“Efficacy with safety”: the north star behind Outpace’s next-gen engineered cell therapies

Could you start by giving our readers a bit of background about your career journey, who you are and what experiences led you to found Outpace Bio?

I've always known I wanted to go into drug design, even before I knew what that really meant. In college, I had a bit of a winding path, where I split time between the engineering school, where I really fell in love with biotechnology research, and the chemistry department, where I was doing organic synthesis for anti-cancer drugs.

What really hooked me was biology’s self-renewal - the idea that systems replicate, evolve, and optimize. At the same time, I loved the atomic precision of chemistry. So, I took both of those threads into grad school. I did my PhD with George Church at Harvard, working on genome engineering - reassigning the genetic code in E. coli and building a lot of foundational technology.

Around that time, I launched my first company, GRO Biosciences, using the reassigned genetic code to incorporate unnatural amino acids into better protein therapeutics. But I realized I was more excited about designing new biological functions. And proteins - not genomes - are the biological unit of function. So, I knew I had to learn protein design.

That brought me to David Baker’s lab in 2014. You probably know David from his Nobel last year - which was a pretty exciting time. When I joined, we could design proteins that folded into the right shape - but they didn’t do anything. I teamed up with my now co-founder, Scott Boyken, and we figured out how to design moving parts and precise interactions, which allowed us to build function from scratch.

Then we started working with Stan Riddell, who is one of the fathers of the chimeric antigen receptor T cell (CAR-T) field, and a co-founder of Juno. His lab developed the construct that became Breyanzi, so he’s already had a huge impact for patients. That collaboration led to Lyell Immunopharma, where I spent two years building the early pipeline and laying the foundations for what would become Outpace.

Eventually, it became clear that we needed to spin out the technologies that we were developing to properly resource them, and that gave us a clean slate to build a more advanced pipeline. That’s when things really took off.

Can you give a more detailed overview of what Outpace is working on and how it can benefit patients?

Just to set the stage: with the second-generation CAR-Ts developed by Juno, Kite, and Novartis, people were like, “Holy crap - we're curing patients!” That led to a wave of investment focused mainly on scalability. The thinking was: “Cancer’s cured. This stuff’s just expensive. We just need to scale it.”

But our view, from day one, was that efficacy is still the core problem. Efficacy always goes hand in hand with safety, especially in oncology.

So, that’s been our north star at Outpace. The central question we’re focused on is: how do you take the kind of curative efficacy we see in certain blood cancers, and bring that to the other 95% of cancers, especially solid tumors?

We think our advantage comes from the AI-powered protein design technologies that Scott and I have been developing along with our teammates, Brian Weitzner and Bobby Langan for over a decade. We’re a team of Baker Lab alums who’ve stayed at the cutting edge of this field.

We’re applying that technology to solve biological problems that people have known about for a long time, but no one has been able to design the right proteins to solve them. What’s unique about cell therapy is that the barriers to efficacy in solid tumors are understood. The problem isn’t identifying targets; it’s building molecules that can overcome those barriers.

That’s a sweet spot for our platform. And now, we’re on the cusp of treating our first patient in our first clinical trial. It’s a really exciting time.

What technical or scientific advances, in the past year, have had the biggest impact on Outpace’s progress?

It’s funny, because we get lumped in with cell therapy companies more than with AI-powered protein design groups. But there are a ton of companies raising massive rounds based on that AI protein design promise. What’s different for us is that we’re very clear on what the problem is, how we’re solving it, and what drug comes out of it.

We went back to first principles and asked: what do T cells need to do in solid tumors to be effective?

There’s a lot of clinical data here. In blood cancers, the patients who achieve durable complete responses have long-term functional persistence of their T cells - months to years after treatment. In solid tumors, the cells vanish in about a month. Even when there’s an initial response, it doesn’t last. Often, there’s not enough tumor shrinkage to even qualify as a clinical response.

So, we asked ourselves as to how we change that? We need those cells to persist, long-term, in solid tumors. That means they need to travel into the tumor, survive, expand, stay functional, and overcome antigen escape, which is a bigger issue in solid tumors.

Rather than trying to build one silver bullet, we designed targeted solutions to each of those problems. We then combined those into a single nucleic acid payload, so we can manufacture a simple cell product. The output isn’t a new manufacturing method that produces more stem-like T cells - it’s a smarter, more functional engineered cell that retains the benefits of stem-like T cells in vivo.

