Immunotherapy is helping cancer patients, including those with melanoma, to more successfully fight their diseases. However, a new study released in this month’s Cancer Discovery highlights the fact that a more personalized approach could be even more successful.
Brief background… immunotherapy works by activating the body’s T cells to find and destroy cancer cells. Obviously, this only works if the T cells are freed up (hence the checkpoint inhibitor approach) and can identify cancer cells as foreign.
How do T cells recognize cancer cells as dangerous to the body? On the cancer cells’ outer membranes are neoantigens, which are basically mutated peptides (peptides are compounds made of amino acids, get enough amino acids together and a peptide becomes a protein). But the tricky thing is that these neoantigens are wrapped in a protein structure called HLA.
Science sidebar – HLA is short for Human Leukocyte Antigen. This system encodes the proteins involved in the immune system function. Let’s say you have the flu. A specific type of HLA in your body (MHC type) would bring fragments of the flu virus to the surface of your cells so your T cells find it and destroy it. Your HLA system is polymorphic, meaning you can have a whole bunch of variation and that’s good because this helps your immune system adapt. Unfortunately, mutations can and do occur. Mutations in the HLA complex are thought to be responsible for autoimmune diseases and HLA is the reason why organ transplant recipients need to worry about rejection of the organ. (And weird fact, scientists think HLA may also be involved in your sense of other people’s odors. Apparently your selection of a mate is based on odor cues that you aren’t even aware of. And most of the time, your mate’s HLA system will be pretty dissimilar than your own. From a offspring viability standpoint, that’s really important because you want the best combination of immune system options to keep your genetic heritage going into future generations.)
OK, so HLA is super important but there are a freaking ton of variations. So how can you know which HLA proteins are offering up those cancer neoantigens? Well, other scientists are using algorithms to try to find them but those are predicting hundreds if not thousands of possible options. It is really time consuming trying to sort through all of those options to find the ones that will be promising for cancer treatments.
These researchers decided to work backwards instead. They took those neoantigens from melanoma cells’ HLA complex and looked at how they interacted with T cells. The scientists discovered that melanoma tumors actually present fewer neoantigens than expected (and unexpectedly discovered a few neoantigens involved that didn’t show up in those algorithms). That is great news because that means there are a lot less potential targets for the T cells to learn. And once the T cells identified those cancer targets, those T cells killed 90% of melanoma cells in the lab.
As the researchers state, while your own neoantigens are numerous, there are only a few that really need to be identified to guide a personalized immunotherapy approach. In their research, they looked at those who had their melanomas metastasize to see if the HLA peptides with the cancer neoantigens were similar. Even though the melanoma had spread to other organs, the profile of the HLA was shared regardless of the location of the secondary cancer. This helps further restrict the scope of the possible candidates for finding those cancer neoantigens. Then by figuring out which T cells respond the strongest with those neoantigens, you could then sequence the genome of those cells and introduce them into the patient – personalized immunotherapy.
Although this is experimental stuff, it opens an avenue of exploration and potential treatment. Immunotherapy isn’t yet this personalized; but this type of scientific research is showing that there is promise for future melanoma (and potentially other types of cancers) sufferers.