On March 1, 2023 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) products for cancer, reported the publication of a case review in Molecular Therapy of the single patient treated with ALLO-501A who presented with a chromosomal rearrangement (Press release, Allogene, MAR 1, 2023, View Source [SID1234628002]). The findings from this report advance the understanding of the presence of genomic variability at the chromosomal level in mature lymphocytes expanding the knowledge in the field of gene and cell therapy.
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The development of "off-the-shelf" (allogeneic) CAR T products that utilize cells from healthy donors have the potential to make CAR T therapies scalable and accessible to more patients. Gene editing is a common technique deployed to create allogeneic CAR T cells and other engineered cell therapy candidates. Gene editing has the potential to induce chromosomal inversions as a consequence of post cleavage genetic recombination.
The Company’s case report details a chromosome 14 inversion in a patient treated with gene edited cells. Initial caution surrounding this case led to a U.S. Food and Drug Administration (FDA) clinical hold in October 2021 across the Company’s AlloCAR T clinical trials. An extensive investigation concluded that the chromosomal inversion was unrelated to TALEN gene editing or Allogene’s manufacturing process and had no clinical significance, resulting in a lift of the clinical hold three months later.
"As the leader in the development of allogeneic CAR T cell treatments, we understand our responsibility to patients as well as the important role we play in advancing this rapidly developing field," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "As we look to deliver on the promise of allogeneic CAR T cell products, this case highlights the need to understand cell-intrinsic biology as well as the theoretical effects of genomic manipulations. Through the efficient investigation of this event, we have increased our understanding of the frequency and mechanisms of chromosomal variability in normal mature T cells without connection to genomic manipulations."
The investigation concerned a population of allogeneic CAR T cells containing a chromosome 14 inversion that was incidentally detected 47 days following the administration ALLO-501A. The rearrangement was not detectable in the manufacturing lots used to treat the patient or in any other lot manufactured by Allogene. Thorough molecular analysis of the inversion, which was distantly located from TALEN gene edited or lentiviral vector insertion sites, revealed that the breakpoints mapped to genomic sites well-known to be used by B and T cell recombination pathways, indicating that the inversion was a result of normal T cell biology. A broad investigation was undertaken, and the inversion was not detectable in any other patient sample assessed by Allogene from this and other trials. The report further concluded that the inversion spontaneously occurred post ALLO-501A infusion. There was no evidence that the expansion of this clone was the consequence of the inversion, and no clinical significance was attributed to the event.
In October 2022, Allogene initiated the industry’s first potentially pivotal allogeneic CAR T Phase 2 clinical trial of ALLO-501A (ALPHA2 trial) in patients with r/r LBCL.