Trials featuring Allogene Therapeutics’ allogeneic CAR-T products have been placed on hold by the US Food and Drug Administration (FDA) following a reported chromosomal abnormality in a patient who received ALLO-501A as part of the ALPHA2 study. Further characterisation of the abnormality will be undertaken, with Allogene giving updates to the FDA over the coming weeks.

The chromosomal abnormality was detected in a Stage IV transformed follicular lymphoma patient with a c-myc rearrangement. The patient had previously failed two lines of therapy and was unable to receive an autologous CAR-T product due to manufacturing issues that meant their cells failed to expand sufficiently. Following the receipt of ALLO-501A, a partial response was seen, and Allogene has reported that the CAR-T cells expanded, peaking on Day 28. A bone marrow biopsy was performed due to the development of pancytopaenia (low levels of red cells, white cells and platelets), which detected the chromosomal abnormality in the ALLO-501A CAR-T cells. The patient was, ultimately, able to proceed to an allogeneic stem cell transplant.

ALLO-501 and ALLO-501A are CD19-directed therapies currently being investigated in patients with relapsed or refractory non-Hodgkin’s lymphomas as part of the ALPHA and ALPHA2 trials. TALEN gene editing is used to disrupt the T-cell receptor α gene, and is predicted to reduce the incidence of graft-versus-host disease. The CD52 gene is also edited to allow for depletion of host T-cells using Allogene’s anti-CD52 antibody, ALLO-647. A pivotal Phase II trial is planned for next year.

This news is damaging to Allogene, however, which initially saw its stocks plummet 46% following the announcement, though these have now recovered somewhat. It is likely to be several months before a resolution is reached and the trials recommenced due to the required time to properly investigate the abnormality. Despite this, more than 100 patients have so far been treated with Allogene’s allogeneic CAR-T products across two trials, indicating such a phenomenon is likely relatively rare. If the CAR-T product is found to be the cause of the pancytopaenia but Allogene can demonstrate that this is the only consequence, that the abnormality is rare and that the pancytopaenia is easily managed, the hold could potentially be lifted.

The clinical results released so far from Allogene’s Phase I trials have been compelling, suggesting that any risk of developing chromosomal abnormalities may be outweighed by the potential benefits of therapy. Data presented at the American Society of Clinical Oncology meeting this year demonstrated an objective response rate of 75%, with a complete response seen in 47% of patients in the ALPHA trial. Importantly, the median time to treatment was just five days from enrollment to lymphodepletion.

The lack of treatments for patients with relapsed or refractory non-Hodgkin’s lymphomas is a major unmet need, and while autologous CAR-T has been transformative for this patient group, this approach is not without its pitfalls. It remains the case that for many patients, autologous CAR-T is impossible to access either due to geographical barriers, or because of clinical features of their disease that can mean a product cannot be generated quickly enough, or at all. Allogene is at the forefront of the race to develop an allogeneic product that could be given more easily to a wider selection of patients. The abnormality is certainly a concern, but pioneers in any field can expect to face unforeseen roadblocks, and it is hoped these can be ultimately overcome.