Thinking outside the box doesn't mean playing outside the team!

Summer 2016 at last, and maybe it's time to ease off on the gas a little, and partake of these amazing days and nights before the always-too-soon and inevitable fall into autumn, and the even more inevitable cocooning of deepest, darkest winter. At this very time, we have Brexit, Euro 2016, Shark Week (!) and the Montreal Jazz Fest as collective distractions from the daily grind, to name but a few!

Ahhh, Brexit. Don't get me started! You know, something about both Brexit and Frexit have gotten me thinking about a word that is a common thread in both, but I will  get to that in a second. Frexit, you ask? Well, Brexit was the British exit from Europe, and Frexit was the British exit from France and Euro 2016! Both results were extremely traumatic outcomes, the aftershocks of which will be felt for eons to come, if not longer. 

The British exit from the European Union as well as England's crushing defeat at the hands of tiny Iceland in Euro 2016 are staggering indictments of the nation's inability to be part of a team, both internationally, as well as nationally. Yes, it is the United Kingdom of England, Scotland, Wales and Northern Ireland, but how much "team" is there actually in that? 

Wales voting to leave may have surprised some "over here", but the crisis over the Tata Steel plant in Port Talbot, affecting some 4,000 jobs (11,000 UK wide), must have had an impact. The UK government was tepid if not downright anaemic in lifting a finger to save the plant, and that did not go down well at all. In many ways the Welsh protest vote was mirrored rather unbelievably on English soil itself, with many so certain the vote would be to remain that they issued anti-establishment leave votes that ended up tipping the scale in the other direction. 

The Scots and the Irish voted to remain in the union, in total contrast to England, so what does that tell you? Additionally, the northern Irish (to a historically much greater and way more violent extent) and the Scots, have each tried their damnedest to get out of that particular union. It has never worked, because England might be quick to leave a union that does not belong to them, but centuries pass before they ever give back something that didn't belong to them in the first place! 

England just never was a good team player; they have been independent for too long and the legacy is too strong to facilitate the type of role that being a member of a European conglomerate dictates. Further, the impact of eased immigration and foreign workers (often perceived as being anti-British) swarming the country has added fuel to the fire of those xenophobic voices that in Trumpspeak want "to make England great again!" The populist voice has rarely resonated deeper than in 2016, it seems. 

You can argue back and forth about the pros and cons of being in or out, but it is unquestionable that with the UK leaving the union, there will follow a period of financial instability and insecurity; not least due to reduced investment in business in the UK, which has already manifested itself with various big banks restructuring and relocating workers out of UK HQ offices in anticipation of the chaos. The markets reacted similarly, and while it is too early to say, it is possible that a full-blown recession could be on the UK menu. Today's news that Europe's biggest airline, Ireland's Ryanair, will now shift investment away from the UK and focus on Europe, backs up provocative CEO Michael O'Leary's pre-Brexit threats. 

There was something truly ironic that during more or less the same week, England saw both their PM resign, as well as the immediate resignation of the manager of the nation's beloved/beleaguered soccer team following a disgraceful defeat at the hands of "a country with more volcanoes than professional footballers". Quite how this came to pass boggles the mind, but what seemingly everyone agrees on is that England players are not a team. 

Make that, England historically plays not as a team, which describes both scenarios rather well, I think. Watching the game against Iceland was a cringeworthy affair whose clearest conclusion was that taking eleven domestic football stars and combining them in one dream team and expecting something great - is just that - dreaming. You can take the individual out of England, but you can't tale the individual out of the boy. It was a group of eleven star individuals, who got trampled by eleven more-or-less unknowns who learnt and understand the value of true teamwork. 

Some people get that point, and others are incapable of seeing it. In fact, one could say that in professional sports, certain big stars are encouraged to be somewhat selfish in the hunt for the goals, even if it's still a team sport and you can't win on your own. But English soccer suffers from a rather unique malaise that involves collecting players who play great team football domestically, but just cannot play together internationally. 

