The "Renaissance" Approach To Cell & Gene Therapy Manufacturing

By Anna Rose Welch, Editorial & Community Director, Advancing RNA

A panel at the recently held by BPI Europe posed an intriguing question about the cell and gene therapy (CGT) manufacturing space:

“Is cell and gene therapy really the shiny, bright object on the field that breaks all the rules and disrupts everything? Or is it just an iteration of the same principles that we had before, with slightly different practices?”

Not surprisingly, this question generated a variety of different answers, thanks to the scientific and therapeutic diversity in the CGT space.

At the root of this question, however, I think there is a much broader philosophical question of identity that companies manufacturing CGTs are facing today: should you be approaching establishing your CGT manufacturing platform as a specialist or a generalist (i.e., a Renaissance man/woman)?

We’re all familiar with the concept of the “Renaissance Man/Woman”— someone who is capable of addressing challenges using a multitude of skills and talents. In fact, there have been some notable (non-pharma-centric) articles penned in recent years arguing in favor of being a “Jack of All Trades” or a Renaissance Man/Woman, as opposed to being a “devout specialist.” In the context of the CGT space, however, can there be such a thing as a “Renaissance Company”?

I found myself thinking about this specialist-generalist debate during a recent conversation with Poseida Therapeutics’ newly appointed CEO, Mark Gergen. A few weeks ago, I invited Gergen to sit down with me and a small group of CGT manufacturing experts for a conversation on how C-Suites and manufacturing teams can best communicate to manage risk when navigating unfamiliar manufacturing terrain. (Stay tuned for Part 2!)

But I also appreciated how much of Gergen’s own approach to leading a growing CGT company hearkens back to that Renaissance ideal of being a generalist. Some of the manufacturing challenges this industry faces may be highly specific and require some unique solutions and technologies. As our conversation emphasized, however, keeping a holistic view of the CGT manufacturing paradigms and amassing a broad set of skills, learnings, and technologies in-house can go a long(er) way toward getting these complex CGTs to patients more efficiently.

The Gradual March To CGT Manufacturing Standardization: Developments To Watch

Don’t get me wrong: there’s a lot about the work Poseida is spearheading that is “specialized.” Its pipeline boasts a proprietary gene editing (Cas-CLOVER™) and DNA modification system (piggyBac^®), along with a suite of proprietary CAR-T safety switches and boosting and armoring methods. Though the industry’s cell therapy successes to date have been in the autologous realm, the company made waves last year announcing its strategic shift toward allogeneic cell therapies, which are being heralded as the future of cell therapies. (Poseida still does have one autologous product in its pipeline for solid tumor prostate cancer – although even there the company speaks of learning from autologous and the potential for an allogeneic version to follow.)

Likewise, in the gene therapy realm, Poseida, along with its partner Takeda, have set its sights on solving the challenges associated with using AAV for in vivo (as opposed to ex vivo) gene delivery. This partnership is centered around delivering integrating technologies to permanently correct genetic defects using non-viral delivery (i.e., nanoparticle) technologies. This focus sets the company apart from a majority of the CGT companies today, which are focused on viral vector-delivered gene therapies that are transient in nature.

But while each of these programs/approaches is specialized in its own right, the sheer breadth and diversity of Poseida’s work provides Gergen and the company a much-needed, holistic view of the manufacturing needs for both cell and gene therapies. In fact, as Gergen himself explained, “We view ourselves as a platform technology company, as opposed to a cell therapy or gene therapy company. This gives us a unique perspective because we see all of the pain points and opportunities impacting both cell and gene therapies.”

It goes without saying that this is an exceptionally important viewpoint to have today. After all, this is a niche industry within which the manufacturing paradigm and supportive technologies have a lot of room to grow.

Take, for example, the industry’s push toward developing a broader portfolio of cell and gene therapy technologies. While a lot has been accomplished in a short period of time, many of these earlier technologies still leave a lot to be desired in terms of flexibility and broader applicability. What may be an important tool for the portion of the industry working within the autologous, lentiviral space will not also be applicable to a company focused on a non-viral and/or an allogeneic approach. In other words, for a large portion of the current generation of technologies, specificity has won the day thus far.

But as Gergen put it best, “To successfully reach commercial scale manufacturing, we need to be thinking holistically about the whole manufacturing process from beginning to end. We and others are starting to make a greater push toward fit-for-purpose technology. It is not yet entirely clear yet who has the platforms and the technologies that will win — although we are excited by our approaches.”

No doubt, this end-to-end view of the manufacturing paradigm will only become more central as more CGTs progress farther into Phase 2 and Phase 3 development. Such progression towards the market puts the spotlight more firmly on a company’s manufacturing infrastructure and ability to supply larger patient populations.

But as Gergen sees it, there are a few critical questions that have to be answered first before manufacturing truly takes its place center stage, particularly in the eyes of the investment community.

