Trials and tribulations of CAR-T cells - too much, too soon?!

Immunotherapy is revolutionising the world (of cancer) as we know it, and unquestionably, huge progress has been made by targeting the checkpoint inhibitor pathways and retooling the immune system to attack instead of ignore tumour cells. This is an approach that is spreading across the field of cancer, and is quite literally changing patient lives in a most hopeful fashion.

Further elaboration of such immunotherapy is to extend it to actual whole cells of the immune system, modifying them outside of the body, and then reintroducing them again to seek out and destroy the cancer nemesis. It's a fascinating concept in this brave new world of rapidly changing modern medicine, but as exciting as the few positive outcomes observed thus far are, we don't know as much biology as we would love to and it remains a dangerous game. 

This was emphasised in the past week with the news that the FDA had halted Juno's CAR-T trial (ROCKET) for patients with adult lymphoblastic leukemia (ALL) in response to the tragic loss of three patients enrolled in the study. It's a crushing blow for Juno who have JCAR015 lined up as their first product to market, and that's on hold now. They are not alone in the CAR-T race, with Cellectis, Kite and pharma giant Novartis all pushing hard. 

The word "game" used above in a non-literal sense is however an appropriate one, because in many ways the biotech space has been seen somewhat as a sport by both investors and many executives alike, in that it's all about creating (even perceived) value and then choosing the right time to jump ship with the spoils, before the ship sinks or just floats off into oblivion, adrift. It's a game many have played, but once you get to clinical trials and begin to hear of people dying as a result of the therapy that's supposed to treat (and ideally cure) them - it suddenly becomes very serious business indeed. 

For their part, the ~$4B biotech Juno have been very quick (some say, too quick) to come out with an explanation, and an eagerness to continue the trial after modification of the protocol. The offending component, they say, was the inclusion of the chemotherapeutic agent, fludarabine, added in after the trial had begun. This agent is an extremely potent lymphodepleting drug and Juno believed that it would further help the seeding and expansion of their modified T-cells after introduction into patients. 

However, after three patients died with cerebral oedema, there was no choice as far as the FDA was concerned but to put a clinical hold on the trial, which had some 20 patients enrolled with closer to 100 planned. Juno's CEO Hans Bishop was quick to state that they know what the problem was - fludarabine - and that they will stop using it and go back to using cytoxan, which had proved very efficacious in a previous JCAR015 trial run at the Memorial Sloan-Kettering Cancer Center. 

It does sort of beg the question as to why they did not just settle for cytoxan, which works, instead of endlessly trying to better previous results by changing-up protocols. But it seems that Juno have used fludarabine very successfully with JCAR014 and JCAR17 in other indications, which prompted the move. In any case, Juno will rapidly respond to the FDA, including submission of a new investigator's brochure for JCAR015, and Bishop appears confident that they will be back on track shortly. The markets were not quite as sanguine, with a 28% drop in share price inside a few days. 

I haven't read all the news articles on this subject as yet, but I have to say that from those that I did see, I couldn't help but feel that Juno, and Bishop in particular, are in too much of a hurry to please investors and appease the FDA, with a shockingly business-like attitude to the human beings lost in their trial. Now, I am acutely aware of the fact that these patients were very ill already, and that life must go on even in the face of death, but when it is your treatment that terminated those lives prematurely?! Showing sensitivity and compassion is not a sign of weakness, particularly when you are 100% responsible, and Juno's urgency to blame fludarabine and race onwards into the ROCKET trial appears hasty to some, if not many. 

This is groundbreaking science that we are talking about here, and Juno do know more about it than most, investing heavily in understanding the biology, as well as having some eight CAR-T programs in their pipeline. While death is part of life in cancer trials, particularly those that use such revolutionary new treatments, safety for the patient must remain an absolute priority, and one must never get too used to seeing patients die, and one simply must suitably acknowledge and respond to the unquantifiable loss of patients who die as a result of that treatment. 

This brave new world of science fiction-like science as modern medicine makes for massive leaps forward, but those leaps are often deep into the dark and further into the unknown. As much we do know, human biology remains remarkably complex, and running before we can walk can be a case of putting the CART before the horse. The patients that died are heroes for the cause, and what is learned from their tragic loss must be credited to them, even (or especially) as champagne is corked upon later successes.  

Rushing things is not always productive, and slowing down to consider all the possibilities before proceeding further might be a better way to go. Speed may be a key driving factor for investors, boards and executives alike, but dropping down a gear (or two!) can be educational, ultimately benefiting both patients as well as relationships with regulatory agencies.  But kudos to Juno for how far they have come in developing T-cell therapies to date, and let's hope they can jump this hurdle with not just the necessary scientific rigour but also while exhibiting the appropriate level of class.   

[PS - Just prior to the publishing of this blog, and still only mere days after the Juno disappointment, Kite Pharma announced enrollment has been completed for a Phase II (ZUMA-1) trial of their CAR-T candidate, KTE-C19, Rather remarkably, their regimen includes fludarabine, which surely will raise some eyebrows given the Juno outcome.]

[PPS - Just after publishing this piece, and mere days after the clinical hold by the FDA, Juno got what they wanted, and the hold was lifted so the ROCKET trial can continue with no further use of fludaribine - that was rocket-like fast!]