Sometimes it pays to put the CAR-T before the horse!

                

The term "personalised medicine" is becoming ever more prevalent these days, and it is partciularly relevant in cancer therapy, where increasinly we begin to talk about individual cancers in, well, a very individual way. It's no longer just the fact that a cancer we have heretofore referred to primarily in generic terms (say, breast cancer) is becoming better understood in terms of sub-types of that cancer; but additionally, science is racing ahead in terms of using an individual's own cells as part and parcel of therapy and even a potential cure. 

Cancer immunotherapy is in an explosive growth phase today, one which is trying desperately to keep up with the prevalence and growth of cancer itself. One such avenue of intense investigation is the approach known as "CAR-T" therapy whereby a patient's own immune cells (T-cells) are engineered ex vivo in a laboratory and then reintroduced to the patient with potent new cancer-targeting warhead receptors. One company that is making big news in this regard currently is French biotech, Cellectis, which is starting to edge (race?) ahead of competitors such as Novartis, Kite Pharma and Juno Therapeutics. 

Why? Well, although all of these companies are in clinical development on various CAR-T immunotherapies, the latter three are focused on autologous adoptive cell therapy (ACT), whereby the patient themselves function as the donor. Cellectis on the other hand are utilising the allogeneic or donor approach, whereby the engineered T-cells come from a matched donor rather than the patient. Their UCART system made the news everywhere this week with some spectacular results achieved at the Great Ormond Streert Hospital (GOSH) in London, England. 

The story revolves around a barely 1-year-old baby girl, Layla, who has been in treatment for a very aggressive form of acute lymphoblastic leukemia (ALL) since she was 14 weeks old - after both chemotherapy and a subsequent bone marrow transplant, her cancer had returned - and her parents were told to prepare for the worst as doctors were out of options. In such drastic situations, doctors are becoming more willing to try essentially anything, and so it was that little Layla became the first human on the planet to be treated with the novel experimental treatment of Cellectis. 

The T-cells that were introduced into her system were edited using the TALEN gene-editing tool, which has been in the news alongside analogous techniques using zinc finger nucleases or Crispr/Cas9 as the future of gene-editing therapy in disease. To cut a long story short, these altered T-cells were silenced in terms of attacking Layla's healthy tissue as well as being resistant to a chemotherapeutic, but exhbited potent targeting and cancer-killing properties. The hopes surrounding this last ditch effort to save the little girl's life were massive, and they were massively rewarded with the outcome that just two months later, Layla is now cancer-free and home with her parents! 

"Her leukemia was so aggressive that such a response is almost a miracle. As this was the first time that the treatment had been used, we didn't know if or when it would work, so we were over the moon when it did." said Professor Paul Veys, Director of Bone Marrow Transplant at GOSH who led the team treating Layla.

A miracle seems like the appropriate word when considering that the technology had only ever been tested on rodents in a laboratory, never on a human. But the team at GOSH, working in collaboration with colleagues at UCL and the specialists at Cellectis, got things bang-on and hit the nail square on the head, with no apparent undesired reactions. Experts working on patient-derived T-cell therapies have criticised the allogeneic approach of Cellectis due to graft-vs-host concerns, i.e. the rejection of foreign donor cells by the host, but Cellectis appear to have put such concerns to bed - and not in the bed of their patient!

Cellectis themselves are clearly very excited about this early result, not least because they claim that their approach is both faster and cheaper than single patient-specific gene therapies. Cost is not something we like to worry about when it comes to cancer, but with drug costs already an extremely political issue of late, and various biologics costing hundreds of thousands per course, any alternative that lowers prices will get the attention of payers/reimbursers in the healthcare system. In their press release of last week, Cellectis COO Mathieu Simon stated -

“We expect to accelerate our clinical development of TALEN gene-edited allogeneic CAR-T therapies to further confirm this encouraging clinical proof of concept”.

Naturally, while Cellectis shares did jump in price upon this news, caution is being expressed by the experts involved, not least because it is a one-off success to date. Science requires multiple repeats of key findings before writing them into the annals of modern medicine, but I will bet that if little Layla now moves on to a cancer-free life that most of us and especially her will delight in even this "n" of one. 

“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children. But, this is a landmark in the use of new gene engineering technology and the effects for this child have been staggering.” said Professor Waseem Qasim of the UCL Institute of Child Health and a consultant immunologist at GOSH.

We are keeping a very close eye on such developments at AmorChem, because we have two related programs in our portfolio - one which utilises a modification of the TALEN tool used in Layla's treatment, and the other which is a high-profile  allogeneic immunotherapy approach also utilising donor T-cells to attack patient cancer cells - and so the success obtained in the GOSH treatment is very encouraging indeed!