribution Prof Vile hosted and funded the preclinical research. The department of radiation oncology will perform the clinical study
Impact Ongoing clinical study. Contributions to the 2012 publications listed.
Start Year 2011
 
Description Immunogenicity of Radiotherapy 
Organisation Mayo Clinic
Department Radiation Oncology Department
Country United States 
Sector Hospitals 
PI Contribution During 12 months spent at the Mayo Clinic I worked with Prof Richard Vile on preclinical models of the immune effects of radiotherapy, and with clinicians in the radiation oncology department to develop a translational clinical study of the immune consequences of SBRT for patients with oligometastatic melanoma
Collaborator Contribution Prof Vile hosted and funded the preclinical research. The department of radiation oncology will perform the clinical study
Impact Ongoing clinical study. Contributions to the 2012 publications listed.
Start Year 2011
 
Description Commended for Max Perutz science writing award 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Shortlisted in 2010 and commended in 2011

Description of two projects published online by MRC
Year(s) Of Engagement Activity 2010,2011
 
Description Pecha Kucha competition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Public/other audiences
Results and Impact Shortlisted for Pecha Kucha competition

Video of presentation being made available online
Year(s) Of Engagement Activity 2011
 
Description Talked to a local group of fundraisers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Spoke to 50 representatives involved in organising fundraising days in 4 local regions to describe the work we do and the need for ongoing funding for medical/cancer reseaerch

N/A
Year(s) Of Engagement Activity 2009
 
Description Yorkshire ACF presentation day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Health professionals
Results and Impact Annual meeting of Yorkshire academic clinical fellows

Won the prize for the best research and talk
Year(s) Of Engagement Activity 2010