Inside the In Vivo CAR-T Boom: Where Does mRNA Fit In?

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

If there was one industry sector that knows just how much can happen in a single year’s time, it would be the mRNA industry. Obviously, the path from 2025 to 2026 was buffeted by political headwinds. However, not everything was hellfire and brimstone; in parallel, we also saw great faith being placed in mRNA’s next-generational therapeutic potential. One of these areas was in vivo CAR-T. 

The $2.1 B acquisition of Capstan kickstarted what turned into a Big Pharma in vivo CAR-T buying frenzy. BMS bought Orbital; Eli Lilly snagged Orna; and most recently Johnson & Johnson joined the melee, paying Sail Biomedicines $785 million in an agreement that could lead to an acquisition. And these are just the RNA-based in vivo CAR-T deals.

According to recent BCG research, there are 140 in vivo CAR-T cell therapies in animal and human testing globally — with 82% of these candidates being developed in China. We can certainly anticipate that the number of products in development will keep growing as new companies launch and existing companies broaden their pipelines to include in vivo CAR-T approaches. Moderna’s (well-named) “007” and Cartesian’s partnership with the Chinese company WestGene are great examples of how current mRNA players are looking to augment their current platforms.

However, we’d be remiss if we didn’t take a closer look at the newcomers to the block. One such newcomer this year was ParcelBio, which came out of stealth boasting its APEXm™ — Amplified & Prolonged EXpression mRNA — platform to confront the durability challenges we’ve been facing with linear mRNA. The company’s lead candidate is an in vivo CAR-T for the treatment of B-cell-mediated autoimmune diseases.

I had the chance to sit down with ParcelBio’s CEO David Weinberg to learn more about the emerging market dynamics in the in vivo CAR-T space, with a particular focus on the challenges facing RNA biotechs looking to navigate this up-and-coming therapeutic class. Part 2 will provide a closer look at how mRNA can start to differentiate itself in this increasingly crowded landscape.

Finding mRNA's Sweet Spot in an Escalating In Vivo Race

As we all know, mRNA is not the only pony in the in vivo CAR-T “race;” several of the deals last year were for companies looking to utilize lentiviral vector approaches — an area which Weinberg emphasizes is worth watching, particularly in the oncology space. In fact, he sees viral-vector and gene insertion-based technologies being particularly well-suited for oncology given that it generally requires a more durable CAR-T-cell population.

“We’re seeing a nice division between the transient mRNA space focusing on autoimmune, and the more durable lentiviral-based approaches focusing on cancer,” he pointed out.

This “nice division” of the market aside, it’s not necessarily going to be an easy journey ahead for biotechs entering the in vivo CAR-T ring in any indication — but particularly in the autoimmune space. When I asked Weinberg the greatest challenges in navigating the in vivo CAR-T space, he pointed to three specific challenges — starting with clinical development. As we can all presume, the rise in investment and the sheer number of clinical candidates raises questions about the feasibility of patient recruitment.

As Weinberg explained, the autoimmune in vivo CAR-T space isn’t just growing increasingly crowded with lentiviral and mRNA-LNP players; there are also other modalities — namely T-cell engagers and FcRn inhibitors — which are also competing for patients with autoimmune diseases. Obviously, this is great news for patients — “There will be so many fantastic modalities to choose from,” Weinberg said — but it poses an operational challenge for companies trying to run an efficient and adequately sized clinical trial.

Secondly, such market crowding also makes the funding landscape even more precarious. As Weinberg explained, a chunk of the investor population was pro “Team T-cell engagers” and was skeptical as to what mRNA-LNPs could add to the therapeutic equation. Others were already invested in the in vivo CAR-T space.

“What’s interesting is that a lot of the early investors got into mRNA-based CAR-T autoimmune assets by investing in companies that were originally working on an mRNA-based in vivo CAR-T for cancer but then pivoted to autoimmune,” he clarified, a detail hearkening back to the seeming viral vs. nonviral modality split emerging between oncology and autoimmune disorders.

In combination, these market challenges speak to perhaps the greatest challenge of all, and that’s answering the question of “why mRNA” in the in vivo autoimmune space.

“I think there’s an appreciation that linear mRNA can do certain things that other modalities can’t,” Weinberg said. “The challenge is that a lot of companies still want to wave the flag that RNA can do everything. We don’t think mRNA is universally the best modality for everything, so we’re really focusing on the particular applications where mRNA really has that differentiation against other modalities,” he added.

In fact, he sees the autoimmune space to be a great place for mRNA-LNPs to differentiate themselves, given the sheer number of autoimmune diseases and the fact that they all differ — both in disease characteristics and therapeutic needs. Not to mention, there remains a decent amount of room to innovate, simply because so many players are currently focused on the same target: CD19.

“There’s room for many winners here because there are so many autoimmune diseases, and what works best in one won’t necessarily be best in another,” he said.

As was mentioned above, CAR-T products aren’t the only options for patients; as Weinberg acknowledged, T-cell engagers are doing some “heavy lifting” on peripheral B-cell depletion. However, clearing B-cells from the blood isn’t enough to promote durable, drug-free remission; they must also be depleted in the lymph nodes.

“CAR-T cells, which traffic into these tissues and further expand there, may have a real edge,” he added.

He also called attention to mRNA’s transience, a characteristic that would be particularly beneficial in autoimmune diseases where long-term B-cell aplasia is a risk. However, as we also know, conventional linear mRNA has yet to break durability records — a fact necessitating higher and/or more frequent dosing. 

“Getting more CAR expression for longer from each dose is the core challenge facing the mRNA-based in vivo CAR-T sector — and that is exactly what we’ve built our APEXm platform to do,” he concluded.

My conversation with Weinberg will continue in part 2, within which we’ll discuss the factors that can make an mRNA-based in vivo CAR-T more differentiated/competitive. Stay tuned!