It's hard to understand the reasons why, but it appears to represent the intensity of domestic competition reaching over into the national team, wherein players who compete fiercely against other on rainy Saturday afternoons cannot play together, period.  Or maybe as some suggest, they have so much fame and make such ridiculous amounts of money from their day job, that the hunger just isn't there, anymore. Either way, I am convinced there is a psychological aspect to the English malaise internationally, and until that is addressed, no amount of coaching or no endless flow of new managers is going to achieve very much. 

The interesting point from a business standpoint is that of course we are all in the midst of related situations every day of the week. Most of us work in teams, big and small, and are surrounded by a diverse group of individuals, some of whom maybe are recognised as stars, some as hard to work with, some eccentric, etc etc. As easy as it is to fall into the deep silos of modern office life, it is worth using the England soccer malaise (or other example) as an analogy and taking something productive out of it. 

England recently proved that having eleven individual superstars who don't work well together is a recipe for disaster, while tiny Iceland recently proved that a real team of eleven individuals working collectively as a group can do the nearly impossible. There is strength in numbers, small and big, when the numbers are aligned and all pulling in the same direction. Individuals can still shine inside the team framework, but the team result comes before the individual result, always. 

Just like musical progression, gliding from major to minor can be a very sweet transition!

It's been quite a while now since the hoopla of the completion of sequencing of the human genome, and the subsequent introduction of the era and promise of personalised medicine into the treatment arsenal of drug developers and physicians everywhere. As commonplace as it has now become, particularly in oncology, one group that seems to be wary would be those like ourselves - investors! 

It's seemingly inevitable that once you begin touting a therapeutic approach that is actually poised to achieve what the term "personalised medicine" was coined to describe, a voice (or a few) from the head of the table begins to express worries about the clear lack of "a product" here, and "how are we going to make money out of this, or scale it?" Cranking out pills by the millions is more cost effective than producing a specialised therapy one patient at a time, right?

As inevitable as such concerns may be, I feel that the concern is often overplayed and maybe even strategically so; it's easier to dismiss and say no (for oft-heard business reasons) than it is to actually go forward, particularly when the technology is novel and not well understood. But you know, not well understood is not at all the same thing as saying there's no use for it nor profit to be made from it - it takes some vision, and the belief that some risk is a necessary evil in the world of venture capital!

Cancer's thrust to evade immune detection and grow exponentially is both fascinating and horrific at the same time, and in recent years the mechanisms used to avoid immune responses have been elucidated, becoming an Achilles heel of sorts for cancer cells. As successful as checkpoint inhibitors are becoming, clinically, one hears all the time of just how heterogeneous a given cancer is between individuals, and additionally, how heterogeneous is the make up of an individual's own tumour, itself! 

So, while efforts will never cease on identifying the ultimate Achilles heel (if there is indeed one) of cancer, I think it is equally inevitable that a personalised approach will remain necessary to better diagnose, stratify and treat patients, and give them the maximal chances of efficacy with the minimal chances of serious side effects or relapse. If that happens to come in the form of something that is not (yet) a one-size-fits-all therapy, then so be it! 

In terms of the business side of things, yes, personalised medicine may become more challenging as a financial model, but you know, various biologics are costing in the several hundred thousand dollars price range for a course of treatment, today, and those treatments are being reimbursed. Albeit, not without some whining on the parts of insurers, the healthcare system and even one or two US presidential candidates, among others!

We are co-funding a most exciting (if not downright heroic!) genoproteomics program in collaboration with both Genome Canada and Genome Quebec that falls squarely into the category of personalised medicine, and which also faces some of the challenges outlined above. The technology involves the use of proprietary human minor histocompatibility antigens (MiHAs) as next-generation targets in haematological cancers, and potentially represents a massive step forward from the current standard-of-care. 

