Affini-T: Jak Knowles, CEO

“Building a good company culture is like laying one brick at a time.”

Nature is the master drug developer. She has tested innumerable combinations of small molecules and proteins, in a process refined over billions of years—ruthlessly discarding programs that don’t pass muster.   

Natural “cell therapy” follows suit: within each of us there are billions of circulating T cells, trained in the thymus to recognize danger signals or “foreign antigens.” These small fragments of chopped up proteins can alert the immune system that a viral or bacterial invasion is afoot. The elimination of a pathogen is dependent on a T cell receptor (TCR) recognizing the appropriate antigen—once this “secret handshake” between a TCR and antigen loaded MHC complex takes place, T cells can kill the infected cells and boost the systemic adaptive immune response.

Nature has leveraged this recognition system to target another condition: cancer. In the same way that a virus drops antigenic clues to be sleuthed by TCRs, tumors contain mutated and dysfunctional proteins that are loaded onto MHC complexes and presented to our immune system: “Nature is really elegant at designing things, and I think we as scientists and clinicians can be a little more humble about how much we actually borrow from nature,” says Dr. Jak Knowles, co-founder, CEO and President of Affini-T Therapeutics.

If we (drug developers) can identify potent, naturally occurring anti-cancer TCRs, these sequences can be engineered into T cells and administered to patients—thus the diverse TCR repertoires from dozens of individuals can be used to combat one of humanity’s deadliest diseases. But refining the natural diversity of donor TCRs into curative therapy is easier said than done. Founded in 2020, Affini-T has created a scalable platform to do just that. The scientific core of the company came from work done at the Fred Hutchinson Cancer Center. The company’s proprietary platform can identify and sort billions of potent and naturally occurring TCRs, to select those useful in targeting key oncogene driver mutations like KRAS and p53. Targeting driver mutations is crucial because they are fundamental to cancer biology and are present in every tumor cell.

Knowles describes this logic of looking to nature first: “it just made sense that if there is a mutation out there, like KRAS, some portion of it is going to be processed, presented on the tumor cell surface and targetable by a TCR.” Affini-T’s lead therapy—engineered T cells recognizing G12V mutant KRAS—is currently in IND-enabling studies. These “souped up” T cells are engineered with a KRAS TCR, an extra CD8 co-receptor gene, and other factors to overcome the hostile tumor microenvironment.  These constructs work in concert to provide increased potency, persistence and durability in preclinical pancreatic, colorectal, and lung cancer models.  

Affini-T was co-founded by Drs. Phil Greenberg, Aude Chapuis and Thomas Schmitt (Fred Hutch), Dr. Arjun Goyal (Vida Ventures) and Dr. Jak Knowles. In March 2022, they announced the completion of an oversubscribed $175 million financing co-led by Vida Ventures and Leaps by Bayer. To accelerate growth, the company has established bi-coastal lab facilities in Seattle, Washington and headquarters and manufacturing infrastructure in Boston, Massachusetts.

Dr. Jak Knowles has been at almost every table in medicine and biotech, including the operating variety. After working as a research assistant at Sloan-Kettering with Dr. David Lyden, Knowles went to Stanford medical school with plans of becoming a cancer (head/neck) surgeon. Yet after two years of surgical training, he started to have doubts. Inspired by the approval of cetuximab (Q#2), he became fascinated by how medicines get to market: “I thought that maybe I could change a lot more lives if I focused on the biotech side rather than being a surgeon.” Knowles then left his surgical program and worked as a health and life sciences consultant at Oliver Wyman, a biotech equities analyst at JMP securities, and eventually joined the investment team at MPM Capital. He then co-founded and became interim CEO of Exonics Therapeutics, an in vivo gene editing company focused on Duchenne Muscular Dystrophy (acquired by Vertex) and then CEO at CytoSen, a Natural Killer Cell company (merged with Kiadis and acquired by Sanofi) (Q#4). While pitching CytoSen to Leaps by Bayer, he was inspired by the VC’s mission: “Leaps’ fundamental philosophy was to enable academic scientists realize their vision for their life’s work - and I always thought that is the way biotech VC should work” (Q#4-5). Knowles remained at Leaps for 3.5 years before making the jump to Affini-T: “I loved my job at Bayer, but I felt there was an opportunity to continue on the path blazed by Juno and Kite curing some blood cancers, and was compelled to build a company to address tough-to-treat solid tumors where there have been too few therapeutic breakthroughs.”

