JP Morgan interview – Crispr hopes its CAR will overtake Cellectis

Crispr stocks took a battering at the start of the JP Morgan healthcare conference after a scientific paper suggested that most people might be immune to Crispr Cas9 genome editing.

One of the leaders in the space, Crispr Therapeutics, has tried to regain lost ground by insisting that it might be immune to the problem, as well as pitching itself as a new player in allogeneic CAR-T therapy, taking on the leader, Cellectis. “They’re advanced in the sense they’ve actually dosed patients, but we believe we have a superior product,” said Samarth Kulkarni, Crispr’s chief executive.

Cellectis uses Talen gene-editing technology to eliminate endogenous T-cell receptors (TCRs). Crispr, as its name suggests, wants to do this using Crispr Cas9, and it also wants to use this to knock in the CAR construct itself, claiming that expression this way is more precise.

Crispr’s first planned CAR-T project is a CD19-directed allogeneic construct, CTX101, designed almost as a proof of concept. “We’re going to file an IND for CTX101 ... by the end of this year, and the other two CAR-Ts are not very far behind,” Mr Kulkarni told EP Vantage at the sidelines of the JP Morgan conference.

These other two constructs hit BCMA – a widely targeted antigen in multiple myeloma – and CD70, which Crispr reckons is unique. “We think we’re the only cell therapy company going after CD70 at this point. It’s a target that’s expressed in lymphomas as well as solid tumours.”

Tmunity

Keen watchers of the cell therapy space will note that Crispr is in a race against Dr Carl June’s Tmunity Therapeutics to begin the first human study of a cell therapy that uses the Crispr technology to make essential genetic changes to the T cells involved.

Back in 2016 Tmunity got clearance from the NIH’s recombinant DNA advisory committee, and a clinical safety trial was expected the following year (First human Crispr trial is a go, but don’t ask about the IP, June 22, 2016). No study has yet begun, however.

Still, Tmunity is not seeking to develop an allogeneic CAR-T therapy; its first study plans to use Crispr to knock out endogenous TCRs, to prevent T-cell subunit mispairing, and PD-1, to release the brake on the immune system. The construct is still an autologous cell therapy, in this case using an engineered TCR to target NY-ESO-1.

In Crispr Therapeutics’ case the technological angle seems more advanced; the group hopes to use Crispr to code for the actual CAR construct, as well as to knock out T cells’ endogenous T-cell receptors – this is done by virtue of the genetic locus where the CAR is “knocked in” – as well as the cell’s major histocompatibility complex (MHC), something Cellectis does not do.

The purpose is clear: deleting T cells’ endogenous TCRs could eliminate the risk of graft-versus-host disease, enabling the development of an allogeneic CAR. Meanwhile, editing out the MHC could eliminate the risk of host versus graft, in effect reducing the risk of the CAR-T cells being destroyed by an immune response against non-self antigens.

And Mr Kulkarni highlights the fact his company uses no viruses at all – groups like Cellectis and Novartis use lentiviruses to transfect the T cells, whereas Gilead and others use gamma-retroviruses. Crispr also hopes later to knock out PD-1, to enable the targeting of solid tumours, though this is further away.

Crispr Therapeutics first presented its CAR-T approach at November’s SITC meeting, but this gained little traction at the time.

Immunogenicity

Mr Kulkarni also did not attempt to dodge the immunogenicity fears over Crispr Cas9. “The data [in last week’s scientific paper] are likely correct,” he said.

“What was exaggerated were the implications. [People] came out and said Crispr’s not going to work for any of these patients.”

He insists that immunogenicity will not be a problem for the company because its technology only involves transient use of Crispr Cas9.

The group’s initial projects are ex vivo. “To do the edit we’re putting the Cas9 enzymes into the cells, and they disappear within hours; the immunity question is irrelevant for the ex vivo cell therapies.”

In subsequent in vivo projects, “It’s only relevant where the Cas9 molecular scissors are being expressed forever”, which he says is not the case with his company’s technology.

Mr Kulkarni is clearly optimistic about the potential of Crispr Cas9. But this week’s setback demonstrated the volatility that could lie ahead for such early-stage companies at their current valuations.

See our full coverage from the JP Morgan conference here.