Bone marrow/stem cell transplants have been on the go for around 40 years, and by some estimates they have saved as many as one million lives, globally. The graft-vs-leukemia (GVL) effect seen in successful transplants is in fact mediated by T-cells recognising foreign MiHAs presented on cancer cells of the recipient, but it's often a win-lose prospect due to the unrefined mixture of T-cells that is given as a donor-derived graft to the recipient. Thus, while there may be a GVL effect (or not), there is a roughly 50% risk of also observing what is referred to as graft-vs-host-disease (GVHD), whereby the graft ultimately attacks host tissues.

This GVHD outcome is mediated by T-cells detecting an undefined number (although maybe one immunodominant peptide antigen might be enough) of non-self "foreign" antigens on the recipient's normal cells/tissues, and then actually doing their job: attacking the unrecognised cells. The beauty of the approach in this program is that investigators are priming T-cells against one (for now!) MiHA that they know is present more or less exclusively on the patient's cancer cells. This meticulously selected single-specificity population of T-cells will then be used as a bone marrow transplant equivalent and given as a graft to the recipient. 

So instead of a patient receiving an unrefined and multifaceted population of T-cells with the capacity to recognise and attack cells presenting any number (probably in the thousands at least) of foreign antigens, in this case patients will receive a selected and focused infusion of T-cells directed at one non-self antigen present on the surface of the patient's haematological cancer cells. This is the essence of the GLIDE clinical trial which will be initiated in Canada later this year, upon approval by Health Canada. 

To say that this trial is eagerly anticipated would be an understatement. It is my personal belief that in this trial, the read-out should be clean; there will either be no effect (and no GVHD) due to the chosen peptide not being efficacious, or in this Phase I trial in patients, the team will hopefully observe actual GVL and even remission in certain individuals. This would be the dream and it would ultimately revolutionise the standard-of-care in haematological cancers, upon further testing. Immunotherapy is big business these days, and MiHA technology would be another powerful addition to the clinician's repertoire.

Of course, business people will still bemoan the apparently cumbersome nature of the process for each individual patient, but this is not diabetes or asthma here - roughly half of all patients with such cancers develop resistance even to chemotherapy, and die - and what value should be put on saving them?! Given the substantial (hundreds of thousands) current cost of a bone marrow transplant, and the associated costs of dealing with GVHD in basically one out of every two patients, I think there are clear business reasons why MiHA-targeted T-cell immunotherapy should reap serious investment today, to become the new standard-of-care (and even cure) of tomorrow. 

We may be a little biased, having invested already, but the potential is explosive in this clinical-stage program, and unlike the currently en vogue CAR-T approach (B-cell specific), MiHA targeting could be applied to all cancers, including solid tumours. We are not there yet, but the possibilities are numerous. In the meantime, development of a novel therapy exhibiting more efficacious GVL with commensurate decreased risk of GVHD remains a top priority, and we believe it makes sense both from a healthcare-based as well as a business-based viewpoint. 

The one-size-fits-all mentality is fine for small molecules or even a mAb, but by its very exquisiteness, MiHA therapy is designed to be individual-specific (for now at least) and take supreme advantage of the self/non-self relationship between donor and recipient. That pretty much puts the "personal" into personalised medicine, using the scientific fundamentals of a technique that actually preceded that trendy term by a few decades!

I think I can speak for not only AmorChem, but also for both Genome Canada/Quebec, in wishing the entire team (at Maisonneuve-Rosemont Hospital) involved in this personalised cancer immunotherapy program all the very best for an extremely smooth glide towards the goal of improving the treatment and prognosis of those suffering from haematological cancers! 

From a KNOCK OUT in Montreal all the way to a knock-out BIO in San Francisco!

Someone nudged me in the last twenty-four hours or so, stating that I had been rather silent of late, and guess what - they were right! It's been a bit of a whirlwind what with our recent KNOCK OUT™ competition event day with Lumira Capital, followed more or less directly with a packing of the bags and heading to BIO 2016 in San Francisco!

The event day went terrifically well, like last year, hosted by the incomparable Christopher Hall, who, as one local lawyer put it, "managed to deftly walk the line between serious science and hilarity". That truly is the magic of Chris (as his inside circle get to call him!) in that he effortlessly manages to take some very serious scientific information, and turn it into something that has everyone falling off their seats - scientists and laypersons alike! 