Thus, the erstwhile cancer surgeon, consultant, equities analyst, venture capitalist and biotech operator found his new home at the helm of Affini-T Therapeutics: “In my mind, taking this opportunity to work on developing potentially curative cell therapies with Phil Greenberg, Aude Chapuis Tom Schmitt, and Arjun Goyal was a no brainer.”

Below is an interview with Jak Knowles, CEO of Affini-T Therapeutics from November 2022:

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1. What first made you interested in science and medicine? Was there an early mentor or teacher that set you on this path? 

I haven't had a lot of “formal” mentors throughout my career, but I think my interests in science did start with my parents—they really encouraged me at a young age to pursue science and medicine. I think I was also one of those kids who said they wanted to be a doctor when I was 10 years old. I’m not sure why exactly, no one else in my family is in medicine. So, I was eventually the first one to go to medical school.

I grew up in New York City, and a lot of my early years were spent in New York public school. I'd say Bronx Science is the first place where I had real encouragement from teachers to pursue science. They had a Westinghouse Science Talent Search competition—I think now it's known as the Regeneron Science Talent Search—which was a great opportunity. You got to meet with academics and go to different university and hospital systems to better understand the science behind your research program. My project, I believe, was on cardiovascular disease and atherosclerosis. This competition really showed me that there was this world where science and medicine intersected.

I was able to kind of explore this intersection further. While I was an undergrad [at SUNY Binghamton], I interned at Columbia Presbyterian Hospital and another summer, I worked at Merck with some very talented researchers there. I worked with Russell Lingham, who was working on what would become the drug Vioxx—one of the selective COX2 inhibitors that was ultimately found out to increase risk of heart attack.

When I graduated from SUNY Binghamton, I went to work at Sloan Kettering in New York City—working with a researcher named David Lyden, and we had a collaboration with Shahin Rafii. I saw that David [Lyden] was an MD-PhD pediatric oncologist, so he saw a lot of kids with cancer, but then also spent significant time in the lab, working on medicines and treatments for those patients. It really was just a great inspiration for me. I was already set on medical school, but the time at MSK ingrained in me this desire to ‘do something’ in oncology. I think, up until that point, I was still a little bit unclear on what area to focus in.

2. Briefly discuss your experience as a medical student and resident. Were you involved in research? When did you become interested in entrepreneurship or following a “non-traditional path”? Was this something that you had always considered?

When I was working at Sloan Kettering, we had a research collaboration with a company called ImClone, which was working on an anti-EGFR, monoclonal antibody that became what's now marketed as Erbitux [cetuximab].This was my first impression of ‘biotech’—seeing the work at ImClone translate from preclinical data to a clinical product and then into FDA approval.

When I was at Stanford, I did some research in a field that ultimately, I didn't pursue. I was working in a plastic surgery lab with a guy named Pete Lorenz. My project was on scarless wound healing using a pretty elaborate model: we took these fertilized chicken embryos and you could cut a hole in the top of the shell and the embryo would keep developing inside as long as you kept it in into incubator. And then I would take fetal mouse skin and graph that onto the chorioallantoic membrane of the fertilized chicken egg, and it would actually revascularize. You could then shoot the newly vascularized mouse skin with a laser to create different size wounds to study wound healing.

So, during this time at Stanford, I was living on Sand Hill Road, which is right across from the campus. This is where a lot of the famous VCs are located. I didn't get a lot of direct engagement with Sequoia, or any of those folks, but occasionally some of the collaborators I was working with would invite me to meetings with venture capitalists. During that time, the real excitement was in the tech community. This was when Facebook, Google and all these companies were coming into their own as real powerhouses. It was a very inspirational time to be in Palo Alto, with a lot of people changing the world very quickly all around me. In any case, for residency I wound up matching into a surgical program at UAB in Alabama.

By the time I got there, UAB had the most volume of tumor cases seen by residents, which really dwarfed the case load in a place like Palo Alto. [At UAB] Some of the patients coming from southern Alabama would present with almost two-pound tumors. So, it was just an interesting training opportunity. But by the time I got there, the drug I worked on at MSK [cetuximab] was now approved and was a useful therapy for head and neck cancer patients. It was clear to me that there was this impact that I could be having outside of the traditional surgical route. I thought that maybe I could change a lot more lives if I focused on the biotech side rather than being a surgeon.

