Update on NIH Trial

All,
This is the response I received from the research scientist at NIH in regards to the tumor sequencing. It is quite an education, especially for my simple mind. I hope this helps and I appreciate his quick response and honesty at the end. This is his reply:

There are several types of sequencing, the most widely used in the clinic is “targeted sequencing”. This type of sequencing only looks at a relatively small number of genes and tests to see if these genes contain mutations. The reason why this is used in the clinic is because mutations in these specific genes can predict whether a certain drug will be effective or not, so this can be used to guide a treatment. However, this type of sequencing would likely not be very helpful to us because only a relatively small number of genes are assessed. With fewer genes assessed, we would have much fewer (or no) mutations to test. It’s already a “needle in a haystack” when we look at all the mutations, so it would be more like a “needle in a football stadium” if we only evaluated a few mutations.

Then there is whole-genome sequencing (WGS), and whole-exome sequencing (WES), both of which can evaluate the presence of mutations in most genes in the human genome. These are the types of sequencing that we can use. Both can give reliable data if the “read coverage” is high enough. What this means is that the “deeper” we sequence (the more sequence reads we get for a particular gene), then the more confident we are that it is a true mutation. For example, if we only detected one sequence containing the mutation out of 5 sequences read, this would be 20% mutation frequency, but we would be more confident that this is a true mutation if we detected, say, 20 sequences out of 100 sequences read (still 20%). This is because there are errors that can occur during DNA sequencing. The 1/5 could be an error and therefore not a real mutation, however, it’s statistically less likely that 20 errors occurred out of the 100.

The difference between whole-genome sequencing and whole-exome sequencing is that whole genome is just that, it reads every single base in your genome. However, you might remember that the importance of DNA is that it ultimately encodes for protein, which is what does all the work in our cells and tissues. It turns out that only about 1-2% of the entire genome encodes for protein. So whole-exome sequencing just sequences this 1-2% of the genome. Since mutations are only relevant to use if they affect the protein, whole-exome sequencing can be more efficient (since you don’t have to sequence 98-99% of the irrelevant DNA). Both have the advantages and disadvantages (which I won’t get into here).

But to answer your question, we have used both whole-genome and whole-exome sequencing, although the vast majority of our experience is with whole-exome. It is also very important that both the tumor and a normal source of DNA from the same patient are sequenced. For example, you can sequence peripheral blood cells (from a blood draw) as a source of normal DNA. We need this as a reference to identify what is a true mutation (since, in most cases, only the tumor will have the mutation).

So in an ideal situation, a patient would come into clinic with their tumor already sequenced. This would save us about 3-4 weeks in our testing process. However, as you know, there are many factors that have to fulfilled before a patient could even be enrolled onto our protocol. There are the clinical parameters that have to be fulfilled, and it turns out when our MDs screen patients, unfortunately many are not eligible. And there are also limitations in our lab and clinical trial capacity, since we can only handle a relatively small number of patients at any one given time.

So I guess one thing I would make clear to potential patients is that even if they get sequencing done, there’s no guarantee that he/she would make it onto our trial. And even if they make it onto our trial, we are at such an early stage of research and development that we don’t know if we would even find mutation-reactive T cells to use for treatment. Although it would be unfortunate if patients got sequencing done and couldn’t get onto our trial, it potentially wouldn’t be for nothing, because the sequencing data could be used to advance science; genomics experts around the world are working together to catalogue the sequences of thousands and thousands of tumors to try to understand cancer better which hopefully will lead to better treatments in the future.

I can’t tell you how much I admire this young man…..hope it helps! Melinda