I think most people would probably agree that apart from the KNOCK OUT™ competition itself, the most memorable moments of the day came from Darrell Fox, brother of legendary cancer crusader Terry Fox. No one in Canada (or elsewhere these days) needs to be told who Terry Fox was and how much attention and funding he continues to raise for cancer research, but what was most touching was Darrell sharing some details that were more personal about his older brother. 

Speaking for myself (if not everyone) I found it to be inspirationally honest of Darrell to tell us that Terry was not a particularly good student, nor even a gifted athlete, but that he was simply an ultra-driven and very competitive individual who refused to ever give up when he wanted to achieve something.  It wasn't so much a question of natural talent, but more one of supernatural work ethic that both drove the guy and got him to where he wanted, and I think I can speak for everyone when I say that this point resonated in each and every one of us. 

Darrell Fox describing the Terry Fox Research Institute

Even (or especially) after some 35 years, seeing/hearing Darrell Fox tear up in public when describing his brother and discussing his heroic "Marathon of Hope" brought the room to a silence level where a pin drop would have been felt, and looking around I could see more than a few less-than-dry eyes in the audience. We owe Darrell and the Terry Fox Research Institute a big thanks for further illuminating the Terry Fox legacy, and reminding us all why we do what we do - whether that be research at the bench, funding research at the bench, running clinical trials, or treating patients bedside. 

Speaking of cancer and cancer research, we were delighted to announce the winner of this year's KNOCK OUT™ bout, Dr. Anne-Marie Mes-Masson of the Research Centre of CHUM, who is a professor at the University of Montreal. She handled our heavyweights with seasoned aplomb and was able to deflect the blows that came her way, standing her ground firmly, and punching back where appropriate! Dr. Mes-Masson will use the $500,000 funds to identify small molecule inhibitors of her novel GTPase target, Ran, and develop them as first-in-class candidate therapeutics for ovarian cancer, among other possibilities. 


Anne-Marie Mes-Masson in pre-KO training in her laboratory

Following the KO celebrations, it was pretty much time to pack and head to San Francisco where we partook of the "speed-dating-for-scientists" that is more commonly known as BIO Partnering! This year had some 16,000-ish delegates heading to the Moscone Center for a record-breaking 35,700 individual 25-minute partnering meetings, spread over three and a half days in two distinct (west and south) Moscone Center buildings. To say it was a wild and wonderful blur would be an understatement - it was a whirlwind of a week!



We had a full slate over there on the west coast, and it was a blast. The one thing that did cause some inconvenience and was a common negative comment between many of the delegates was the fact that you could have one meeting ending at 8:30am and the next meeting scheduled at 8:30am in an entirely different building on the corner down the street. Whether this was intended to keep us healthy (!) by forcing us to walk in fresh air a few times a day, or was simply a problem that could have been solved by keeping partnering in one building and exhibitions in the other, remains unclear. 

But, it could have been worse, had it been pouring with rain! People said it rarely rains there, which is a good thing or it could have been a disastrous move, having all those business suits and dresses getting royally soaked between one meeting and the next. It's a small complaint though, and all 16,000 of us made it work, exchanging smiles and hellos as we passed various colleagues on the streets of glorious San Francisco! 

In fact, the online partnering system worked much better this year and we definitely had a most productive BIO 2016. BIO never gets old, no matter how often one goes, and something about the sheer size and scale of the event inspires one to make the most of its potential and get sitting down in as many business meetings as humanly possible. Personally speaking, I can honestly say that my last one or two meetings at the very tail end of the convention on day four, alone, made the entire trip worthwhile and that is saying something!

I wouldn't exactly say that "I left my heart in San Francisco", but it's safe to say that maybe a part of it is still there, along with my head, which remains a little foggy just like the early mornings in the city on most days. But we are Tuesday already, and I daresay that in another 24 hours or so, business-as-usual will be restored and one will begin to look forward to BIO 2017 in San Diego!