[On what path to pursue just after leaving residency]

I'd gotten into Stanford Business School, but instead, I looked for real-world experience, and joined the consulting practice at Oliver Wyman which was mostly focused on value based care.

It was great training to learn the business skills of Excel spreadsheets and PowerPoint, and I even gained experience with pivot tables and wrote SQL code—which thankfully no one has ever asked me to do again.

Before I went to venture, I also worked at an investment bank. I wound up joining a guy named Mike King, who was a very famous equities analyst. He's been around Wall Street forever. And I think that's where I really got the experience of “drinking from the firehose” by covering some great companies like Celgene and many other smaller biotechs.

My time as an analyst gave me an opportunity to kind of learn who the players were. As an analyst you would see these companies that were “backed by Atlas” or “backed by MPM.” At this time, there was an air of inevitability: these companies came out of stealth mode, and you knew they were going to IPO or sell to Pharma. So, I wanted to understand how that worked, how you could actually pull off building a company from the beginning and turn it into something so exciting and interesting. You could really feel there was going to be something positive that came out of these types of ventures. I was lucky enough to be interacting with a few headhunters and eventually had two venture offers—one was to Osage University Partners and the other was to MPM, which I accepted.

3. What types of things did you work on when you first started in venture at MPM Capital? What was a memorable early investment or experience (first board?) from this time?

MPM was an excellent training ground. My mentor there was Todd Foley, but I also got to spend time with Kazumi Shiosaki,  Robert Millman and also Mitch Finer who joined from Bluebird at the tail end of my time at MPM. It was just a great place to soak up all the knowledge from these different leaders in the biotech space. I don't think I would be the investor or company creator I am today, without this experience.

[On some of his first and most memorable investments]

One of the first investments I worked on [from end to end] was a mitochondrial biogenesis play, based on research from Vamsi Mootha’s lab. We were basically trying to alter aberrant metabolism, and the conversion of certain amino acids. This is a long time ago, but it didn't ultimately end up working out, unfortunately. Despite this outcome, it was a great example of what disciplined investing is supposed to be—you take a stab at it, you raise enough money, you try everything to make things work, but never continue to throw good money after bad.

At MPM, I also saw companies like TCR2 and would be in the room when Greg Sieczkiewicz and Patrick Baeuerle literally drew the IP on a whiteboard.  My favorite deal I saw at MPM was Semma therapeutics, a company started by Doug Melton and Felicia Pagliuca, based on their work. Robert Millman really brought it all together at MPM to create a company, and it was inspiring to hear Doug's story: how he had started out of a completely different area of research, but pivoted to immunology because his children, Sam and Emma, were Type 1 diabetics. I found that career switch of sorts to be really inspiring—especially given that I left medicine for biotech.

4. What was your first operational role at Exonics like?

MPM is a great place to train. But like a lot of venture funds, there's not really a defined path to partnership and they are pretty clear about that. So, I kind of knew that I eventually would have to look for other opportunities. A patient advocacy group called Cure Duchenne, actually reached out to me.

They had just made a little bit of money investing in a company called Prosensa, which was acquired by BioMarin. This was one of the first antisense oligonucleotide (ASO) plays. And I had been doing some work on Duchenne at MPM. What struck me is it was very similar, at least from a pathogenesis perspective, to cystic fibrosis—DMD is also a monogenic disorder. Now, there were lots of different places in the gene where you could get the mutation, and the location drove clinical variability. But like CF, it was very simple to understand the root genetic cause of why people develop Duchenne.

But there wasn't really a strong foundation for DMD, like there was with the CF foundation. So, I worked with Cure Duchenne to come up with a venture philanthropy model that would allow us to raise money from philanthropic sources, invest in companies and then, put the returns back into the space. Before I started Exonics, I actually led an investment in a company called Bamboo Therapeutics, which was one of the spinouts from AskBio—Sheila Mikhail and Jude Samulski were the principles there.

