The new face of cancer immunotherapy for 2016!

Immunotherapy and immuno-oncology used to be futuristic-sounding terms or even pipedreams in cancer treatment, yet in what seems like a rather short time they have become more and more the norm, and more in vogue than ever. The brilliant concept of using the immune system, particularly one's own, to attack and defeat the beast that is cancer is at the forefront of modern medicine and blazing a fearless trail into the future; that trail is now being filled with new hope for those diagnosed with this deadly disease category.

Of course, while those of us even remotely connected to the pharmaceutical world tend to be aware of latest developments before they make the domestic news headlines each night, nothing raises the profile higher than some famous face who has faced and (apparently) beaten an aggressive form of cancer.  Thus is the case for a beloved ex-President of the United States, a certain Jimmy Carter. 

On one of his recent Sunday visits to his local Baptist Church in the Atlanta area, Carter announced that not only is he cancer-free, but that he in fact no longer needs treatment, period. Coming after a battle with multiple melanoma in his brain, that is one incredible piece of news. Carter told the applauding audience that he had been put through over two hours of MRI analysis, after which doctors concluded that he didn't need further treatment. 

"So I'm not going to have any more treatment."

I can only imagine what that statement must feel like and mean coming from one who has suffered not only the disease itself but the brutal therapy it often requires, though it's safe to say those sound like words of pure elation. Clearly, he will have to continue to have scans to monitor his condition, and if things did go south then he will have to return to treatment, but that is not the situation today. 

Some news reports stated that Carter had melanoma discovered in his liver, and that it had spread to the brain, but that is not the case in all likelihood. It seems that once doctors found it on his liver, and resected it, they made the conclusion that it had gotten there from somewhere else. So after his surgery, they put him through MRI and PET scans and sure enough, they found four other tumours in his brain. 

While this sounded like a death sentence to many, and not least to Mr. Carter himself I imagine, well, modern medicine and some hotshot oncologists thought otherwise! After four rounds of radiation therapy every three weeks, Carter was to receive the very latest in cancer treatment - immunotherapy. That immunotherapeutic, pembrolizumab, was then given to him intravenously, and the praying began. 

That therapy is better known by its trade name today, which is Keytruda, a novel immunotherapy developed by the Merck pharmaceutical giant; its novelty is underlined by the very fact that it was only approved for melanoma by the FDA as recently as September, 2014. It was given to Carter at three-week intervals between last August and February of this year, and now the results are in. 

Those results are not only of life-changing significance to Jimmy Carter, but are of game-changing significance to oncologists-patients everywhere, and you can bet that Merck management were feeling the paradigm shift themselves! Questions still remain about the duration of such treatments, and whether a shorter period is better than continuing until it is considered safe, but that's par for the course for a game-changing therapeutic, and oncologists will work things out with more hands-on experience with the treatment. 

Naturally, hardcore science and research is the foundation on which "drugs" such as Merck's Keytruda or Bristol-Myers Squibb's Opdivo are constructed, and in this case such therapies are targeted at cancer's ability (and malignant brilliance) to evade the immune system's attack via vulnerability at an immune checkpoint, often referred to as PD-1. 

Essentially, cancer cells reprogram T-cells from being in attack mode, sending them towards a programmed cell death pathway which renders them useless in the fight against cancer. Therapies such as Keytruda inhibit that ability of cancer cells, thereby sending a green light "attack!" signal back to our T-cell armies - giving patients at least a fighting chance of winning. And winning is indeed possible, if you ask Jimmy Carter, or many other patients who have benefited from the treatment, and it's also win-win for Merck (deservedly so) who took in $566 billion in global sales of Keytruda in 2015 alone. 

It's a brand new day in immuno-oncology, and as more and more novel approaches hit the decks (including both the "CAR-T" and "MiHA" immunotherapy approaches), well, things can only get more exciting from here on in. But it's worth remembering that aside from a concerted effort such as Obama and Biden's cancer "moonshot", it is the hordes of research scientists working tirelessly at laboratory benches everywhere, in academia as well as in industry, that are fueling the innovation that is at the heart of new drugs such as Keytruda. 

Here at AmorChem, we get that, and it is why we will continue to fund exciting and innovative university-based research as often as we can. We have a number of oncology projects in our current portfolio, including two that are very much immunotherapy plays, and with our AmorChem II fund drawing ever closer, well, it's a pretty safe bet that we will add on some more in the not too distant future!   

Being Broad may not be enough, if you're the "David" and Berkeley is the "Goliath"!

I reported in a recent blog about Eric Lander's painting in broad strokes regarding the history of the discovery and utilization of the gene-editing tool known as CRISPR, and how its timing was seemingly a proactive if not preemptive strike ahead of a hotly anticipated patent interference case about to be heard by the USPTO. 

