ASH 2013 - New Orleans, LA, USA 

T cell immunotherapy for leukaemia in preclinical setting

Dr Michael Kalos - University of Pennsylvania, Philadelphia, USA

It’s called a chimeric antigen receptor. It’s synthetic, this is synthetic biology, and the CAR is composed of three independent genetic elements. We fuse the part of an antibody that is responsible for binding to cells to part of the T-cell receptor complex that’s responsible for transmitting signals into T-cells so we make this chimeric molecule that’s composed of different genetic elements.

So we have three studies on-going at the University of Pennsylvania evaluating CAR technology and CTL019 is simply the CAR technology targeting CD19, a molecule that’s expressed on the surface of a number of B-cell malignancies as well as normal B-cells. So we have three studies, one study that evaluated the ability of CAR to target CLL and most recently ALL, so that study allows us to evaluate both of those diseases; one study where we evaluated the CTL019 in the context specifically of CLL asking whether the dose of cells that were infused made a difference, and it doesn’t seem to, by the way, and one study where we evaluated CTL019 in paediatric ALL. The response rates in ALL have been really very spectacular so far; greater than 80% of the patients that we’ve treated have achieved complete, or approximately 80%, have achieved complete and on-going complete responses with no evidence of disease following a single or maybe two infusions of these gene engineered T-cells.

To what are you attributing the effectiveness of this treatment?

What we’ve noticed is that not everybody is responding. What we’ve noticed in the patients that do respond we have certain things are happening to the engineered T-cells, most notably they’re expanding dramatically in patients. At the peak about, let’s say, 6% of all the T-cells in the responding patients are the engineered T-cells. Those levels decrease, of course, and some patients as high as 90% of the T-cells in the patients are the engineered cells. That magnitude of expansion in patients is not seen in patients that have partial responses where we see some expansion but less and it’s not seen in patients where we don’t see a response, where we do not see the expansion. So at least one measure, one effect of what is going to be an effective therapy, is the magnitude of the expansion of the T-cells in patients along with their persistence long-term. These cells survive. These are patients in the ALL setting, these are patients that have failed every available treatment including allogeneic cell transplant if that has been available to them. They have frankly, at best, weeks of life left to them.

What about the patients who did not respond as well? What can we learn from those cases?

We have collected specimens from each of these patients, a large number of specimens, that we’re now busy interrogating. You can imagine that the difference between responders and non-responders can be due to the nature of the T-cells that we engineer. Remember, in each case we manufacture these cells, we take blood from the patients, we genetically engineer them, we grow them outside of the patients for a couple of weeks and then we give them back to patients. So each product is individual so the nature of the product may drive the complete response or not complete response. It could be the tumour in each patient, there may be differences in tumours that might make them more resistant or less, and it could be the genetics of the patients or some other factor - there’s something about the patient that makes them more or less able to respond to treatment. We’re investigating all of those very actively.

What do you see as next in terms of therapies and treatments?

At Penn our programme is partnered with Novartis who is very actively looking to develop this technology in further trials with the ultimate goal of as quickly as possible commercialising it. So we are going to see trials, bigger trials in ALL, bigger trials, potentially, in CLL involving multiple centres in the United States and throughout the world and we’re going to be seeing trials in other hematologic malignancies. We heard about lymphoma being a trial in which there’s efficacy, well we’re going to be evaluating our approach in lymphoma also, for example.

How do your study’s findings fit in with the findings of Dr Grupp’s study?

Dr Grupp’s studies are part of the studies that I’m describing so Dr Grupp and we are working together; he has simply presented in more detail the ALL studies that I referred to at a top line level. So that’s CTL019 also.

What overall conclusions can be drawn for practising clinicians?

The lessons that the practising clinician should take is this therapy is incredibly potent; that there is, as we all talked about today, there are adverse events – patients that receive the therapy can get quite sick and require ICU but that may well be related in part to the fact that these are very sick patients to start out with, notably not one patient in our studies, and we’ve treated over forty now, has died because of the adverse events so there is a way to treat and there is a way to treat the side effects effectively. This essentially is a treatment that can be done by individuals at places that have experience of bone marrow transplantation. So we can look to that being more widely applied as we move forward.

Is this potentially applicable to other types of patients?

Absolutely. Part of the Frankenstein nature of the CARS is that they’re modular so you can imagine… or in fact, what is being done is you can replace the antibody derived component that right now is derived from a CD19 specific antibody with an antibody that recognises any gene, any protein that you’re interested in: HER2/neu for example, any molecule that’s expressed on prostate cancer cells. So the modularity of the CAR design allows us to target any disease as long as we have appropriate antibody reagents to add. We and others are very actively in the middle of doing those studies.