ASH 2013 - New Orleans, LA, US
Treating ALL patients with T cells targeted for CD19
Dr Laurence Cooper - MD Anderson Cancer Center, Houston, USA
We’ve been talking about genetically modified T-cells and these T-cells are programmed ex vivo, in other words outside of the body, to be specific for both paediatric and adult cancers and, in particular, acute lymphoblastic leukaemias, chronic lymphocytic leukaemias and lymphoma. The way this technology works is that we recognised that antibodies, proteins that have been made in the mouth, for instance, can target antigens on the surface of these leukaemia and lymphoma cells. One of the antigens we’ve been very interested in is a molecule called CD19; it’s both on malignant B-cells, in other words B-cells give rise to leukaemias and lymphomas and it’s also, of course, on normal B-cells. So we take those antibodies and we graft them using a process called gene therapy onto the surface of the T-cells. Typically speaking these are T-cells that come from the very patient themselves who has the leukaemia or lymphoma. Once these T-cells have been engineered ex vivo to be CD19 specific by the insertion of this antibody hybrid, and that goes by its own name called a chimeric antigen receptor. In other words, these chimeric antigen receptor modified T-cells, CAR modified T-cells, can then be returned to the patient and then we asked the question what happened.
Many of these patients who have really large burdens of disease and refractory disease sadly cannot be treated with conventional therapies. These CAR modified T-cells sweep into the body and essentially eradicate all of the malignant B-cells, all of the leukaemia and lymphoma. They also damage the normal B-cells but that’s OK for this subset of patients and we are now watching to see what happens with those patients as they return back to their communities to see if, indeed, they’re cured.
Do these cells persist?
The question around persistence is a good one because what we’d like to be able to understand is when we put the T-cells in, how long do they live in the patient. That makes sense because just like you give any drug it’s really the quote-unquote area under the curve, in other words the kinetics of how the drug is absorbed into the body and then lost from the body. Instead of thinking of a drug that you take as a pill, think of the drug now as these CAR modified T-cells. So once they’re put into the body how long do they live for and if they live for long enough to eradicate really lumpy, bulky disease so that they can eradicate it.
So the best data really now is coming from both our understanding in using QPCR, genetic tools, as well as flow cytometry tools to look for the presence of these T-cells in the body. We know that these T-cells, if they’re going to respond to these high burdens of cancer, persist. Not just they’re detectable but actually they expand in number so, in other words, one cell becomes many cells and we can see that within the first weeks of infusion. Then over time, as the B-cell problem goes away, as the leukaemia and lymphoma goes away, so the numbers of T-cells we infuse declines. But the best data that has been presented, for instance at this press briefing, is that these T-cells, albeit at low levels, can still be seen really months, if not years, after the initial brush with leukaemia and lymphoma was detected.
What does the future look like for this therapy?
The future for this stuff is very promising and it really, indeed, will challenge chemotherapy as well as other types of therapy, for instance radiation therapy, for the role in a patient’s treatment regimens. It’s too early to say, to be honest, whether or not it might be a replacement therapy but one way to think about it is that the war on cancer was launched with radiation therapy, chemotherapy and surgery. Added rapidly to that now, in the last years, has been small molecule therapy and it’s really been a lifesaver for many patients. Added to that is this world of immune therapy and one piece of the puzzle is these CAR modified T-cells and of course the other piece being these checkpoint blockade, the antibodies against CTLA4, PD1, PDL1 etc. So now patients have options, they have options of not just the three chemotherapy, radiation therapy and surgery, but of these precision medicines, these targeted medicines, whether it be with molecules or with changing the immune system.
What about the toxicity of the treatment?
Two levels of toxicity, one is associated with the infusion of the cells and that is where the cells are busy killing tumour cells and there’s a side effect from that measured by, essentially, these high levels of cytokines, these calling cards, these proteins that are made by the immune cells to call in recruits. Those result in high fevers and sometimes a drop in blood pressure, sometimes confusion for the patient, and they have to be managed in an expert setting, really by skilled practitioners. Then there’s a second class of toxicities and those are sort of the longer term toxicities. Here these are actually being quite tolerable and that is where the infused T-cells have destroyed and prevented the re-emergence of the patient’s normal B-cells. So these patients are immunosuppressed, they lack the ability to make their own new antibody. So as practitioners we have to give them antibody back and that’s in the form of intravenous immunoglobulin. So these patients are monitored and they’re given IV IG, intravenous immunoglobulin, at scheduled intervals really to protect them over the long term.
The patients being treated in the press conference really were in extremis. They had terrible burdens of disease and they really had no other options. So these therapies really were lifesavers and certainly for some of the patients they indeed are still in a remission where essentially they had no hope of survival outside of these CAR modified T-cells.
