2017 shaping up to be pivotal year for CAR-T and CRISPR therapies

2017 is promising to be a pivotal year for synthetic biology as two landmark technologies—CRISPR/Cas9 and CAR-T—head toward critical milestones.

In the coming months, it is possible that the first therapy based on CAR-T (chimeric antigen receptor T cells) will get regulatory approval, with candidates from Novartis and Kite Pharma that promise to reprogram the immune system to fight cancer currently leading the race to market.

CAR-T cells are genetically engineered to express artificial receptors on their surfaces, which bind to specific antigens on the surface of cancer cells, directing the body’s own immune system to recognize and attack tumors.

Buoyed by positive Phase II data and backed by FDA breakthrough designations, Kite has already filed a rolling submission for its KTE-C19 therapy for patients with diffuse large B-cell lymphoma (DLBCL), while Novartis has said it plans to submit CTL019 for acute lymphoblastic leukemia early next year.

It has not all been plain sailing for CAR-T in 2016 however, with the FDA imposing, relaxing and then re-imposing a clinical hold on Juno's JCAR015 leukemia candidate after side effects—including cerebral edema—were seen in a Phase II trial.

All three products are based on anti-CD19 CAR-T cells, but differ with regards to the way the cells are modified and their manufacturing processes, and could mean side effects seen with one therapy may differ markedly from those with another. 

Nevertheless, Juno's setback has helped to inject some skepticism into the potential for the technology, along with uncertainties about how they will be priced in the current payer climate, difficulties getting CAR-T to work with solid tumors, and an increasingly competitive landscape in hematological cancer treatment.

Meanwhile, the first data should also emerge from human trials of CRISPR, a gene-editing approach that is being explored initially in cancer but could have potential in a host of gene-mediated diseases.

The technology is deceptively simple, involving a guide RNA which binds to a targeted DNA sequence and an enzyme (nuclease Cas9) which introduces a break and triggers a self-repair mechanism. The guide RNA serves as a template to change the original sequence. Importantly, both elements can be introduced into cells using a single vector.

There is no question that CRISPR has already revolutionized the way gene sequences are manipulated, rapidly becoming an indispensable tool in research labs around the world despite a contentious intellectual property landscape. But its potential as a therapeutic approach in its own right is also being explored.

In November, a Chinese research group made history when they started the first human trials of a CRISPR therapy, injecting genome-edited immune cells into a patient with advanced non-small cell lung cancer. The trial is focusing on safety, particularly with regard to potential autoimmune effects, and will enroll 10 subjects. So far no news is good news, but emerging safety signals could peg back the development of the technology.

Studies in the U.S. are also planned and should get underway in 2017. In June, the National Institutes of Health (NIH) gave its blessing for a trial—bankrolled by Internet billionaire Sean Parker—that will involve editing cancer patients' T cells so that they are better at attacking cancer cells, with targets including myeloma, sarcoma, and melanoma.

The last few months have also seen further tantalizing steps towards combining CAR-T and CRISPR, with a series of deals struck between CRISPR specialists and pharma companies with CAR-T programs. Notable examples include alliances between Editas Medicine and Juno Therapeutics, CRISPR Therapeutics and Celgene/GlaxoSmithKline and Intellia Therapeutics and Novartis.

And while the technology is blossoming, it's worth acknowledging that the public—which will have a greater say in regulatory reviews in the wake of the 21st Century Cures Act—continue to have doubts about therapies that involve the modification of gene sequences.

A Pew Research Center survey of 4,700 U.S. adults, published in July, found that more than two thirds were somewhat or very worried about the implications of this form of therapy.