ASH 2013 - New Orleans, LA, US

Chimeric antigen receptor produces complete responses and long-term persistence in children and adults relapsed, refractory ALL

Dr. Stephen A. Grupp - University of Pennsylvania, Philadelphia, USA

We have been looking at a particular way of doing immunotherapy, cell therapy, using CARs, or chimeric antigen receptors. The basic approach is that each patient must provide cells for their own treatment. These patients to collect T-cells, the T-cells are genetically engineered with an antiviral vector which actually is a modified form of the HIV virus and that puts a gene in the T-cells that then allows the cells to produce this CAR protein. The CAR protein targets the T-cell to the cancer cell and it also activates the T-cell so that the T-cell can efficiently kill the cancer cell and also, we hope, proliferate significantly in the patient.

Right now, most of the work in this area has been focussed on B-cell cancers because we use the antigen CD19 as a target and that’s a great target. The only other cells, obviously, that express CD19 are normal B-cells; we do expect the normal B-cells to be destroyed by the cell therapy and that’s fortunately something that we can tolerate because we’re able to do antibody replacement in these patients.

The issues are really you need to target and the CAR does that and there are lots of folks who have done that; you need to grow enough cells to be able to treat patients and there are various ways to do that and they are clinically compliant, what we call GMP. The issues have really been what happens to the T-cell after it goes into the patient so what we’re really looking for in an effective cell therapy is significant proliferation, so lots of growth of the T-cells in the patient, and ideally persistence over months so that there is continuing surveillance against the possibility of relapse. That has been hard to find in a lot of prior immunotherapy studies but now we’re starting to see it.

We see a remarkable degree of proliferation of up to ten thousand-fold in these patients after the cells are placed into the patient which is an important part of the clinical efficacy. But we also see persistence; it’s variable, the first patient that we treated is now eighteen months out, she’s still on a complete response and she still has these engineered T-cells at low levels which has produced continuing B-cell aplasia. We’ve actually treated a total of 27 patients, the group at Penn has treated five adult patients and we’ve treated 22 paediatric patients so a total of 27 of whom 24 have gone into a complete response for a complete response rate of 89%. So we’re very hopeful about the short-term complete response rate. These are patients who are relapsed refractory or relapsed after donor transplant, they’re not patients who have a lot of other treatment options so we’re very gratified by this short term response rate. We have seen some recurrences among the group of patients who go into a complete response. Six of the 24 patients who actually went into complete response have subsequently had their leukaemia come back; one of those patients was successfully re-treated with the engineered T-cells and went back into remission.

Are you instilling a memory for relapse patients?

We are unquestionably having a memory, the question is is the memory going to be life-long and the answer is it probably won’t. The first two patients that were treated on the CLL trial by Penn still have T-cells and still are in complete responses so in principle these cells can last for a long time. But I find it unlikely that the cells are actually going to last for a lifetime but during the period when they are present they are providing a memory function and they are providing immunosurveillance against the possibility of relapse. Once the T-cells go away there is no further protection for the patient and, of course, the question is what happens at that point.

Do you see any problems in doing the transplantation again?

Our goal is not to retreat but we don’t really know what the rules are or whether that’s going to be necessary or not. I don’t find that there are significant problems but we would prefer to be in a situation of not having to do that and our experience with that is very, very limited. Essentially we’ve retreated two patients that recurred after a complete response and where we had some ability to test whether retreatment would actually work or not and in one patient it worked and in another patient it didn’t.

What are some of the side effects?

There are side effects that these patients almost all experience. They almost always experience a cytokine release syndrome and that’s characterised with a very high fever and muscle aches. My paediatric patients were all admitted to the hospital because that’s standard of care for a leukaemia patient who has a fever. Some patients have a more significant toxicity reaction, a more significant cytokine release syndrome and about 25-30% of the patients that we treat do end up in the intensive care unit for a short period of time with hypotension or breathing difficulties or both. What we have found is that those patients have very high levels of a particular inflammatory cytokine, interleukin-6, and because there’s a drug that directly targets interleukin-6, which is tocilizumab, we’ve treated a number of these patients who have had the more severe cytokine release syndromes with this IL-6 targeting drug and we’ve seen dramatic resolutions of the toxicity responses, disappearance of the fever, disappearance of the hypotension and resolution of the respiratory difficulty, often in hours and certainly in less than a day or two. So the responses for the patients who have had the more severe toxicity to tocilizumab have been very strong.

Do you think treatment will be without chemotherapy in the future for these patients?

That’s a great question. I think we’re not at the point right now to be thinking about substituting this for initial treatment in anyone, we really are looking at a group of patients who are relapsed or refractory. They’re a group of patients, for instance, who have already had a bone marrow transplant and that hasn’t been successful for them. We can see moving that a little bit earlier in treatment but in terms of starting out with this, that would be a very high bar to get over so I don’t think we’re at the point of thinking about doing that right now.

Will this treatment be possible in solid tumours?

That, of course, is the key question is whether that’s possible. We would like to move out from leukaemia to B-cell type lymphomas, that seems like a very logical step and there are groups that have shown that this is going to probably work. But then the key thing is whether solid tumours can be targeted including the adult cancers and there’s very little experience for that right now, that’s everybody’s hope that that’s possible but we really have to show that that’s possible and there are a number of groups, ours included, who are trying to see if that’s going to work.

Pancreatic cancer is one of the potential targeted areas and so we’re just beginning to try this. The issue in solid tumours is that you can target the tumour - as long as you have an antibody that recognises the tumour you’ll be able to target the tumour but you can’t have that target overlap with a vital normal cell because the T-cells aren’t going to be able to tell the difference. So that’s a key thing with solid tumours that we’re going to have to work out in terms of safety.

How will this be done?

You need to find tumour antigens so, as an example, this isn’t work that I do but mesothelin is a potential antigen that can be used in this situation and may be tolerated. On the other hand, there have been toxicity concerns in other trials with HER2 as a potential antigen and that needs to be engineered a little differently. So it’s definitely a higher bar to get over to treat solid cancers that are not in the B-cell area but everybody is very interested in whether that might not be possible.