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On October 7, 2021, the U.S. Food and Drug Administration (FDA) placed a clinical hold on a series of trials investigating the use of allogeneic chimeric antigen receptor (allo-CAR) T-cell therapies for adult patients with hematologic malignancies. This was due to a safety report regarding the bone marrow biopsy of a single patient receiving the therapy in the phase I/II ALPHA2 study (NCT04416984). Results revealed the subject had aplastic anemia and ALLO-501A CAR T cells carrying a chromosomal abnormality of unclear clinical significance.1,2
The patient in whom the abnormality was detected had Stage IV follicular lymphoma with c-myc rearrangement, refractory to two previous lines of immune-chemotherapy and additional radiation treatment. Following ALLO-501A infusion, the patient experienced Grade I cytokine release syndrome and Grade II immune effector cell-associated neurotoxicity syndrome, necessitating a course of high-dose steroids. The study participant had achieved a partial response to therapy when progressive pancytopenia developed.
Previous translational data indicated the expansion of the CAR T cells, with a peak at Day 28 and contraction subsequently. The patient was unable to receive autologous CD19-targeted CAR T-cell therapy as a result of a manufacturing failure linked with an inadequate expansion of autologous CAR T cells.
The clinical hold affects five allo-CAR T cell trials for relapsed or refractory malignancies, namely the ALPHA, ALPHA2, UNIVERSAL, TRAVERSE, and IGNITE trials, which include therapies for non-Hodgkin lymphoma, multiple myeloma, and renal cell carcinoma. Prior to this incident, data from the ALPHA trials had demonstrated a favorable clinical profile of ALLO-501A. Nevertheless, clinical evaluation of the case remains ongoing, and additional details as to the immediate and underlying causes of this event are being collected, including evidence of clonal expansion or a potential relationship to the gene-editing technique used to develop the treatment.
At the same time, the U.S. FDA is reviewing end of phase I materials for a phase II pivotal trial of ALLO-501A. Supplementary updates will be provided in the coming weeks following consultation with the regulatory authorities.
Allo-CAR T cells are derived from induced pluripotent stem cells from healthy donors that are genetically modified using the transcription activator-like effector nucleases gene-editing technology. Allo-CAR T cells overcome some of the manufacturing challenges of using autologous CAR T cells, reducing the timelines significantly and eliminating the need for bridging therapy. To this day, >100 patients have been dosed with these products in clinical trials.
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