Federal Oversight Group Has Complaints But Says Yes To CRISPR Trial

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[Updated, 6/21/16, 5:40pm. See below.] Despite worries about conflict of interest, a National Institutes of Health committee that oversees the use of gene therapy and other cutting edge biomedical technologies voted today to let researchers move ahead with a landmark clinical trial. Depending on timing, it could be the first to use the gene editing system CRISPR-Cas9 in a human treatment.

There are still hurdles. The University of Pennsylvania School of Medicine team, led by high profile cancer researcher Carl June and funded by billionaire Sean Parker’s new cancer institute, must get a green light from the FDA, according to NIH regulations. It’s not clear when Penn hopes to start a trial, which would be small and designed to evaluate the safety of an experimental treatment for several types of cancer.

[Updated with Penn Medicine statement.] In response to questions about the conflict of interest and a timeline for the trial, a spokeswoman emailed a statement that said Penn Medicine “was pleased” by the vote and looks forward to presenting the trial for FDA review. It did not address the conflict or timelines. The spokeswoman did not respond to follow-up questions.

Penn wants to extract specialized immune cells called T cells from cancer patients, modify the cells outside the body with CRISPR-Cas9, then re-insert the cells to go after the cancer. T cells (like the one pictured above) are typically good at tackling cancer, but sometimes tumors use specialized proteins to evade detection. The CRISPR modifications would give the T cells a counter-strategy.

CRISPR-Cas9 is a bacterial defense system being harnessed to edit genes. “CRISPR” is a strand of RNA that guides a particular enzyme, “Cas9,” into a cell’s nucleus to perform genetic surgery. Several groups, including June-led teams, have tested T cell therapies in humans, often with success. But this would use CRISPR-Cas9 to make three genetic changes in the patients’ T cells to better fight cancers that produce in abundance a protein called NY-ESO-1.

Safety is a major concern. What if CRISPR’s “scissors” cut the T cell DNA in the wrong place and create unintended consequences—spurring more cancer, perhaps, instead of fighting it?

The review committee today overall seemed satisfied with the Penn team’s description of the safeguards they were putting in place. At times, committee members expressed excitement about the trial. “Hopefully it will form the basis of new types of therapies,” said Michael Atkins, an oncologist at Georgetown University.

“I think you’ll get some interesting biology from this Phase 1 trial,” said Paula Cannon, an immunologist at the University of Southern California.

The committee was more vocal, however, about the ethics of the potential trial. Penn, and specifically June, have a conflict of interest. The committee’s review document, released before the meeting, said that June had a “‘significant’ financial interest as inventor of the technology used in the study,” but noted that Penn did not disclose further details. Nor did the school offer any ways to resolve the conflict, according to the committee review document. The lead investigator on the program, Penn oncologist Edward Stadtmauer, was not reported to have any conflicts.

Citing Penn’s history with gene therapy and financial conflict, committee member Lainie Ross, a pediatrician and medical ethicist at the University of Chicago, said that Penn’s plan to be deeply involved in the trial would be “doubling down on conflict,” not resolving it. Penn was the site of a gene therapy trial, in the late 1990s, that ended with the death of teenager Jesse Gelsinger. Years before, Penn had loosened its conflict rules to keep gene therapy expert Jim Wilson, who ran the trial, and who also had a large stake in a private company that was connected to his academic research.

All agreed that Penn should be involved in the potential CRISPR-T cell trial because of its expertise in manufacturing T cells. But Ross and others questioned whether the school should also be allowed to recruit and treat patients. Or should the school recuse itself from that part, leaving recruitment and treatment to MD Anderson Cancer Center in Houston and the University of California, San Francisco, the other centers involved, and simply help with the manufacturing?

When asked if MD Anderson and UCSF have conflicts of interest, June said, “Not to my knowledge. But that hasn’t been pressure tested yet.”

The committee acknowledged it could not force Penn’s hand. With its unanimous yes vote (one member abstained), the committee left the school to decide how to deal with conflicts—but strongly recommended that, at the least, messy and potentially misleading language in its consent form, which patients must read and sign before joining the trial, should be cleared up.

For example, Stanford University pediatrician Mildred Cho said that it wasn’t clear enough that the treatment, once administered, can’t be reversed. The engineered cells multiply in the body and pursue their course. (Some T cell therapies have so-called “kill switches” meant to deactivate them if they go awry. This particular therapy does not.) Cho said that patients need to understand clearly that once they receive their cells, they will be followed for results.

There was also confusion about the role of two major corporations in the study. Language in the study documents made it seem that Novartis (NYSE: NVS) and Life Technologies (NYSE: LIFE) had financial ties, but June said it wasn’t so. Novartis, for example, only has rights to Penn’s work in a type of cancer therapy called chimeric antigen receptor T cells, or CAR-T. “There’s no CAR here,” said June, referring to the T cells modified with CRISPR-Cas9 that he and his colleagues have been developing.

The committee recommended other consent form changes. Patients need to know that a Phase 1 safety trial is not likely to lead to medical benefits, and they need to know that this is the first time CRISPR-Cas9 would be used in a human therapy. There were also concerns that the trial doesn’t pay enough of the costs, which could limit the trial to people who can afford it. “Will it exclude the poor who can’t pay for testing?” asked Laurie Zoloth, who runs the Center for Bioethics, Science and Society at the Northwestern School of Medicine.

If the Parker-funded program reaches the clinic soon, it would be a remarkable milestone. CRISPR-Cas9 was only described as a potential human therapy a few years ago. Other gene editing technologies have made more headway. Sangamo Biosciences (NASDAQ: SGMO) of Richmond, CA, owns the system known as zinc fingers and has moved a prospective therapy into clinical trials to treat HIV infection, a program June has been involved with. Sangamo also has FDA clearance to start trials in patients with hemophilia B and two types of the rare disease mucopolysaccharidosis.

Yesterday, the French biotech firm Cellectis (NASDAQ: CLLS) announced that its development partner Servier has begun dosing patients with a T cell immunotherapy modified with the gene editing system known as TALENs.