I was talking about the analysis of the HLA ligandome of tumour cells and of normal cells. Our aim is to find peptides presented on tumour cells but not on normal cells, so tumour specific peptides or antigens which could be used for antigen specific cancer immunotherapy.
Can you tell us a bit about ligandomes?
The ligandome is part of the proteome. The proteome is describing all proteins in a cell and actually the ligandome is essentially all the fragments of proteins which are presented on these specialised molecules, the HLA molecules. So actually the ligandome is a fraction, a sub-fraction, of the proteome which is not found by routine proteome analysis.
Could you tell us more about mutations in the peptides presented by MHC 1?
These mutations in these peptides are very interesting for the immune system because they are not self, they are new for the immune system. It has been described that these cells respond very strongly to these mutations. The problem is that many tumours just do not present such mutations, such mutated peptides, or at least we do not find them. We find such mutated peptides in a few tumours with high mutation load like in melanoma but we do not find, or we did not find, them so far in tumours with intermediate or low mutational load like ovarian cancer or hepatocellular cancer or in glioma.
How does this fit together with past or ongoing trials?
Yes, this fits very well together. It has also been reported or discussed at this meeting that the response to checkpoint inhibition is correlated to the number of mutations. So patients with a high number of mutations in their tumour tended to respond better to checkpoint inhibition than patients with low mutational load in their tumour do not respond or only small fractions of patients respond. So this fits very well with our observation that the mutated MHC ligands are low in frequency.
How do you then implement this into a vaccination?
What most people obviously in the vaccine field are trying now is to find mutated antigens, peptides, or using the different forms, and this has shown some good success in melanoma and melanoma patients. But even for melanoma patients with a low mutation rate or those not presenting mutated peptides this will not work. So what our strategy is is to analyse the tumour of a particular patient for tumour specific peptides by the HLA ligandomics approach, maybe with a preference for mutated peptides but if we don’t find them we just take the peptides which are on the tumour but which we do not find on any normal tissue. That’s why we started this large database on tumour versus normal HLA ligandome. The idea is that we will be able for every patient to find tumour specific peptides, like ten or so, and put these together as a vaccine and use this in patients.
These non-mutated ligands are very well conserved, they are germline sequence but they are still different in every patient. So we find them in some patients and these peptides might occur in some other patients but not in many. There could be a global vaccine approach which would be in the ideal case a patient comes in, the tumour is resected, the tumour is analysed for HLA ligandome expression and then we or somebody selects those peptides present in the tumour but not in any normal tissue of the same patient or in the samples we have analysed already and then synthesises, produces a new drug for this particular patient. In the meantime there will be cheaper ways like an off the shelf approach, so take those peptides which are conserved or frequently found in tumours. This would be the cheaper and faster approach but in the long run, since synthetic peptides are really easy to make, the main problem is regulatory issues. I think there will be ways to manage this that a patient comes in and within, let’s say, six weeks a new drug has been produced for this particular patient and being applied.
Is timing crucial here?
Yes, it would be a matter of timing. Of course only the vaccination with a good adjuventation and in the ideal world one would first induce a new immune response against these new peptides. If one can document that these T-cells are there in the patient then I would come with checkpoint inhibition.
How long until we could reach the 6 week period?
It could be done very fast but, as I said before, the main problem is regulatory issues and regulatory issues cannot be changed fast. So the regulations might take ten years to change it, maybe never in my lifetime, but in the meantime we have to deal with the existing rules and maybe can do such. We could do an off the shelf approach very fast, within six weeks after resection of the tumour, but if you would have to add a new peptide, which we would like to have, of course, personalised, it would be, let’s say, six more weeks for every new peptide.