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FDA Halts Off-the-Shelf T-Cell Cancer Trials

Stop sign

(dimitrisvetsikas1969, Pixabay)

8 Oct. 2021. The Food and Drug Administration stopped a company’s clinical trials of off-the-shelf engineered T-cells after a patient showed an abnormal chromosomal reaction. Allogene Therapeutics Inc. in South San Francisco says it reported the adverse reaction in one of its clinical trial patients to FDA, which then put a clinical hold on all of the company’s trials of modified T-cells.

Allogene Therapeutics is developing treatments for blood-related and solid tumor cancers with engineered T-cells, white blood cells in the immune system. T-cells are altered by adding chimeric antigen receptors, proteins attracting antibodies that bind to and destroy blood-related and solid tumor cancer cells. Most current methods producing chimeric antigen receptor T-cells, known as CAR T-cells, genetically engineer a patient’s own T-cells, then re-infuse the altered T-cells back into the individual, with successful results for blood-related cancers in some cases.

The company’s process is designed to produce off-the-shelf CAR T-cell treatments from T-cells provided by healthy donors. Allogene says this approach provides a ready supply of CAR T-cell therapies in patients, where their often critical conditions won’t allow harvesting of these cells. The process also removes the need for leukapheresis, the process of separating white blood cells in the lab from whole blood donations and returning the remainder to the patient. Allogene produces its T-cells, called AlloCAR Ts, to seek out and bind to cancer cells expressing specific characteristic proteins on their cell surfaces.

Lower than normal blood cell counts

Allogene’s lead products, code-named ALLO-501 and ALLO-501A target a protein called CD19 found on the surface of B cells — another type of white blood cell — associated with several blood-related cancers. The company says a participant in the clinical trial testing ALLO-501A among large B-cell lymphoma patients for safety and efficacy indicators showed signs of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, or ICANS, adverse reactions sometimes occurring in these kind of trials. After treatments with steroids, further tests showed the patient with pancytopenia, a condition marked by lower than normal red and white blood cells and platelets.

A subsequent bone marrow biopsy, says Allogene, indicated aplastic anemia, a condition where lower blood cell counts result from malfunctioning bone marrow, as well as ALLO-501A CAR T-cells with a chromosomal abnormality. The company does not spell out the precise abnormal characteristics in the patient’s chromosomes, but National Human Genome Research Institute, part of National Institutes of Health, says two types of abnormalities can occur: numerical and structural. Numerical abnormalities are when one of the 23 chromosome pairs is missing, or an extra chromosome is found. Structural abnormalities result from altered chromosomes, such as missing or duplicated chromosome parts or pieces transferred to other locations in chromosomes.

Allogene says FDA then put a clinical hold on all of the company’s AlloCAR T trials until the chromosomal abnormality can be further explained and its cause. “Patient safety is our highest priority,” says Allogene’s chief medical officer Rafael Amado in a company statement, “we are committed to working closely with the FDA to evaluate any potential clinical implications of this finding, and determine next steps for advancing ALLO-501A and our clinical programs.”

The company says more than 100 patients already received AlloCAR T treatments in clinical trials, and this is the first adverse reaction of its kind. Allogene says it still expects to report favorable results from its early-stage AlloCAR T studies, and eventually proceed with later-stage trials.

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