Gene therapy and virotherapy in the treatment of cancer

Published on November 4, 2014   46 min

Other Talks in the Series: Gene Transfer and Gene Therapy

Other Talks in the Series: Immunotherapy of Cancer

0:00
My name is Leonard Seymour. I'm professor of gene therapy at the University of Oxford. And I'm going to talk to you today about gene therapy and virotherapy for the treatment of cancer. And I'll tell you where I think we are with this field, what are the main aspects of the field which have been important, and what we can expect from the field.
0:19
So in terms of the lecture, I'll speak briefly about the background of cancer to give some introduction to what I think are the important contexts and why gene therapy and virotherapy are useful treatments. I'll talk about cancer gene therapy. Specifically I'll mention the challenge of delivering DNA and viruses to tumors. And I'll talk about some of the approaches which have been employed using p53 replacement and TNF. But mainly I'm going to talk about the use of virotherapy, what it is, why it's good, how it works. And I'll give some examples of the sorts of treatments which are being developed and where they are clinically and where we're expecting them to go.
0:58
So if I might start talking about the hallmarks of cancer, this is a concept that has been developed over the last several years as being the features that distinguish tumor cells from normal cells. Hanahan and Weinberg put together the exposition of this. And they've developed it again recently. And there are now about 10 different hallmarks of cancer. These are features which tumors and tumor cells develop which make them distinct from normal cells and gives us an opportunity for intervention. So for example, they evade apoptosis. They are self-sufficient in maintaining their growth. They tend to be insensitive to signals that turn off growth. They grow limitlessly. Many other aspects, several of which are exploited in chemotherapy. But increasingly, many of which are being developed in the field of virotherapy. So I will pick up on several of these different features of tumors as ways that we can develop viruses that will selectively treat tumors.
1:57
On the next slide, I've shown the microscopic structure of colorectal cancer. And I've done this simply to show you the complexity of the tumor. So the tumor cells you can see here are the ones which are darker blue. That's because they have a lot of chromatin. And you'll see that they're stacked up in what we call tumor islands. So the cells tend to stick together and form sheets. And in this cross-section through, you can see a couple of tumor islands which are surrounding small vesicles, which are actually reminiscent of the lumen of the intestine. And the cells are polarized. And they're maintaining some function of behaving a bit like the colorectal enterocytes from which they're derived. What we believe is going on here is that the tumor cells are to some extent still maintaining normal activity. But they've lost some component of DNA integrity. They've lost, as I was referring to in the previous slide, the ability to respond to normal growth signals. And the purpose of the slide really is to show you that they don't do this on their own. So what they've done is they've accumulated one or two or by this time probably several different changes which have been able to exploit the body to provide many different cell types that then come along and support the tumor. So if you look inside a tumor at this sort of level, you see that typically 20% or 40% of the tumor cells are actually cancer cells. But the rest of cells which have derived from the normal host and which are there for different reasons, and we think increasingly are there because they think that the tumor needs support. And many people nowadays believe that tumors are recognized by the body as wounds and the body is actually trying to heal them. And it's providing fibroblasts to provide matrix and growth factors to try and heal this lesion which it considers to be a wound. But in fact, the tumor is something which is never going to heal and which is going to keep exploiting the fact that the body is nourishing it and it's growing more and more. Now the reason I'm showing the slide really is to say that there are several components. There are the stromal fibroblasts of the immune system, which is very often involved in the tumor, but which seems to be inactivated within the tumor micro-environment. And there are blood vessels, which are supplying nourishment to the tumor. So it's a complex micro-environment. And it's wrong to consider it as just tumor cells forming a tumor. There are many different components of the normal body helping the tumor to grow. And that's really why it is so difficult to treat it.
4:18
So on the next slide, I've shown an everted caecum from somebody with probably a familial disease giving a lot of polyps. And you can see different polyps on the caecal wall which are at different stages of development. You can see some very early ones, little white ones which are white because they're not properly vascularized. And so they haven't at that stage attracted a blood supply. And they're unlikely to have spread around the body. But you can also see dark red ones which are fully vascularized, which have attracted a blood system. And when they attract a blood system they not only grow more quickly, but also they can spread the cells into the blood system. And in that way the tumor can colonize around the body and cause what we call metastatic disease. So that is a much more life-threatening environment. The difference we think between these different lesions is the level of genetic change that's happened. And Vogelstein's progression, which I've shown at the bottom of the slide, suggests that the normal epithelium gradually picks up mutations in both tumor suppressor genes and in oncogenes, which gradually moves the cell through stages of early adenoma through intermediate and then late adenoma to carcinoma, and ultimately to metastatic carcinoma. And that all entails the acquisition of more and more mutations. Now, a few years ago we thought that that was about it. And I remember teaching a few years ago that tumors typically had half a dozen mutations that explained their modified behavior.
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Gene therapy and virotherapy in the treatment of cancer

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