An ‘off-the-shelf’ CAR T-cell product for relapsed or refractory B-cell acute lymphoblastic leukaemia is a step closer after its feasibility was demonstrated in early-stage human trials for the first time.

UCART19 is one of several allogeneic, genome-edited CAR T-cell therapies currently being investigated in clinical trials of haematological malignancies and solid tumours.

In a Phase I study led by haematologists at University College London (UCL), the therapy was linked with good response rates in patients with a high tumour burden and rapidly proliferative disease and adverse events were similar to that seen with autologous CAR T-cell products.

However, there were also issues including UCART19 persistence and an increased risk of viral infection, due to the heavy-duty lymphodepletion regimen necessary to pre-empt rejection and prolong persistence, according to the paper published in The Lancet Haematology.

Dr Claire Roddie, an Associate Professor at UCL and Consultant Haematologist at UCLH, told the limbic that the trial had demonstrated where the limitations of allogeneic CAR T therapy in its current form lie.

“In principle, it’s a fantastic idea and really lovely, innovative science, but in some respects the technology isn’t quite there yet”.

The trial is “very much the beginning of the journey for this particular product,” but it has “been really informative in that it’s already told us the kind of things we’re likely to see as problems,” related to lymphodepletion, infections, and short persistence, she added.

The next phases of research will need to look at these aspects, such as exploring further engineering of T cells to remove cellular signalling systems that allow for them to be rejected, which might facilitate longer therapy persistence, she said.

“If we could iron out these issues we’d have a really attractive therapeutic for patients and physicians,” Dr Roddie noted. “I think it’s going to be hugely important in the future to make these kinds of therapies more readily accessible”.

This trial is the first step in the direction towards “a widely accessible and perhaps even at some stage in the future cheaper CAR T option”, that would allow for the treatment of more patients more quickly than what is currently the case with autologous CAR T therapy, she added.

More on the trial

The Phase I open-label study was carried out at eight centres in the UK, France, the US and Japan, and involved 25 adults aged 16-70 with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had relapsed or minimal residual disease and had tried standard treatment options.

Patients initially underwent lymphodepletion (with fludarabine and cyclophosphamide with or without alemtuzumab) before receiving UCART19 doses of 6 × 10⁶, 6–8 × 10⁷, or 1·8–2·4 × 10⁸ total CAR T cells intravenously.

After a median of follow-up of 12.8 months, the overall response rate was found to be 48%, duration of response and median relapse-free survival were 7.4 months,  progression-free survival was 2.1 months, and overall survival was 13.4 months.

Twelve (48%) of 25 patients had a complete response or complete response with incomplete haematological recovery, and of note 75% of these underwent subsequent allogeneic HSCT at a median of 1·71 months after UCART19 infusion.

Response rates were found to be higher in patients with lower tumour burden before lymphodepletion and in those who had previously received less than four lines of therapy, the research team said.

UCART19 persisted in blood for a median of 28 days, and was detectable beyond 42 days in just five of 14 patients, with early indications being because of a T-cell mediated rejection of the therapy.

Range of adverse events similar to autologous CAR-T

On the safety side, researchers said the range of adverse events observed with UCART19 was similar to that seen with autologous CAR T-cell products, the most frequent being cytokine release syndrome and anaemia, with mostly mild neurotoxicity and minimal GVHD.

In the trial, three patients developed dose-limiting toxicities, 24% Grade 3 or higher cytokine release syndrome, one patient developed grade 3 or higher neurological toxicity, grade 3 or higher infections were reported in 28% patients, and 16% demonstrated grade 4 prolonged cytopenia.

Just two patients developed grade 1 acute cutaneous graft-versus-host disease. Overall, 14 patients died, with four deaths related to UCART19 or lymphodepletion, or both.

According to the authors, the findings demonstrated “the safety and feasibility of using allogeneic CAR T cells in patients for whom autologous CAR T cells might not be an option, and represents a substantial step forward in CAR T-cell development”.