FDA stops all Allogene's CAR-T trials over safety scare, raising questions about future of gene editing

The FDA has sent shockwaves through the off-the-shelf CAR-T space, slapping a clinical hold on all of Allogene Therapeutics’ AlloCAR T clinical trials in response to an abnormality that could theoretically cause cancer.

At this stage, there are a lot of unknowns, and the range of possible outcomes run from a short delay to Allogene’s programs right up to a more intractable problem for the entire off-the-shelf cell therapy space. Analysts at Jefferies expect the clinical hold to be resolved, albeit after many months of work, but at this stage it is impossible to rule out other scenarios. 

Here’s what we know: A heavily pretreated lymphoma patient suffered a reduction in all blood cell lines after receiving an infusion of Allogene’s anti-CD19 CAR-T candidate ALLO-501A. Analysis of the biopsy discovered anti-CD19 CAR-T cells with a chromosomal abnormality.

Allogene reported the abnormality to the FDA, prompting the agency to put a clinical hold on all of the biotech’s AlloCAR T clinical trials. The magnitude of the FDA’s response reflects the potential for chromosomal abnormalities to cause cancer.  

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Beyond that, there is more conjecture than fact at this stage. One fundamental outstanding question is how the cells came to have the abnormality. The cells may have acquired the chromosomal change in the gene editing process or as they expanded quickly. 

Depending on the root cause, the TALEN editing technology used by Allogene or any therapies that alter a specific part of the chromosome could face problems, potentially delivering a setback to the biotech or the broader off-the-shelf T-cell therapy space. Equally, the impact could be limited to a delay and the adoption of additional precautions at Allogene. Jefferies analysts are optimistic.

“Ultimately, we think the hold will be removed after our estimate of 'many months' of review and looking into manufacturing, release assays, the risk of the underlying gene edits and risk of transformation, and other confounding factors w/ the patient. We think a short term delay and stock hit—but the risk/benefit is still high for patients and a clinical trial should be allowed to move forward—and stock should bounce back,” the analysts wrote in a note to investors.

Allogene’s stock fell more than 30% in response to the news, tumbling from above $24 to below $17. The fallout from the hold affected other companies, too. Shares in Cellectis, the biotech behind the TALEN gene editing technology, fell 17%, and CRISPR stocks suffered dips, indicating the potentially far-reaching implications of the news. In contrast, shares in Autolus Therapeutics rose 7% as investors reevaluated its autologous CAR-Ts in light of the troubles of its off-the-shelf rival.