“We’re currently at a point in the market where everyone is waiting for data on who has the right answer and approach to overcoming the biggest challenges the early market entrants have encountered,” he explained. “Compelling clinical data for both cell and gene therapies — and in more than one indication — will provide us with these answers. Once we start to develop and release that data, the conversation is going to naturally shift to how a company can manufacture that therapy at scale.”  

Additionally, Gergen anticipates more aggressive business development and M&A efforts from Big Pharma will validate certain approaches and provide greater structure and more resources toward manufacturing and supply-chain management. While it may be trickier for the investment community to understand the many scientific — and in turn manufacturing — nuances of companies’ programs, Big Pharma has entire departments dedicated to evaluating and identifying the best technologies and markets to pursue. Such buy-in — especially in early-stage advanced therapy companies — goes a long way toward encouraging the CGT industry at large that the path forward is scalable and that we can overcome one/several of the earlier development and clinical hurdles.

The “Build Vs. Buy” Decision Through A “Generalist” Lens

CGT companies today are under pressure to do a lot of things well. They need to garner enough funding, hire the right talent, produce and share the right data, and get safe and high-quality treatments to patients in a timely manner — and, eventually, at the appropriate commercial scale. But if there was one decision Poseida has made that exemplifies looking holistically at the manufacturing ecosystem and responding accordingly, it was to build a pilot GMP manufacturing facility for its allogeneic programs. 

“Looking back at the past four years I’ve spent at Poseida, one of the best strategic decisions we made was to invest in building our pilot allogeneic cell therapy facility before we even knew that the industry would be gravitating toward allogeneic therapies,” Gergen continued.

The benefits of having in-house manufacturing capabilities are loudly and regularly sung in the CGT industry today. But what was most interesting about Gergen’s build-buy discussion was why the company chose to not build an autologous CAR-T manufacturing facility at a time when it was the “cool thing to do” in the cell therapy space. 

Of course, some of this decision was dictated by the finances; the costs of the square footage, utilities, equipment, and personnel to run a facility are not to be taken lightly. But it’s also important that companies don’t pigeon-hole themselves into a single direction very early on that may not make sense strategically in the long run.

For Poseida, this meant admitting that — even though its autologous pipeline was an important starting step for the company — building an autologous facility would not tie into its long-term goals of transitioning toward allogeneic cell therapies. (For one, the layouts of autologous and allogeneic facilities are drastically different thanks to the latter’s scaling-up, as opposed to scaling-out.)

“Five years ago, we were regularly asked why we weren’t building a facility like a lot of other players in the space,” Gergen said. “But even five years ago, our goal was always to get to allogeneic therapies, which, at that time, weren’t ready for ‘prime time’— or their own facility — yet. We also didn’t want to make a $100 million investment up front to pursue the autologous path if that wasn’t our long-term goal.” In turn, the company made the decision early to lean on CROs and CMOs to develop its autologous product candidates.

Even though the company has since shifted its primary focus in cell therapy to its allogeneic pipeline (and its one remaining auto program), Gergen certainly wouldn’t characterize the autologous development programs as a means to an end. Rather, it was an essential stepping-stone to the next-generation work that the company is doing with allogeneic therapies. “There were so many learnings that came out of our autologous development programs,” Gergen added. “In order to get allogeneic right, you have to undertake autologous development first.” (If you’re interested in reading more about the learnings of moving from autologous to allogeneic, be sure to check out this previous Cell & Gene Collaborative article.)

The Biggest Benefit Of Being A “Renaissance Company”

This industry is seemingly full of either/or battles: Build vs. Buy. Auto vs. Allo. Application-specific vs. end-to-end. At the end of the day, it’s highly unlikely one strategy, therapy type, or technology will be declared the winner. Indeed, my discussion with Gergen was a fantastic example of the value that can come from a company setting its sights on a variety of diverse efforts and approaches in the CGT space.   

When Gergen is asked by investors to defend the company’s decision to focus on a broad array of technologies and therapy types, as opposed to just one, his answer feels nicely akin to a quote from Peter Marks at a recent conference: “If [a therapy] is designed to [reach] 10-20 per 100 million people, any one country won’t have enough patients to sustain commercialization.” As the FDA’s Marks explained, the industry’s foremost goal should be expanding patient access to these essential therapies.

In the same way, Gergen emphasized how taking a broad, well-rounded platform approach to developing CGTs diversifies risk and enables a wide network of partnerships and eventual proof-of-concept data for a larger pipeline. But outside of strategy and risk, Gergen reiterated that being a jack-of-all-trades in the CGT space is essential for advancing manufacturing and efficiently meeting patients’ great needs.

“When I’m asked why we don’t just focus on one program or one technology, I say that it is because the unmet medical need demands that we move multiple technologies forward,” he concluded. “If we do one thing at a time, we will never be able to develop the technology in my lifetime — and to me, that’s unacceptable for patients who are waiting for better options.” 

Be sure to check out part 2 in which Gergen and I delve into the best communication strategies he and Poseida’s manufacturing team have employed as the organization continues to grow its headcount and advance its pipeline.