Lynch syndrome is the most common colorectal cancer predisposition syndrome conferring approximately 70-80% lifetime risk of developing colorectal cancer. We originally thought that Lynch syndrome was relatively uncommon; now, however, as more and more people have their genome sequenced or are having panel sequencing, for instance patients who have colorectal cancer and also other cancers – endometrial cancer, stomach cancer, ovarian cancer – we now think that Lynch syndrome is actually much more common, affecting approximately one out of every 280 Americans and in Scandinavia studies suggest about one out of every 250. Lynch syndrome is seen worldwide so although there have not been precise estimates for Asia or Africa or South America we anticipate that the levels will be similarly high.
What did you speak about today?
Lynch syndrome is caused by mutations in DNA mismatch repair genes. These are sort of like a spellchecker so you can imagine that if you’re copying a document in Microsoft Word and you had to do it by typing in the words you’d make some errors. Then if you copied a copy or a copy of a copy of a copy that you’d accumulate errors. The same thing happens during cell division when they replicate their genomes in mismatch repair deficient cancers. Consequently, because the mutation rates are very high and enriched in specific sequences you develop recurrent mutations, for example, the TGF-β type 2 receptor is mutated in approximately 60-80% of colorectal cancers that have mismatch repair deficiency. In addition, these types of tumours, because they’re specifically enriched in insertion and deletion mutations, for example adding an extra T or subtracting an A which introduces completely new amino acid sequences, are the most immunogenic. This is the basis why in advanced malignancy patients with Lynch syndrome respond, about 30-50% of them respond, to checkpoint inhibitors. So our approach was to try to go earlier in the paradigm. Advanced tumours have very immunosuppressive microenvironments; they have cells that basically try to suppress the immune response against the tumour. If you go earlier, to the point where you have single cells or very few cancer cells, you’re actually most likely to have a strong effect. Therefore, we adapted a tumour mutation vaccine approach using the fact that these mutations are recurrent and we wanted to make sure that this is safe and efficacious so we used mouse models.
The interesting thing about our result was that suggesting that a vaccine that had as few as four recurrent mutations was able, essentially, to prevent cancer in mice with Lynch syndrome. The simplicity of that is exciting because it means that we might be able to translate it. We’re currently hoping to do a phase Ib trial so we’ve submitted a proposal to the National Cancer Institute to be able to have a trial in Lynch syndrome patients with the goals of demonstrating, one, that a vaccine is safe, which we believe it will but is important, really, for all phase I studies, and, second, that it induces the immune response in these patients. If that trial is successful that would be followed up by a phase II/III trial with a clinical endpoint that is reduction in colorectal carcinomas in these patients.
Do you think we are going to be moving towards a more preventative approach in oncology?
If one looks at actually the number of cancers that occur in both the developed and less developed world there are overall fewer cancers, actually, per age, just because different countries have populations that are aging. But most of the benefit in the reduction in cancer is really from prevention so actually the excitement in particular with the vaccines for human papilloma virus, hepatitis B and hepatitis C has encouraged this idea for a cancer vaccine for non-viral cancers. So I would make the point that because they have high rates of immunogenic mutations if it takes a hundred steps to go right, to be able to make an effective cancer vaccine, I would advocate that Lynch syndrome is the right place to start.
If we’re able to do this successfully I think we can broaden it, actually, to other diseases. So there are recurrent mutations that occur in sporadic cancers. First, actually, let me say that in the sporadic form of the disease about 4% of all solid tumours are mismatch repair deficient, so a substantial number of patients who are at risk for secondary malignancies and could benefit from this. But, more broadly, there are other genes, for example KRAS, BRAF, FLT3, DNMTA etc. and others that have recurrent mutations and this approach would actually hopefully be amenable to using a more broad cancer prevention vaccine. By any means I’m not saying this would eliminate cancer but the point is that even because the burden of cancer is so large that in the same way that a pneumococcus vaccine is able to reduce the rates of pneumonia in elderly individuals, even if we’re able to reduce the rates of cancer by a few percent that would be quite a substantial boon to public health.
Would you like to add anything else?
The potential benefits of immunoprevention are the economics. We’ve seen the cost of therapies for advanced cancers has gotten quite substantial, to the point where patients, really, in the United States have to decide can you afford to keep your house. You have to mortgage your house to be able to have your spouse, for example, receive some of the state of the art therapies. The idea of immunoprevention, we’re currently funded through the National Cancer Institute and we’d like to try to make this as open source as possible and to be able to make this a low cost alternative so that it could be of general public benefit.
