First U.S. clinical CRISPR data give early safety signal for ex vivo editing

CRISPR cleared its earliest safety hurdle with the first clinical data on the gene editing technology in the U.S., but it's still too early to tell whether that safety signal will persist and apply to other types of CRISPR-based therapies.

In an abstract released in advance of the American Society of Hematology (ASH) meeting on Wednesday, a group from Tmunity Therapeutics Inc. and the University of Pennsylvania unveiled initial clinical data from three multiple myeloma (MM) and myxoid/round cell liposarcoma (MRCL) patients treated with Tmunity's NY-ESO TCR T cell therapy.

The data are the first presented on any CRISPR-based therapeutic in the U.S.

The abstract's authors showed that CRISPR-edited NY-ESO-1 TCR-expressing T cells were well tolerated without neurotoxicity or cytokine release syndrome in two patients with MM and one with MRCL. The cells were edited to disrupt expression of endogenous TCRA, TCRB and PD-1.

One patient had progressive disease at day 60, one had stable disease at day 90 and the other was too early to evaluate.

Safety concerns including off-target gene edits and immunogenicity from the bacteria-derived Cas9 enzyme have surrounded the gene editing technology.

In the patients, the cells expanded in vivo, persisted and targeted the tumor, suggesting minimal immunogenicity.

Although this short term data suggest the CRISPR-edited cells are well tolerated, using CRISPR to modify cell therapies ex vivo should be safer than delivering the CRISPR machinery directly into patients for in vivo gene editing.

Cell therapy products edited ex vivo can be screened for off-target edits before administration, and the immunogenicity concern is mitigated because Cas9 has a short half-life in culture and very little, if any, of the enzyme is delivered with the cell therapy.

The team detected between 0-0.37 ng/mL residual Cas9 concentrations in the cell products.

A more revealing safety indicator may come when Editas Medicine Inc. (NASDAQ:EDIT) and Intellia Therapeutics Inc. (NASDAQ:NTLA) present data on their clinical trials evaluating in vivo CRISPR-based therapies.

In July, Editas and Allergan plc (NYSE:AGN) started a Phase I/II trial of locally injected AGN-151587 (EDIT-101) for Leber congenital amaurosis 10 (LCA10). Intellia and Regeneron Pharmaceuticals Inc. (NASDAQ:RGEN) plan to kick off clinical testing in mid-2020 of a systemically delivered CRISPR-based therapy for transthyretin amyloidosis (ATTR).

Targets: NY-ESO-1 (CTAG1B) - Cancer/testis antigen 1B; PD-1 (PDCD1; CD279) - Programmed cell death 1; TCR - T cell receptor; TCRA - T cell receptor α chain; TCRB - T cell receptor β chain

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