We’ve heard about CAR T-cells for ALL, CAR T-cells for diffuse large B-cell lymphoma and now I will try to show you how we’re trying to improve CAR T-cell therapy for a different kind of disease called chronic lymphocytic leukaemia. The key point is that in most cases this is a slow growing hematologic cancer involving B-cells so they express the CD19 antigen. It’s actually the most common leukaemia in adults and the common symptoms are elevated lymphocyte count and swollen lymph nodes. The problem that arises is when patients do not respond or relapse after conventional therapies and prognosis can be poor, in particular in patients who do not respond or relapse after an oral agent called ibrutinib which prevents the CLL cells from growing by inhibiting an enzyme called BTK.
That we’ve done is we’ve carried out a phase I/II study at our institution using a CAR T-cell product of a defined composition of CD4 T-cells and CD8 T-cells that is called checker 14. We have published that this approach could lead to durable responses in patients with CLL that had relapsed or were refractory to ibrutinib. What could be the rationale to try to combine ibrutinib with CAR T-cells? There’s actually a variety of reasons why you would want to do so, because sometimes when you interrupt ibrutinib patients may experience a rapid tumour progression that we call a tumour flare. We think as well that ibrutinib can help mobilising the CLL cells into the blood and based on some preclinical and clinical data there is evidence that ibrutinib may improve the function of CAR T-cells and may decrease the toxicity related to CAR T-cell therapy.
I’m going to show you a retrospective analysis of two cohorts sequentially treated on this trial including 43 relapsed refractory CLL patients with detectable disease after ibrutinib therapy. The key point in the no ibrutinib group, all patients had interrupted ibrutinib at some point before leukapheresis or before lymphodepletion. In contrast, in the concurrent ibrutinib cohort all patients were scheduled to receive ibrutinib at least two weeks prior to leukapheresis, up to at least three months after CAR T-cell infusion. The key distinctive feature between the two cohorts is that all these patients hence received ibrutinib from the time of lymphodepletion onwards.
Of course this was not a randomised head-to-head comparison but most patients and disease characteristics were comparable between the two groups and I will refer you to the full length abstract.
The first finding is that the use of concurrent ibrutinib with CAR T-cells was well tolerated in most patients and 13 out of 19 patients could receive ibrutinib as planned without discontinuation. Now if we look at the response data early on at four weeks the first finding is that this approach was highly efficacious with 83% of patients achieving a response in the concurrent ibrutinib group compared to 65% in the no ibrutinib group. This is using a classification called iwCLL which basically means that we observed a significant decrease in the percentage of CLL cells in the blood and in the size of the lymph node. Then further on when we look using very sensitive methods such as flow cytometry and further deep sequencing which can detect one tumour cell within a million cells, we observed that 73% of patients went into this deep remission by flow cytometry and within these patients 85% had no detectable disease in the bone marrow using this deep sequencing method.
We know that CAR T-cells are important and the kinetics of CAR T-cells in vivo is important to induce a response. Here I’m showing you the kinetics of CAR T-cells for two different subsets, the CD8s to simplify, which are the killer cells, and the CD4 cells, the helper cells. This is the kinetics, the number of CAR T-cells in the blood from day 0 to day 30. Here this is only looking at the peak of CAR T-cells in the blood. As you can see there was a trend towards better expansion of CD8s and a significantly higher, better expansion of CD4 CAR T-cells in the concurrent ibrutinib group.
We also know that CAR T-cells can cause toxicity and we did observe toxicity in both groups but, strikingly, no patient developed a severe form of cytokine release syndrome in the concurrent ibrutinib group. We did note two fatal events, one in the concurrent ibrutinib group from a presumed cardiac arrhythmia and one patient in the no ibrutinib group from CAR T-cell related toxicity.
In summary, in this retrospective analysis of 43 CLL patients with refractory or relapsed disease treated in two sequential cohorts the concurrent administration of ibrutinib with CD19 specific CAR T-cells was feasible in most patients, induced high response rates and deep responses early on at four weeks, was associated with higher in vivo expansion of CD4 CAR T-cells and lower rates of severe toxicity. The next step is to hopefully validate these findings in a prospective phase I/II study. Thank you.
