Initially it looked like a U.S. biotech to be the first; then a team funded by the billionaire co-founder of Napster; now, it looks like it will be Chinese researchers who will start the first-ever human trial using CRISPR gene editing.
In an official announcement made on July 21st, Chinese researchers, led by You Lu of Sichuan University, plans from next month to begin the world’s first human CRISPR trial at the West China Hospital, Sichuan University, after being cleared by the hospital’s ethics board.
It plans to use the new gene-editing tech, known as CRISPR-Cas-9, on advanced non-small cell lung cancer (NSCLC) patients in a Phase I test primarily designed to test safety, but with secondary endpoints including progression-free survival, overall survival and response rate.
The study will use a cocktail of treatments. Under the trial’s design, as outlined on clinicaltrials.gov, peripheral blood lymphocytes will be collected and the programmed cell death protein 1 gene will be knocked out by CRISPR-Cas9 in the laboratory (known as PD-1 knockout T cells).
The lymphocytes will be selected and expanded ex vivo and then infused back into patients. Cyclophosphamide at 20 mg/kg single dose will be administered 3 days IV before cell infusion.
Interleukin-2 (IL-2) will also be given in the following 5 days, with patients getting a total of two, three or four cycles of treatment.
The design is dose escalation of ex-vivo knocked-out, expanded, and selected PD-1 knockout T cells from autologous origin. After the lower number of cycles are considered tolerant, an arm of the next higher number of cycles will be open to next patients.
Chengdu MedGenCell, a biotech company and a collaborator on the trial, will validate the cells to ensure that the correct genes are knocked out before the cells are reintroduced into the patients.
Up until now, CRISPR has only been studied in a preclinical setting, but much hype has been generated over the past year with a horde of biotechs and pharmas trying to get in on this potential new class of drug that could alter the way diseases–notably cancer–are treated in the future.
CRISPR Therapeutics, Caribou Biosciences, Editas (EDIT), Intellia (NTLA) and Novartis (NVS) were some of the bigger names vying to be the first into the lab–with many betting Editas would win that battle, as it planned to start human trials next year.
But on June 22nd, in a slightly bizarre twist, the co-founder of Napster and first president of Facebook, Sean Parker, threw his weight and wallet behind T-cell biology specialist Dr. Carl June, and a series of major U.S. medical academic centers led by the University of Pennsylvania, in an effort to get their team to run the first-ever CRISPR trial.
It looked like they had won the battle as in June, a National Institutes of Health panel ruled that their study could go ahead. All they had to do was gain the nod from the FDA and the universities, and they would be able to start this year.
But China has now come in and stolen the limelight after its researchers gained a speedy review that will in theory allow them to start the first CRISPR trial and patient enrollment in the coming weeks.
This follows on from China being the first in using CRISPR-edited human embryos, as well as CRISPR-edited monkeys.
Two checkpoint inhibitors are already on the market targeting PD-1/PD-L1 in certain NSCLC patients in the form of Merck’s (MRK) Keytruda (pembrolizumab) and Bristol-Myers Squibb’s (BMY) Opdivo (nivolumab).
They are both now fighting for first-line licenses in the U.S., but while some patients respond well to the treatments, a high percentage do not, and it is difficult to know on a per-patient basis if these antibodies will block PD-1 and activate the desired immune response.
The great hope with this trial and others like it in the future is that by knocking out the gene that blocks PD-1, while multiplying the cells, will only increase the chance of a response–and ultimately become a more powerful tool against cancer than the antibodies.
Safety however will be paramount in these early trials. There are long-running concerns about whether this gene-editing tech could produce some severe side effects (notably, an unwanted autoimmune response).
Regulators are already on high alert after the four patient deaths this year coming from a midstage blood cancer trial from Juno (JUNO), using a technique known as CAR-T, which is different from CRISPR-Cas9 but billed as the “cousin” to its methodology.
A trial was briefly halted by the U.S. FDA when the deaths were attributed to a cerebral edema, although it was quickly reinstated when the biotech and the regulator found that it was a preconditioning chemo agent, fludarabine, that was likely to blame for the deaths. This was removed from the restarted trial.