This is a phase I study looking at a bispecific CD19 and 22 CAR T-cell in a paediatric B-cell malignancy population, relapsed or refractory B-cell malignancies. The background on this study is that we’ve had a lot of exciting advances in the monospecific CAR field where we’ve had a lot of excellent reports on remission in the CD19 experience. But what we’ve learned is that the long-term outcomes aren’t correlating with those initial complete remissions and we are seeing that many patients go on to develop relapsed disease with CD19 negative disease. So antigen modulation under the targeted pressure of CAR is becoming more of an appreciable problem.

So to address that the lab of Crystal Mackall and Terry Fry have developed a bispecific CAR that can simultaneously target CD19 and 22 with the hope to expand the catchment of cells that can be killed to hopefully catch subclones, minor subclones, that may have antigen downregulation. So our hope is to be able to prevent or address antigen downregulation by multispecific targeting.

What was the methodology?

This is a phase I dose escalation study so patients were aged 1 to 30 and we have a counterpart adult trial which you’ll hear about too. Basically it’s a 3 3 design where we’re starting with a dose of 1x106 and we’ll escalate accordingly depending on the safety data.

What have you found so far?

So far, to date, we’ve treated four patients and, again, this is a bispecific 19/22 targeting CAR with a 41BB costimulatory domain. We’ve treated four patients to date and all four of the patients did achieve morphologic complete remissions which we were really excited to see as we don’t expect this CAR to be inferior to the CD19 CAR. So we were excited to see those remissions, three of the four remissions were MRD negative by NGS and flow which was wonderful. Some of our patients have gone on to receive consolidative transplants so we are waiting to learn, we had one relapse and that patient did have CD19 positive and 22 positive disease after loss of CAR. So our hope is to understand in patients that can achieve long-term persistence, understand T-cell properties and profile these T-cells to learn what drives persistence and anti-tumour responses. Additionally in event of relapse we do hope to study the antigen modulation in response to the multispecific targeting.

Were there any adverse events?

Safety actually was our primary objective and our CAR was very well tolerated, we saw very low rate toxicities. Our three patients who had low burden disease only had grade 1 CRS or grade 1 neurotoxicity and our patient that came in with a higher burden disease, defined as over 5% , he did experience grade 2 CRS and was treated with tocilizumab and precipitously responded. So to date we haven’t had any toxicities beyond grade 2 and the majority of our patients tolerated this very well and with only grade 1 toxicities.

What’s next?

We hope to continue accrual so we can amass more data and see if we can dose escalate because we do believe potentially at higher doses we may get better persistence. So continued accrual is definitely our ongoing effort but in addition we are collecting broad deep correlative data to try to understand how these cells change over time in vivo. So we’re collecting CyTOF data, epigenetic data using ATAC-seq and single cell TCR data to allow us to track the TCRs in T-cells with time to understand which are the phenotypes that are expanding and contracting and persisting to help us discover drivers of what allows us to achieve long-term persistence. So we’re excited about our correlatives, we think as we gather more data and get really good deep correlatives we’ll be able to understand how to predict which patients will respond, which T-cell subsets are the optimal T-cells to infuse. Right now we’re infusing a crude product of T-cells that mimic a spectrum of phenotypes so we’re hoping to be able to target our CAR products and eliminate exhaustion and promote persistence so that’s part of our ongoing efforts.