Long-term outcomes of subjects with EBV driven PTLD following solid organ or allogeneic HCT treated with tabelecleucel

Dr Sarah Nikiforow - Dana-Farber Cancer Institute, Boston, USA

As will be presented in a poster tonight, we’ll be presenting long-term outcomes on the use of tab-cel, an allogeneic off-the-shelf Epstein-Barr virus specific cytotoxic T-lymphocyte product, in patients with post-transplant lymphoproliferative disease after either allogeneic haematopoietic stem cell transplant or solid organ transplant. We actually enrolled 61 patients in this expanded access programme that we can analyse for safety and then there’s a cohort of 26 true post-transplant lymphoproliferative disorder patients on whom we are presenting efficacy data.

This is based on work that is going back about 25 years by various groups, including Susan Prockop and Rick O’Reilly’s group at Sloan Kettering. They had previously established a mechanism by which they would transform lymphoblastoid cell lines with EBV and then expose T-cells to these EBV transformed cells to generate out over time EBV or Epstein-Barr virus specific T-cells for the purposes of adding these back in patients who had out of control EBV driven diseases including lymphoproliferation. So that technology had been shown to be efficacious and safe in single centre studies so now this is under the auspices of the sponsor Atara using a very similar technology but on a GMP commercialisable scale to treat, as I said, both PTLD and other diseases with the emphasis here being on the multi-centre aspect of the trial, the long-term follow-up, up to two years in some patients, demonstrating the safety and efficacy as registration studies using this same tab-cel product in PTLD are getting under way.

The safety was reported on all 61 patients enrolled in the trial which, as I said, included PTLD but a variety of patients, whether other EBV driven diseases such as leiomyosarcoma or EBV viremia in the setting of paediatric immunodeficiency. It proved to be incredibly safe during the infusion process and there were really very few, I think it was 9%, grade 3 or higher treatment related, treatment emergent SAEs. Really, the main cause of AEs in more than 15% of patients were primarily fevers, fatigue, diarrhoea, mild LFT abnormalities and disease progression. But, nicely, in those patients who responded none of them died of EBV lymphoproliferative disease progression and none of the other fatalities were considered treatment related.

So that was the safety profile and then in terms of efficacy we report on the HSCT and solid organ transplant groups and there were 12 and 14 in those groups respectively. We were able to track overall response rates as well as one and two year survivals. That was also broken down not just across the trial but in terms of those who would have met eligibility for the registration studies.

Before I give you that data let me take a step back and mention who was eligible for this particular trial. This was offered as an expanded access programme as the inventory and the sites were getting up to speed for the registration studies .So, looking at these patients, in the PTLD, or post-transplant lymphoproliferative disease, cohort the overwhelming majority of them, it was about two-thirds in the stem cell transplant population and one-third in the solid organ transplant patients, had ECOG scores of two or higher. These were paediatric and adult patients so some of them had poor Lansky scores. So these were high risk patients from a comorbidity point of view. Then if you refer back to a study by Chouet who published a PTLD risk score which helped stratify patients who had failed Rituxan therapy for their PTLD, their ECOG status, age and LDH were poor prognostic factors and about 80% of the stem cell transplant group would have fallen into that high risk profile. So I do want to mention that there were extremely high risk patients, both on the HSCT and solid organ transplant group, that were coming into here. Even patients who had tremendous organ dysfunction that was related to the PTLD, so we felt reversible with successful therapy, were allowed on the trial.

In terms of responders, we stratified into two groups, the stem cell transplant and solid organ transplant which has been looked at before in this manner. The overall response rates receiving therapy which, by the way, is given in cycles of three infusions each, and even if after that first cycle at the evaluation period around day 35 there is a complete response the patient always gets one more cycle of consolidation. So patients received two million/kg on average cells, tab-cels, and they got a median of six infusions, so about two cycles. As I said, even if they get a complete response there’s a consolidative cycle after that and they receive at least three cycles if they have a partial response. With that mode of dosing and that cycling the overall response rates in the HSCT cohort for people who had failed either Rituxan or Rituxan plus cytotoxic chemotherapy was 50% with an overall response rate in the solid organ transplant patients of above 80%. This led to one and two year overall survivals of about 60% and 83% respectively in those cohorts. These are in line with prior data that was accumulated earlier in this study and published in poster form as well, abstract form, but also with a larger single centre experience from Sloan Kettering using this same technology.

One of the things that was nice is that the duration of response was quite prolonged. So in patients who initially had a response the overall survival was between 86-100% at one and two years. Additionally, the same encouraging efficacy numbers bore out for the subset of patients who would otherwise be considered eligible now for the registration studies. So we have every reason to think that these results will be seen in the registration trials with potentially even a slightly more healthy group of individuals although there is an expanded access protocol being offered by Atara underneath this for patients who don’t qualify.

So there are some biologic questions in terms of how persistent are these cells, what is the mechanism of long-term disease control when you’re using allogeneic only partially HLA matched cells. Then also how can we predict who will respond to these therapies and who won’t, to either further improve them or help with choice of patients coming on.

The other things are obviously the registration studies have been designed for commercialisation so that there would be more widespread accessibility of these therapies to patients with PTLD. Then, if you recall, I had mentioned that there were 61 patients enrolled and I’m reporting on 26 for efficacy with PTLD so there’s now analysis ongoing of those other patients who did not meet PTLD definition but have other diagnoses. There also are trials ongoing outside the expanded access for those disease subgroups. You can imagine that PTLD is one EBV-driven cancer but there also are EBV positive nasopharyngeal cell carcinomas so some of the next steps in other diseases would include NPC, leiomyosarcoma, so we may have applicability outside of just PTLD.

One thing to emphasise is that tab-cel is expanded against antigens, there is no actual genetic engineering. So in terms of monitoring for 15 years, worrying about where’s the new genetic material being introduced into the chromosome, that is not a concern here. In addition, these are allogeneic off-the-shelf so what I’ve experienced with some of my patients, even as I am giving them Rituxan which is still the first line of therapy for post-transplant lymphoproliferative disease, I have the option to reach out to query with informed consent whether there is a relevant EBV CTL HLA match line in their bank. So that if my patient is among the 50% who does not respond to their first line of therapy for PTLD we can extremely rapidly access these for patient care. So the turnaround time, the incredibly well-tolerated infusion, the lack of cytokine release syndrome, there were three instances only in the post-allogeneic transplant setting of GVHD but none of them were felt at this point in time to be directly treatment related, all of this safety profile, the ability to give these outpatient, make these an extremely attractive and timely mode of therapy for patients with these diseases.