With next-generation sequencing, clinicians can test the blood plasma of patients with large B-cell lymphoma to see the amount of cancer DNA – known as circulating tumor DNA (ctDNA) – that exists, thus predicting their risk of relapse.
For over a decade, blood samples were telling of acute lymphoblastic leukemia and other blood lymphocyte disorders, mainly by measuring the white blood cells, called lymphocytes. Analyzing the plasma is a much newer idea.
“But what we’ve tested and what the nature of this important finding in this paper is, we took the plasma and said: ‘what about what’s in the liquid component of the blood, not the cells and not the red cells,'” said Dr. David Miklos, associate chief, Blood and Marrow Transplantation and clinical director of the Cancer Cell Therapy at Stanford University, in an interview with CURE®.
In this video, Miklos gives an overview of his research on ctDNA, that was conducted alongside his co-authors, Dr. Matthew Frank, Dr. Nash Hossain, Dr. Saurabh Dahiya and Dr. Fred Locke.
This is our introduction to circulating tumor DNA. We’re going to start on the left-hand side. While circulating tumor DNA can be used from a number of different cancers and tumors, the specificity that a rearrangement of the immune receptor in the lymphocytes of T cells and B cells is a huge advantage for us investigators and for the patients to have their cancer sensitively and specifically measured.
So let’s imagine that the patient has a cancerous lymph node and a normal lymph node in their body. And in these lymph nodes, there are lymphocytes. That literally is the definition of lymphoma, that is the collection of the lymphoid neoplasia in the lymph node, as opposed to leukemia where the lymphocytes are in the blood. Now, for over 12 years, we have been able to measure acute lymphoblastic leukemia and other blood lymphocyte disorders by collecting a tube of blood. And in the tube of blood, there are white blood cells, the lymphocytes themselves, and we can do this fascinating next-generation sequencing testing on the on the cellular component.
But what we’ve tested and what the nature of this important finding in this paper is (this): we took the plasma, we said, ‘What about what’s in the liquid component of the blood, not the cells and not the red cells? What is their DNA specific to the cancer being shed into the liquid component of the blood at a distance from the lymphoma that could then be collected from your vein, and be able to provide the docs a specific quantitative assessment of your cancer without having to take pictures by PET scan? And how would it compare to the standard physical evaluation? And how would it predict for the patient’s clinical outcome over the next 12 and 24 months?’
This is possible in a B cell because on the surface, there’s a receptor that ultimately is what we call antibody. When this B cell matures, it will become a factory cell that just pumps out the protein that’s sitting on the surface. And this protein is unique for each one of our B cells in our body. That repertoire is huge. This is my Carl Sagan moment, it’s billions and billions of different receptors. And we call that the repertoire. So we think it’s 10 to the 12th. It’s huge.
Now, if you have cancer, though, instead of having a bunch of different rearrangements of the gene that we call VDJ, doesn’t really matter. You take a bunch of cassettes of different components of the gene, and you put it together like a party tape; I used to make party tapes on cassettes. This is a party tape. This is a little bit of The Who next to Janis Joplin next to some Led Zeppelin. And there’s a little bit of difference in the spacing and timing in between each song track. And that makes me a unique party tape, I can sequence across the party tape. Now with next generation sequencing, we can test billions of unique sequences in a tube of blood, we can measure a million or more B cells for a very inexpensive test and say what is the specified what is the number of times that we see a shared cancer clone in that tube of blood, and we could have done this for the cells and called leukemia, next generation are minimal residual disease testing, or we could do it for the liquid component and call that circulating tumor DNA testing. So that’s the gist of what we’re trying to accomplish. And this testing of the immunoglobulin receptor both heavy chain and light chain is provided by a company called Adaptive Biotechnologies, our partner in this work.
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