Kite, Sangamo Partner on Gene-Edited Cell Therapies

To create universal chimeric antigen receptor (CAR) T-cell therapies—and a range of other autologous and allogeneic T-cell and natural killer cell treatments for patients with cancer—Santa Monica, CA–based Kite, a subsidiary of Gilead Sciences, inked a deal with Sangamo Therapeutics of Richmond, CA, to gain exclusive rights to its zinc finger nuclease (ZFN) gene-editing technologies. Under the terms of the agreement, announced on February 22, Sangamo will receive an up-front payment of $150 million—and could receive $3 billion more for meeting certain milestones, as well as royalties on sales of up to 10 products.

By partnering with a gene-editing specialty firm, Kite is following in the footsteps of other major companies developing CAR T-cell therapies. For example, Novartis has allied with Intellia Therapeutics; Juno Therapeutics (now owned by Celgene) with Editas Medicine; and Pfizer with Cellectis.

However, given Kite's relatively late start, “there are few dance partners left,” says Ronald Dudek, a consultant on CAR T-cell therapy development in Gaithersburg, MD. That means most companies with the intellectual property behind newer gene-editing technologies, such as CRISPR/Cas9 or transcription activator-like effector nucleases (TALEN), are already locked into exclusive partnerships, which could help explain why Kite is pursuing ZFNs instead.

To Sangamo's credit, Dudek says, the company does have “bona fide chops in editing T cells with their zinc finger technology.” For the past decade, the company has been testing an autologous CD4+ T-cell therapy in which ZFNs are used to render CCR5, the receptor through which HIV enters immune cells, permanently dysfunctional. That therapy is now in multiple phase II trials for the treatment of HIV infection. Previously, Sangamo shepherded a ZFN-edited IL13 receptor–targeted CAR T-cell therapy into phase I trials for glioblastoma, but development never went further.

Despite that clinical head start and an expansive ZFN library, Kite and Sangamo may find themselves behind other companies like Tmunity Therapeutics of Philadelphia, PA, which began recruiting for the first clinical trial of CRISPR gene-edited therapy in the United States in February. That product uses a patient's own T cells engineered with a viral vector to express a T-cell receptor (TCR) with affinity to the NY-ESO-1 antigen, as well as CRISPR to disrupt the genes for the endogenous TCR and the PD-1 checkpoint protein. “Technically, everything is ready to go,” says Tmunity cofounder Yangbing Zhao, MD, PhD, of the University of Pennsylvania in Philadelphia.

Kite and Sangamo will be looking to use ZFN technology to make similar kinds of autologous TCR-based therapies. They will also be trying to emulate what Cellectis has done with its TALEN-edited allogeneic CAR T-cell candidates, the only off-the-shelf CAR T-cell therapies clinically tested in the United States and Europe.

Cellectis's two allogeneic CAR T-cell products in phase I testing—one directed against CD123, the other against CD19—both use TALENs to inactivate the TRAC gene, which encodes part of the TCR, to prevent cell rejection and graft-versus-host disease. However, the anti-CD19 product additionally involves TALEN-mediated disruption of CD52 to prevent depletion by any residual anti-CD52 alemtuzumab (Campath; Sanofi) given during the conditioning regimen prior to T-cell infusion.

“We're really just getting to the end of the first wave of the [CD19 CAR] stuff,” says Waseem Qasim, MD, PhD, of University College London, UK, who is leading one of Cellectis's anti-CD19 trials. The next frontier, he says, will involve combining CAR transduction and gene editing so the construct positioning itself disrupts the TCR-encoding locus. “It's in the mix for something you could do,” he says—likely making it something that Kite and Sangamo will pursue. –Elie Dolgin

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.