Our lead program, OPB-101, is a mesothelin-targeted CAR-T. It carries four technologies to enhance function, prevent exhaustion, resist checkpoint suppression, and expand without triggering terminal differentiation. In doing this, we’ve overcome some of the classic challenges with molecules like interleukin-2 (IL-2) in a way that can only be accomplished with protein design rather than protein engineering.

The preclinical data has been outstanding. We’re seeing cell persistence in animal models over several months of tumor challenge. That’s never been achieved before.

Our second program is a T cell receptor T cell (TCR-T) therapy targeting PRAME to treat endometrial and ovarian cancers. We’ve minimized correlated pipeline risk by using different modalities targeting different antigens in different indications using different technologies. One of the most exciting results was that we’ve been able to achieve cytokine-independent expansion, which typical TCR-Ts can’t do.

What cost improvements are needed, industry-wide, to make next-gen engineered cell therapies more scalable?

First of all, for OPB-101 and OPB-2011, we focused on efficacy and safety over scalability. Those are prerequisites. If you don’t have efficacy and safety, it doesn’t matter how scalable your process is.

Now that those programs are moving into the clinic, scalability becomes real. That’s why our third program is tackling it directly.

To that end, let’s focus on scalability over cost. Cost definitely matters. But even if you had unlimited money, you’d still hit barriers for scaling manufacturing and clinical access of autologous cell therapies. The core problem for manufacturing is that each dose is made one at a time. The whole pharmaceutical model is built on large-batch production; you make a huge run, vial it, and ship it. That doesn’t work for autologous.

The core problem for clinical access is that we are going to rapidly run out of beds in tertiary treatment centers if we don’t figure out how to improve safety and bring these therapies into community clinics. To do this, we need to eliminate lymphodepletion and reduce toxicities like CRS and ICANS.

There are three approaches: The first is to miniaturize doses to allow parallelized autologous manufacturing - companies like Cellares are working on that. Secondly, develop allogeneic therapies - but immune rejection is still a major unsolved biological problem. The third approach is to deliver the transgene directly to T cells in vivo.

In vivo CAR-T is super exciting. You can dose it off-the-shelf. You don’t need to lymphodeplete, which means you can potentially treat patients in community clinics, and not just at academic centers. It could massively expand access.

It moderates costs, and if it delivers durable complete responses, it’s actually extremely cheap compared to the long-term costs of managing cancer, today.

Which internal milestones matter most for Outpace, heading into your next raise?

Clinical proof of concept - 100%.

That’s where we are now. OPB-101 and OPB-201 are clinical stage programs.

We’re about to find out whether our hypotheses are correct. Preclinical models are always approximations. We’ve done our best at modeling human biology, but at some point, you just have to go into patients.

Looking ahead to 2026 and beyond, what are the biggest CEO-level challenges?

If our programs work, then we scale fast into pivotal trials and towards commercial readiness. That’s a massive lift.

It’s not just about advancing those assets. We also need to figure out pipeline prioritization. Our antigens are expressed across many solid tumors, so we’re thinking about basket trials and broader indication expansion. At the same time, we’re developing OUTDRIVE, which is our in vivo CAR-T platform.

If we can prove efficacy in solid tumors and show scalability in hematologic malignancies, we could really bring something transformative to patients.

Would you consider commercializing OPB-101 or OPB-201 yourselves, or would you look to partner or out-license?

Our long-term goal is to develop drugs that cure patients. And launching a commercial therapy is a huge undertaking.

We’re certainly prepared to advance these programs ourselves, but it’s unlikely we’d take all three programs forward ourselves without considering some help. Partnering makes a lot of sense, especially in today’s funding climate. Pharma knows how to run pivotal trials and launch products.

And if BMS were listening?

We know those guys, and they have been incredibly supportive of Outpace. I think the whole field is just waiting. There’s been a decade of overpromise, after the success of Breyanzi and Yescarta. There have been a few bright spots - like Carvykti and anito-cel for multiple myeloma - but no general solution.

If we can show that our next-gen cell therapies drive meaningful efficacy in solid tumors, everything changes. And then scalability of in vivo CAR-T drives widespread adoption.  Our field is in a moment like monoclonal antibodies were in the ’70s.

Initially, you had recombinant insulin, which was life-changing for some, but narrow. Then came monoclonals, and suddenly, you could treat “everything”.

Early antibodies had poor yields, awful cost of goods sold (COGS), immunogenicity issues, safety issues, and so on. But people made it work because the outcomes were transformative for patients. The same thing could happen here, and that’s where we think that cell therapy is headed.

We just have to prove it first.

What questions should we ask Marc next? Let us know in the comments.