The first clinical trial in the US of a therapy based on the CRISPR–Cas9 gene editing
system is more likely to be conducted by an academic group than by one of the biotech firms most closely associated with the commercial development of the technology. As Nature Biotechnology went to press, new entrant The University of Pennsylvania (UPenn), in Philadelphia, and its partners, the University of California, San Francisco, and the MD Anderson Cancer Center at the University of Texas, in Houston, planned to start a phase 1 trial of a T-cell-based cancer immunotherapy in the first quarter of this year, subject to US Food and Drug Administration (FDA) approval of its investigational new drug (IND) filing. The emergence of the UPenn-led academic consortium— to say nothing of a group led by Lu You, of Sichuan University, in Chengdu, China, which achieved a world-first last year in administering CRISPR–Cas9-modified T-cells to lung cancer patients (Nature 539, 479, 2016)—shows that the competitive landscape for therapies based on CRISPR– Cas9 is already starting to gain complexity. Cambridge, Massachusetts–based Editas Medicine is the only one of the companies established by the main inventors of the CRISPR–Cas9 technology with concrete plans to move into the clinic this year. The others, Intellia Therapeutics and CRISPR Therapeutics—as well as Casebia Therapeutics, the latter firm’s joint venture with Leverkusen, Germany–based Bayer— are all in earlier stages of development (Table 1). Between them, these ventures have accrued a formidable $1 billion in aggregate funding—and with access to the key, albeit disputed, patents to the technology—they remain in the driver’s seat in terms of commercial exploitation of CRISPR–Cas9. Although these young biotech firms already have extensive capabilities in CRISPR–Cas9 gene modification, their therapeutic development efforts are necessarily early stage. Basel, Switzerland–based CRISPR and Editas were both established in the second half of 2013 (Nat. Biotechnol. 32, 127, 2014), and Cambridge, Massachusetts–based Intellia was only formed in May 2014 (Nat. Biotechnol. 33, 247–255, 2015). Meanwhile, several academic centers are attempting to apply to CRISPR their experience in introducing several other novel therapeutic modalities. Carl June, professor of immunotherapy at UPenn’s Perelman School of Medicine and director of the UPenn arm of the newly established Parker Institute for Cancer Immunotherapy, is scientific advisor on the forthcoming trial. Best known as a pioneer of CAR-T cell therapy, June has previous clinical experience with another gene-editing technology to develop an HIV therapy. His team used zinc-finger nucleases, to modify autologous CD4 T cells from individuals infected with HIV (N. Engl. J. Med. 370, 901–910, 2014). The T cells were engineered ex vivo to disrupt the gene encoding C-C chemokine receptor type 5 (CCR5), which most HIV strains exploit when entering T helper cells. The strategy—designed to mimic the CCR5D32 homozygous carriers from HIV infection—has already been emulated in the small-molecule drug Selzentry (maraviroc; ViiV Healthcare, Brentford, UK). The UPenn-sponsored phase 1 study was primarily designed to test safety. It also demonstrated that, although the gene-edited T cells persisted, the dose was insufficient to prevent viral rebound occurring when patients interrupted their drug regimens. “What we know for sure is zinc finger nucleases are safe,” June says. The therapy, SB-728-T, is now in a phase 2 trial at Richmond, California–based Sangamo BioSciences. CAR-T cell therapies, have achieved highly promising responses in cancer patients, but the approach is largely limited to hematological malignancies at present, however, and safety continues to represent a challenge (see page 6). The forthcoming trial using CRISPR–Cas9 gene editing, in patients with multiple myeloma, melanoma or sarcoma, involves an autologous T-cell therapy designed to attack cancer cells that express NY-ESO-1, a highly immunogenic cancer antigen. It builds on an earlier clinical study in myeloma patients, which involved the administration of T cells expressing an affinity-enhanced T-cell receptor (TCR) that programs all target liver cells—LNPs exploit the apolipoprotein E4 transporter to deliver their CRISPR–Cas9 payload, but the particles can be formulated for preferential uptake to other tissues, such as muscle, the eye and the central nervous system, Bermingham says. Editas is following a dual strategy. It is employing an adeno-associated virus (AAV) vector for therapies aimed at eye diseases, but it remains open, for now, to either AAV or LNP delivery for genetic diseases, such as Duchenne muscular dystrophy and cystic fibrosis. CRISPR Therapeutics has not disclosed its delivery strategy for in vivo applications. Its first in vivo programs, according to a recent quarterly filing with the Securities and Exchange Commission “will leverage well-established delivery technologies for gene-based therapeutics.” It has also entered several research collaborations to explore new delivery methods. The UPenn-led trial will operate under safe harbor provisions, which obviate the need for a patent license, but if it is successful, Tmunity Therapeutics, a Philadelphia-based spin-off from the university, would seek to commercialize the program. The company would then require a commercial license from at least one of the patent holders, although at this point it is not clear which one. “I wouldn’t know who to get a license from anyway, given the [uncertain] state of the technology,” June says. A decision in the ongoing patent dispute would clarify that issue—and set the terms for the evolution of CRISPR–Cas9 from being a wildly popular research tool to an commercial-grade therapeutic modality.
Cormac Sheridan Dublin