And Bamboo is probably one the best deals I have worked on. I did some diligence, but Sheila was really doing everything from an operations perspective and I got to see what high quality operators look like up close. With Cure Duchenne, we invested about $2 million, and then Pfizer bought the company about 7 months later—so a 5x return in 7 months, which is pretty great. But this experience gave me a lot of confidence that I knew how to pick a winner.

And then I was lucky enough to get introduced to Eric Olson at UT Southwestern. And he was just about to publish a paper showing he could effectively do what BioMarin and Sarepta were trying to do—create an exon skip—but instead of using an ASO, you could use CRISPR to permanently disrupt the site. He had shown this in mice and then ultimately in dogs [King Charles Cocker Spaniel model] with DMD.

So, I started the company with Eric and pulled in some IP from his lab and raised some money from the Duchenne Foundation. A really important thing we did was to get an exclusive license on a new dog model of the disease—previously most of the Duchenne dogs were golden retrievers, which I think had mutations in exon 4. The King Charles Cocker Spaniel, which we used, is one of the only dog models where the mutation is in the same place, exon 51, as in boys.

So, this made the dog amenable to that same approach of targeting in a PAM site with a single cut that could lead to a permanent exon skip for 51. So that was really the only dog model that would work from a translation perspective. However, we didn’t have IP around Cas9 so when the company was acquired by Vertex, we had to pay 100 million to CRISPR Tx, for the rights to the Cas9. But, we did have probably the most important translational disease model out there.

[On his transition to Leaps by Bayer]

When I was introduced to Bayer, I was actually pitching to them for CytoSen. And they just raised or created this new entity called Leaps. They sold me on this grand vision of having billions of dollars to invest off the balance sheet of Bayer, really intended to help academics, entrepreneurs, and people with a vision for how to improve human health. And I always thought that's the way biotech should work—the Eric Olsons and the Phil Greenbergs of the world are really the people driving most of the success in biotech. The venture folks are more like insurance underwriters. We're coming in, repricing and risk adjusting, but the actual foundational work is still mostly done in the academic setting. What I found at Leaps was a real home and remains, other than Affini-T, the best job I've ever had.

5. How did the founding of Affini-T take and come together?

What we were able to do at Leaps is work with lots of different physicians, scientists, entrepreneurs, and I was lucky enough to get to know the Fred Hutch a little bit through another deal. We wound up not investing in that other company, but I kept a good relationship with the tech transfer folks there. When Phil Greenberg  started pulling out these TCRs that recognize KRAS, they gave me a call, let me get into the data room and start to talk to Phil.

This was right at the beginning of the pandemic. I think I had the hard conversation with my boss Jürgen Eckhardt at Leaps, probably in July of 2020. I told them this could be the next Juno or Kite, and I felt compelled to do this. Jürgen worked with me, and we went all the way up to the head of legal to get permission for me to start the company. Affini-T really grew slowly at first. We started the company in August of 2020, and I raised the first 5 million on Christmas Eve of that year. And then I hired my first employees in March, both from the Hutch—Marty Campbell and Ailsa Dalgliesh—who are both still with the company.

Things just started to pick up from there. We were able to recruit our first C-suite hire Kim Nguyen, who came to us from Precision Bio. Then a month or two later, Loïc Vincent, our CSO joined from Takeda. At this point, I'd already pitched to Vida, and they were on board. So, the whole time you are building consensus, getting the right ingredients, but you don't have everything you need at once. You get a little something here, a little something there, a little money here, some IP there, and then it starts to kind of take shape over time.

I then started talking to Kathy Yi, who was the CFO at Cerevel. She came on full time in January, and that's when I think things really took off.

To Vida’s credit, I had spoken with Arjun [Goyal] and Stefan [Vitorovic], and they encouraged me to raise a significant amount of capital. Vida knows oncology very well, and therapeutic development is expensive. If you don't raise enough money, you don't get to a good value inflection point before you have to then raise more money. With Vida’s support, I went out and raised capital People loved the story. They loved the targets, and they loved our team. But financing in this environment was challenging, and so we felt very lucky in March when we were able to close $175 million. We’ve been off to the races ever since.

We are up to 77 people today and have space here in Boston. We're subleasing our office in Watertown and building a beautiful 40,000 square foot lab that should be done in January. We also have a 12,000 square foot lab in Seattle that was our first location with state-of-the-art equipment and modern furniture to give the space a great feel.

