Dr Frank Ward

Research Overview

Understanding immunological tolerance is an important step towards developing new therapies for diseases that do not respond well to current treatments. Immunological tolerance can be described as the ability of the immune system to selectively recognise an antigen and choosing not to respond to it. For instance, our immune system usually will not attack tissues and cells of our own body but can recognise and respond to an infectious agent. This decision-making process is highly sophisticated but is heavily reliant on context and the presence or absence of danger signals that alert the immune system to the presence of a pathogen.

A full understanding of immunological tolerance will allow exquisite control over the immune system, switching responses on and off, according to the needs of the patient. For patients with autoimmune disease (e.g., multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes) selective intervention would allow effective disease treatment. A good example of such a therapy are the anti-cytokine therapies, which are now being used to treat psoriasis, while similar techniques could also control the immune responses underlying transplant rejection and even allergy.

Current Research

Immune checkpoints

Understanding immune tolerance can also be used to boost immunity and the last 10 years has seen this being exploited with some success to treat cancer. By removing immune checkpoints that suppress the adaptive immune response, the immune system can detect and destroy cancer cells anywhere in the body. Targeting these checkpoints is done using antibodies. In parallel with these clinical advances, we are also learning how cancers can escape the immune system and grow uncontrollably. As we learn of each escape mechanism, we can develop new therapies to shut them down. There are currently four checkpoint targets used to treat a broad range of cancers - CTLA-4, PD-1, PD-L1 and LAG-3.

Research interest and commercial development

The soluble isoform of CTLA-4 (sCTLA-4) is my focus of research for understanding tolerance. It also represents a target for checkpoint inhibitor immunotherapy. This less well-studied alternative isoform of the CTLA-4 receptor is produced by regulatory T cells, as well as cancer cells. It is important for driving reparative immune responses towards the end of an immune response but can also be used by cancer cells to evade and control the immune response.

Supported by a collection of global patents (see below), we developed a panel of high affinity antibodies specific for conformational epitopes on sCTLA-4. These antibodies bind both human and murine sCTLA-4 but not CTLA-4 receptor to selectively target sCTLA-4. We are currently seeking funding to take our lead candidate antibody into IND. Antibodies specific for sCTLA-4 have demonstrated anti-tumour activity but have the advantage that they do not rely on destruction of regulatory T cells, rendering them safer and applicable to any tumour types that produce or induce sCTLA-4 as part of an immune evasion strategy.

(Antibodies specifically directed to a soluble form of CTLA-4 https://worldwide.espacenet.com/publicationDetails/biblio?FT=D&date=20140415&DB=EPODOC&locale=en_EP&CC=US&NR=8697845B2&KC=B2&ND=5)