The study that we’re talking about is the so-called ELARA trial. It’s a trial of tisagenlecleucel which is a CD19-directed CAR T-cell therapy which has been previously approved for diffuse large B cell lymphoma and for paediatric and young adult ALL in patients with relapsed or refractory follicular lymphoma. So these are patients that are beyond our current standards of adequate care and so this trial was a multi-centre phase II trial of this CAR T-cell approach. It’s based on a pilot trial that we ran at the University of Pennsylvania that began in about 2014 for which we treated 14 patients and have about 5 years’ follow-up. So it’s much the same design.
It’s gratifying that the overall response rates, at least at this preliminary look that we had, match very much our pilot study that was done at Penn. The complete response rate was about two-thirds, 66%, with a partial response rate of about 20%. That’s pretty close to what we had in the Penn pilot trial. At 11 months of median follow-up, which is what we presented earlier this month, the median durations of response had not been reached for those that had partial or complete responses. The probability for any responding patient to remain in response for more than six months was 79% - very close to what we had in our pilot trial.
Interestingly, this probably relates to the timing of imaging on this study versus the pilot trial but of 31 partially responding patients 12 of them converted to complete responses, generally between months 3 and 6. In our trial we didn’t do the first imaging unless it was clinically indicated until month 3 so we didn’t see that early conversion of partial to complete response.
I’m optimistic that this trial will continue to show that these responses are durable because in the pilot trial that we ran 60% of the patients were still in complete response after a single treatment with this agent at 5 years. So this is exciting, it will complement the existing CAR T-cell therapy that’s already approved, that’s the Yescarta or axi-cel product, in follicular lymphoma and it will offer another treatment approach. The toxicity is very, very acceptable with this agent – there were no cases of grade 3 or higher cytokine release syndrome and only one neurologic adverse event that was grade 3 that resolved. So it’s very, very well-tolerated. In general I treat these patients as out-patients.
Once a patient is identified as a candidate for this approach to therapy, and this will generally be a patient that has had C20-based monoclonal antibody therapy as well as chemotherapy. Again, the patients in this trial had to have failed at least two prior lines of therapy and these would be the types of patients that would need something else that could achieve this type of response and the durability that we see with CAR T. So once you’ve identified that kind of patient the process is to collect the peripheral blood lymphocytes. This is done by leukapheresis – you hook a patient up to a machine, take the blood out, give the blood back with the exception of the white cells which include the lymphocytes. They can be frozen down and then shipped to the manufacturing facility where they are thawed and cultured and transfected with a gene for the chimeric receptor that becomes expressed on the surface. Once the product has expanded and we have an adequate number of cells for dosing, which is in the order of magnitude of 108 cells, between 0.6 and 6x108 cells, total CAR T-cell viable cells, it gets frozen and then shipped back to us. Then we give some lymphodepleting chemotherapy followed by these cells.
So the process takes about three or four weeks from apheresis to when you get the cells back so occasionally these patients require some additional therapy to try to keep them fit or stable medically to receive the CAR T-cells; if their disease is rapidly progressing this may be the case. Other patients that are reasonably stable you can wait until you get the cells back prior to commencing with lymphodepletion and CAR T-cell therapy.
It’s ideally suited for this group of patients because in the aggressive lymphomas where this is approved it’s much harder to keep a patient stable during that 3-4 weeks of manufacturing time; it’s a little easier with the follicular lymphoma patients. So it’s a product that will be utilised because of its tolerability and its efficacy, the ability of a single treatment to achieve a durable response. I think it will be a powerful agent in our armamentarium for treatment of those cases of follicular lymphoma that actually need something more than our CD20 based monoclonal antibody chemotherapy combinations.
The toxicity was very minimal. There were no cases of grade 3 or higher cytokine release syndrome using the Lee scale but there was some usage of tocilizumab. It was about a third of patients did receive some anti-IL6 therapy, tocilizumab that is, for early stage cytokine release syndrome or early grade cytokine release syndrome. So part of what we see in terms of toxicity here is the result of early intervention, which is something we’ve learned from all the other CAR T-cell trials that we have run that understanding the potential complications early intervention can prevent those complications. Neurologic toxicities were generally managed with corticosteroids.
These are very important results because unlike chemotherapeutic approaches or small molecule approaches for treatment of follicular lymphoma this immunotherapeutic approach is agnostic to those features that cause resistance to traditional chemotherapeutic or small molecule based approaches. For example, patients with mutations in p53 who are generally resistant to chemotherapy, that has no impact on response rates with this approach. Similarly, patients who have had more than four lines of therapy have the same response rates as patients who have had two lines of therapy. So the amount of pre-treatment with the existing agents doesn’t appear to affect the response rates. Similarly, patients who are just no longer responding even to the therapy you’re giving them prior to using this approach, even if the disease is not responding to anything, those patients still have a response rate to this that’s the same as those whose disease is controlled but with existing therapy. So it’s powerful therapy.
Also, it’s been long recognised that the patients who progress after immuno-chemotherapy with follicular lymphoma, who progress within the first 24 months of therapy, tend to be a group of patients, and it’s about 20% or so of all comers of follicular lymphoma that actually need treatment. About 20% of them progress within 24 months and they tend to be a group of patients that have a poor prognosis. The survival at 5 years for that group of patients is about 50% which for follicular lymphoma is very poor. In any event, this therapy achieves the same response rates in that group of patients; actually, it wasn’t statistically significant but maybe even better in some sense. In any event, it achieves equivalent response rates in that group of patients, again gratifying and very, very important for that subgroup of patients with follicular lymphoma that are refractory to existing therapies and even with progression of disease on the currently available treatments.
It’s important to note that CAR T-cell therapy is already approved, not the one that I’m talking about, tisagenlecleucel, but there’s the axicabtagene ciloleucel product that is already approved for follicular lymphoma, has similarly high response rates but is a little more complex to use in terms of toxicities and the necessity for hospitalisation. So this product, tisagenlecleucel, that I’m discussing will be a welcome addition to our treatment tools for these patients.