In the Downward lab we research cancers which are driven by mutations in the KRAS gene. This gene is responsible for promoting cell division and survival but it’s also one of the most frequently mutated genes in all of human cancers. It is particularly frequent in pancreatic cancers, colorectal and lung cancers. So, for example, approximately 30% of lung cancer patients will have a KRAS mutation, 90% of pancreatic cancer patients will have a KRAS mutation and about 50% of colorectal cancer patients will have this mutation as well. Unfortunately, these cancers remain some of the biggest killers and they tend to have fairly limited treatment options unless they’re caught very early.
In the lab we try to tackle this in three main ways: firstly, understanding the basic biology of KRAS signalling pathways; secondly, discovering new therapies to treat KRAS-driven cancers and, finally, investigating novel drug combinations which could potentially improve cancer treatment. In recent years a big finding has been that stimulating an immune response against KRAS-driven cancers can be very beneficial. So, for example, KRAS reactive T-cells have been identified in patient biopsies of lung and colorectal cancers and these were shown to be protective to the patient. Likewise, immunotherapies such as PD-1 blockade using inhibitors such as nivolumab have proven to be very effective in the treatment of non-small cell lung cancers clinically.
These discoveries have prompted our lab to start looking into how the immune system can be manipulated to treat KRAS-driven cancers. In particular, my project aims to design a cancer vaccine which stimulates an immune response against the three most common KRAS mutations, G12V, G12D and G12C. Just like a flu vaccine, a cancer vaccine stimulates an adaptive immune response and the CD8 T-cells which are expanded can then home to the tumour and begin to destroy the tumour cells. One of the biggest challenges of cancer vaccine design is stimulating a strong enough immune response to generate an effect which is beneficial to the patient. Most vaccines consist of a mixture of antigenic peptides and adjuvant which historically we know that this format doesn’t work particularly well for cancer vaccines.
So instead I’ve developed a method of conjugating KRAS peptides to an antibody targeting a protein called DNGR-1. When this antibody-peptide complex is injected the antibody will bind to any cell in the body expressing DNGR-1, in effect acting as a vaccine delivery system.
So why do we want to deliver the vaccine to DNGR-1 expressing cells? Published research has shown that one of the only cells in the body expressing DNGR-1 is a particular type of dendritic cell which is part of the immune system and is absolutely essential for activating T-cells in response to vaccination. So the unique thing about the vaccine we’ve designed within the lab is that all of the peptide is delivered directly to the DNGR-1 dendritic cells which can then stimulate a very strong T-cell response.
So as this project is still in the early stages we’ve done several studies in mouse models of lung cancer using both prophylactic and therapeutic vaccination strategies. What we’ve seen so far is that the KRAS vaccine is capable of both stimulating a T-cell immune response against mouse models of lung cancer expressing the G12V, G12D and G12C KRAS mutations. If the vaccine is given prophylactically it was able to protect 40% of mice from tumour development completely while the remaining 60% of mice showed significantly slower tumour growth. When the vaccine was given therapeutically to mice which had well-established tumours the vaccine significantly slowed down the growth of those tumours and deeper analysis of tumour biopsies confirmed the presence of KRAS reactive CD8 T-cells in these vaccinated mice.
The future work within the lab will be to test these vaccines in enough mouse model of cancer such as pancreatic cancer and also to test the vaccine in combination with other chemotherapies and immunotherapies to see if they beneficially combine with one another. The eventual aim is to take this research into clinical trials but currently we’re still very much in the pre-clinical stage.