Applications of chimaeric antigen receptor T-cells in leukaemia
Dr Carl June - University of Pennsylvania, Philadelphia, USA
The University of Pennsylvania is really streets ahead in this whole area of CARs. First of all, what’s a CAR?
So I’ll step back: immunotherapy is really an offshoot from bone marrow transplantation and I was trained in that. We’ve now learned that a lot of the reason that bone marrow transplants work for patients with leukaemia is because the new immune system fights off the tumour. What we’re trying to do then is to make it so that the patient can have that effect but not have to go through a bone marrow transplant. So using the patient’s own immune system and then we make something called CAR T-cells. CAR stands for chimeric antigen receptor and chimeric comes from the Greek word about a two-headed… an animal comprised of two species. A CAR, in fact, is a molecular chimera so it’s made part of what’s a B-cell, which is one of the white cells in the immune system, and a T-cell. So what we have is part B-cell and part T-cell and we do that with gene transfer.
And you take a patient’s own cells and then how do you fix them in the lab?
This is a form of gene transfer, so the patient donates cells via simple blood donation and then they’re taken to the laboratory. It takes about ten days and the cells are modified actually using a modified form of HIV. So HIV can be disabled but it evolved as a virus, normally it causes AIDS but now HIV can be made so that it won’t cause a disease but it can be… the virus molecularly engineered so it will transfer and insert this CAR molecule that we made right into the patient’s own T-cells. Then it stays there permanently. So this is the first time living drugs have been used, if you will. We give these engineered T-cells back to the patient and they divide and they have lasted for years and years in the patient following an initial infusion. So we have a national review process and we gave the first… In fact, for ethical reasons we had to first test it in patients with HIV so that if the virus went wrong and became infectious then the patient would already have HIV. Then after we got done with tests in HIV then we were able to test this in cancer with a CAR T-cell.
It’s a really smart idea using HIV which targets T-cells anyway to carry in the chimera. And most people were fixed on the astonishing clinical results. Can you just summarise what’s really hit the headline?
We began in patients with refractory chronic leukaemia, which is not curable unless you have a bone marrow transplant. So we treated elderly patients who were too ill otherwise to have a bone marrow transplant, so that was again for ethical reasons. What I reported today was that the first patients treated more than four years ago now remain in remission and we can’t find any evidence of residual leukaemia in the patient. They also still have these CAR T-cells in them. We think that they patrol around, if you will, and then prevent relapse. So one of the characteristics of immunotherapy is that responses when they do occur are very durable.
The number of patients you’ve treated now has grown substantially.
We’ve now treated more than 150 patients at the University of Pennsylvania and have very high… We also didn’t know initially were we lucky and whatever but it’s now been reproducible and in not just chronic leukaemia that we started but there are many kinds of B-cell lymphomas and leukaemias and in every one we’ve tested we’ve had a really gratifying response rate.
B-cells, of course, suffer, that’s one of the downsides of this so you have to give gamma globulin, that’s right? What are the other problems for the patient?
So we do have to correct… we give the patient basically an acquired B-cell deficiency and the day job of a B-cell is to make antibodies. So the patients can’t be vaccinated with standard vaccines anymore because they don’t have the B-cells. So what we do is give them… it’s called gamma globulin, which has been used for many years when people lose their antibodies, and that’s a replacement therapy. What we hope to do is find out is there a point when we can get rid of these CAR cells and there are ways called suicide genes where we can put those into these CAR T-cells and then kill them at will with giving, for instance, a drug to the patient. So that is what the field will test, is how long do you have to have these and then can we kill them off? Then the immune system would return to normal and the B-cells would regenerate.
We’re beginning to see a bit of experimentation in solid tumours.
The data in solid tumours, for instance we have tested in lung cancer from patients who had surgery and they had recurrent lung cancer, we found that with a CAR against lung cancer in the laboratory, so this is in petri dishes, not yet in humans, that about nine out of ten lung cancer cells will die when they run into a CAR T-cell. So that’s good hope that at least if we can replicate everything in the patient, meaning the cells have to get to where the lung cancer is, they have to be able to get inside the lung cancer and maintain activity, that there may be activity in solid cancers as well.
Well, we’ll be looking at ASCO next year and looking forward to hearing the data. Thank you ever so much for giving us the time, it’s really been a pleasure.
Well thank you, thank you very much.