That so-called history by Lander might have done more damage to him, personally, than to the case of the two ladies (Jennifer Doudna and Emmanuelle Charpentier) whose ownership of CRISPR he was effectively challenging; it didn't take long for a backlash, and the fact that it is two female scientists on one side fighting the stereotypical boy's club on the other made Lander a new target for those who truly believe (or chose to believe) that it was yet another case of rampant sexism - even (or especially!) in the corridors of power of big science. 

While the Lander strike may have backfired in his case, it did not impact the standing of Doudna, Charpentier and Berkeley, and if anything, actually strengthened the belief and support among many scientists that the trio is the David fighting the Goliath. However, that is actually not the case, as far as the legal system and the USPTO are concerned. Why? Well, because Doudna filed first, that's why! 

Now, before we get confused by the legalese, let's clarify a major point. In today's patenting world, ownership is given to the first to file a patent; in the good old (bad old?!) days it was given to the first to invent. So, even though the system changed mere hours after Doudna et al. filed, which would today make them the winner, the change was not retroactive - so given that the invention was made prior to the Doudna filing - if someone can prove that they had in fact come up with key inventive steps - then that person is the winner. 

That person is of course Feng Zhang and his gang at the Broad, current holders of over a dozen patents granted on CRISPR technology. The stakes are extremely high, and many are calling it the billion dollar case; one about to be heard by a three judge panel at USPTO, led by Deborah Katz of Alexandria, Virginia. Proceedings kick off with a discussion today, where opening arguments and some trump cards may make their way to the surface. But anyone who is hoping to hear of a quick settlement of the dispute to allow everyone to get back to work is probably going to be extremely disappointed. 

I might vouchsafe that it may not even be the scientists themselves who will be the key drivers of deciding between settling versus continuing, but rather the huge shadows that the heavier frames of their respective institutions will likely cast over the proceedings. There's a lot of prestige and money at stake, and the latter may have even more significance for UC Berkeley whose coffers are under pressure currently, with a projected deficit this year.

A win in this case would not only confer bragging rights to the winning institution but could well facilitate a steady stream of substantial income down the line. Quite how much money is the million (no, make that billion) dollar question but it is likely to be massive, if CRISPR companies such as Editas, CRISPR and Intellia make it and get to clinical phase and marketing for some futuristic-sounding human gene-editing therapeutic. 

Only time will tell what the value of the disputed patents truly is, but the rare examples of NYU's >$1B payday for Remicade or Columbia's ~$800M for one of their patented technologies are just that - rare. Although, a recent example involving UCLA may be a teaser in that context, in that they recently sold their rights to future royalties for a prostate cancer drug for some $500M. It seems inevitable that CRISPR will be used clinically in the future, so I think one can safely say that we are talking half a billion dollars, minimally, and probably a lot more. 

Now, to get back to a point I made earlier: even if it seems like UC Berkeley versus the Broad (MIT and Harvard) is a case of David fighting Goliath, in a legal sense it may twist to the other way around. Even if to date it is the Broad and Zhang who are on top, it is unquestionable that Doudna et al. filed first, which is today's yardstick upon which to measure ownership. So legally, Doudna could be viewed as the de facto originator of the technology in a patent sense; even if she filed first at a time when invention was king, the legal system may well see her patent as the senior of the two, with the onus on the challenger to provide irrefutable proof of individual and separate inventorship - and that is not likely to be easy.

It's going to get very technical and very legal - Doudna et al. were first to show CRISPR could be used to cut naked DNA in a test tube, while Zhang et al. showed it could be used to edit rodent and human genomes in cells derived from those species - and so the key and critical question is whether Zhang's development/improvement was actually obvious, or not. I would love to hear the lawyers debate that point, and it's likely to come down to a staple of laboratory life for scientists everywhere: the lab notebook. 

What is in there, or perhaps more importantly what is not in there, in each of the two cases, could decide the outcome of this patent interference proceeding. That outcome will almost certainly impact the future business of those companies currently forging ahead in developing CRISPR-based therapeutics for human use. 

“It's important to have clarity on intellectual property for those companies to be successful. It’s even more critical for pharmaceutical partners, which will view the uncertainty as a major overhang in working with the company.” said John Maraganore. Given that Mr. Maraganore is CEO of gene-silencing outfit Alnylam Pharmaceuticals, which faced a similar battle over its own technology, it's safe to assume that he knows of what he speaks!

It's going to be very interesting to watch this fight play out in the coming months and (hopefully not!) years, and I am not sure it would be smart to place bets either way, until we hear some context and flavouring from Debbie Katz and her co-panelists. One aspect that I find most intriguing about this case is the date that Doudna et al. originally filed - March 15th, 2013 - and on the very next day the law changed, and it became whoever filed first that owns. I bet she wishes now that this had all happened after that date!