6. What excites you most about working at Affini-T, and what is the real competitive advantage in cell therapy (over other CART and NK cell)?

For me it was the combination of Metagenomi and Affini-T. I found Brian Thomas when he was three people in a WeWork in Berkeley—no data but a couple of sequences they thought might work from a gene editing perspective. But this was before Prime Medicine or Beam were up and running.

I knew that there was a lot more that could be done in the gene editing space. At Affini-T, we are going out and trying to source 3 to 5 billion TCRs from healthy donors and then screen them to find what nature has already solved for. Nature is really elegant at designing systems, and I think we as scientists and clinicians, can be humble about how much we actually borrow from nature. So, I saw some real opportunity here to do something that was different, but not actually that risky.

Working with someone like Phil [Greenberg] gives you a lot of confidence. It made sense to me that if there is a mutation out there, like KRAS, some portion of its going to be processed and presented on the cell surface. Even if you can't see it with mass spec, which has been a big rate limiting step for a lot of people. But if you engineer a good TCR into a T cell, well that kills cancer cells. And Phil was showing me, you know, 7-10 cell lines all being successfully killed with an engineered KRAS TCR. To me, that was the most important dataset, even if you can't see the epitope empirically [by mass spec], we know it's there because the TCRs are working [when loaded onto a CD8 T cell].

And to me that approach was pretty novel and differentiated from what other people are doing. I knew there would be a market and a lot of interest in this type of approach, and then it just made sense to me, rationally—once tumors acquire oncogene drivers like KRAS, they almost never lose them. It is exceedingly unlikely that a tumor cell will lose a KRAS mutation, though it likely develops other mutations. For that reason alone, KRAS is a great target to go after with a TCR. We don't need much of the epitope to be presented. We have found that sometimes even a single copy can induce a TCR to kill. In my mind, it was kind of like a no brainer, and I think Arjun [Goyal] felt the same way.

But there are questions [in the cell therapy space] about durability of response, and persistence of T cells, and our company is trying to address these issues, which have not been addressed yet in some academic studies [or by other companies]. Ultimately, we are focused on product development. How you get something to a commercial product is really the secret sauce—the value that biotech brings is getting great academic work to market—turning a paper into a commercial product for patients. That's really where we can add the most value.

7. Describe Affini-T’s company culture. What are the core values you try to give the team and how do you build this culture?  How was this informed by your prior experiences?

It’s not complicated. Building a good company culture is like laying one brick at a time. You have to make individual decisions over and over again and try to eventually encourage other people to start taking over some of the responsibilities—I’m not the only one laying bricks. From a culture perspective, that's been the real shift for me, because I think in venture and certainly surgery, you're very much an army of one.  Everything has got to run through you, and you are the one making the recommendation or deal, operating or really “doing the thing.” It can be very hard to be hands off and let other people drive things.

This still feels a little bit alien to me, but I had a great coaching session where someone gave me the following advice: most of my career I've been trying to demonstrate that I can create value--I'm a great doctor or great investor. But my job as the CEO is to build an organization that creates value. I need to take myself out of the process as much as possible—one for my own mental health, so I can go on vacation. But two, because that's literally what the shareholders want. They don't want an organization relying on a single individual, with every decision going through that person. Ultimately this model with a supreme ruler at the top is not scalable and I don't think it can be successful. The culture I'm trying to create is one of accountability, but also one of collaboration where people really are pulling for each other.

8. In today’s climate what is one short piece of advice you would give to prospective biotech entrepreneurs.

Starting a company in this type of environment [2022 biotech capital markets] is really challenging, but ultimately going to be very rewarding. You have to make the assessment about the technology, the team, and what you think the marketability of the asset will be. Valuations are coming down, but there’s still a lot of private capital out there. You can still raise in this environment.

I would encourage people to think about: what's the long-term plan? You can raise a few million bucks, but that's not going to get you to a clinical trial or even close to a readout. So, you kind of build in the value inflection points along the way so that you can raise more capital and get to your end goal. I do think the companies that are built and survive in this type of environment will be very successful in the future. There’s an old saying that “tough times breed hard people, and hard people bring good times.” I think this is true for companies—the companies who survive these challenging environments will make biotech better in the long run.