Opinion - Interviews

‘We’re preparing for clinical trials’ on melanoma

— Photo: K. Murali Kumar

David Baltimore: “We would like to make the immune system’s response to a particular antigen more robust.”

Well actually most of the cancer-related work we are doing now is related to therapy — immunotherapy — for melanoma and other cancers, but mainly melanoma. It’s also part of the general programme on “engineering immunity” that I talked about. For HIV, the idea is to programme the B-cells of the immune system to look for the antigenic proteins on the virus and make those small proteins that can bind to them. For cancer, we engineer the T-cells to look for a peptide to which they can bind. Cancer cells make proteins that are different from the normal, in particular differentiation. Though the immune system is supposed to clear the tumour cells, it is unable to do so. It is inhibited from doing so by inhibitors due to autoimmunity. So what we would like to do is to counter these inhibitors and target differentiation. We would like to make the immune system’s response to a particular antigen more robust. So the melanoma programme that we have is trying to get genes for T-cell receptors that allow T-cells to particularly focus on melanoma. And this is a joint programme with a group at UCLA.

The problem here is to get the right T-cell receptors. We can use protein design techniques to make receptors with the structure that we want. Then make retroviral vectors to express these T-cell receptors and target them to modify the stem cells so that the T-cells that these stem cells produce are specific to cancer antigens. You have to have the immune system react slowly over a long time.

Yes, that’s right. It’s a permanent change in the genetic arrangement of the immune system.

It’s by integration of the virus carrying the gene. It’s also thanks to reverse transcription. It’s retrovirus that carry genes into the cell and makes them part of the DNA of the cell.

We can do it. We know we can do it. We do it in mice and it works all right.

Yes. I am actually doing that in association with a structural biologist. We are not trying to do that ourselves. I have a little consortium of people working on this.

Safety issues became important following the experiment in France of retrovirus-based gene therapy in treating a certain immunodeficiency in children called XSCID [X-linked Severe Combined Immunodeficiency], which arises because the children lack [the cytokine receptor] the Common Gamma Chain. The idea was making a vector that will express Common Gamma Chain and inserting it into haematopoietic stem cells [that give rise to all types of blood cells including immune cells which are found in the bone marrow], and then the kids make T-cells that in particular have Common Gamma Chain. In most cases they do; may be in some they don’t. And so there is a group in Paris that has been doing this and reported quite remarkable success in eight out of ten kids. But then a few of the kids came down with cancer — T-cell leukaemia — and when they characterised the tumour cells, they found that in the tumour cells the virus that carried the gene had integrated next to an oncogene, the gene known to be involved in cancer. And this occurred only in two cases but it was too remarkable owing to, first of all, the gene happened to take hold over an oncogene; also it meant that the tumour cells were clonal, that they all had the same site for expression. So all this is bad news because it is just that whenever you do this kind of experiment, you run that risk. And that may be true. I don’t know. But these were with vectors that were made with a mouse leukaemia virus. And that’s genetically kind of similar.

We prefer to make vectors with an HIV-based lentivirus [slow acting virus] vectors. And those vectors don’t integrate and activate genes anywhere near as efficiently as the mouse leukaemia virus. So I think they are much safer. And what we are trying to do doesn’t involve the Common Gamma Chain. It turns out that Common Gamma Chain is an oncogene because it is such a strong stimulus to the growth of the T-cell, which is good for the immunodeficient child but ultimately bad. So we now think that those two things working together caused those tumours. And if you have only one of that, you are not running that risk.

We are not going to introduce the [gene for the] Common Gamma Chain. The genes that we are interested are benign from that point of view and by switching viruses we get vectors that don’t integrate and activate genes so easily. Those two protections added together really reduce the probability of that kind of danger. And then, of course, when we are trying to deal with things like cancer, patients are going to run a small risk if there is one. Even then Common Gamma Chain deficient kids...if I had a kid like that I would want them to be transduced and take some risk because the consequences of not doing it are worse than consequences of doing it.

Well. It’s emerging in my lab. If you are asking if there are many people doing this kind of thing, there are a few.

Well, most of the work is being done on cancer.

The one that’s farthest we have is the cancer treatment because we are preparing for clinical trials but you know doing clinical trials and having a treatment are two different things.

Yes. That’s right. Melanoma treatment.

In a few months’ time. I would love it to happen in a month’s time. But I think it will be a few months. There are lots of things. You’ve got to make materials in GMP [good manufacturing practice] conditions; you’ve got to get approvals from many different sides.

Ah! That’s interesting. I think there probably are. But there isn’t anybody I know who is trying to do that. The other two big challenges are malaria and tuberculosis. But so far I don’t think anybody is trying to do that.

(The first part of the interview, which relates to HIV, was published on Thursday.)

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