The In Vivo CAR-T Playbook: Differentiating Your mRNA Candidates
By Anna Rose Welch, Editorial & Community Director, Advancing RNA
It never ceases to amaze me how markets take shape, grow, and evolve. Every market has peaks and valleys, but I’d argue there have been more peaks than there have been valleys in the mRNA space thus far.
Of course, over the past few years, we’ve faced big challenges on the policy front. But since COVID, we’ve seen mRNA get its fair share of attention — the majority of which has been positive. Linear mRNA was the industry (and world’s) hero (at first) thanks to its vaccination prowess. Circular RNA followed in linear mRNA’s footsteps, with many being drawn to the promise of enhanced expression. But most recently, I think it’s safe to say that 2025-2026 were the years in vivo CAR-T became the pharma industry’s/ATMP sector’s darling, with several RNA candidates (linear & circular) garnering huge Big Pharma buy in.
There are a lot of reasons why we can look at this rush as a great thing; on the one hand, it promises a more streamlined approach to cancer and autoimmune disease treatment than autologous CAR-T does today. Likewise, it enables each CAR-T modality — both viral and nonviral — the opportunity to continue defining its clinical value proposition in the cancer and autoimmune spaces.
However, as we also explored in my previous article, this is an increasingly crowded space, making it particularly challenging for young biotechs to compete for funding and for patients to enroll in clinical trials. In turn, this places additional pressure on biotechs to differentiate to make their products stand out in the eyes of investors, potential pharma partners, and physicians/patients.
Fortunately, as my conversation with ParcelBio CEO David Weinberg emphasized, there’s still a lot of room to grow in terms of what our RNA-based products can be and how they can perform. Here in part 2 of this two-part article, Weinberg walks me through how ParcelBio is approaching this market and helping define what a competitive mRNA product will look like in the in vivo CAR-T space.
Best Practices for the In Vivo Era: Manufacturing Simplicity and Indication Selection
In the past few years covering the ATMP space, I’ve come across several best practices that cut across any modality — be it a cell, gene, or mRNA therapy. But there are two that Weinberg emphasized throughout our conversation that have been guiding principles behind the building of ParcelBio and its goals for developing more differentiated in vivo CAR-T candidates:
- Start with the end in mind: Broadly speaking, the cell and gene therapy sector learned the hard way that manufacturing cannot be an afterthought. In the RNA sector, we haven’t necessarily encountered the high-profile regulatory CMC challenges that cell and gene therapies did a few years ago — at least not yet. But having come from an academic background, Weinberg was particularly sensitive to the fact that lab-scale innovations do not necessarily transfer to a GMP platform in a CDMO facility. He pointed to many of the innovations that have been explored to improve mRNA’s stability — for example, decorating an mRNA with multiple caps or tails.
“You have to take off your academic hat and put on your drug making hat and ask, ‘How do you actually make that drug at gram scale?’” Weinberg offered. “This has been one of my biggest learnings launching a new biotech: To think about manufacturing when it’s not necessarily natural as a platform scientist to think about that from day one.”
There’s also something to be said about the choice to work with linear mRNA as opposed to working with next-gen constructs. Linear mRNA enables companies like ParcelBio to take advantage of existing infrastructure, unlike circular RNA for which the analytical and manufacturing paradigms remain somewhat “wild west”- ish.
“One of the key focus areas we had as we developed this platform was it had to be super simple,” Weinberg explained. For one, ParcelBio’s APEXm™ molecules are capped and tailed linear mRNA made with N1-methylpseudouridine — the same format as the COVID vaccines. In turn, the same CDMO processes, analytics, and quality attributes apply.
“‘Super simple’ also means that you can go to a CDMO with a track record of making mRNA and tell them to do what they do best, which is making mRNA under GMP conditions. This way, we don’t have to invest in novel manufacturing, and we’re relying on the same chemistry the field has already validated in hundreds of millions of people.”
- Select your indications carefully: This is a best practice we’ve heard prescribed many a time, but for many reasons — be it biology, patient need, and/or risk aversion — we often find that some indications get more attention than others. This has certainly been the case in the autoimmune CAR-T space, in which many of the in vivo CAR-T candidates in question are targeting CD19. Likewise, as Weinberg explained in part one, the autoimmune space continues to grow more crowded as RNA candidates transition from oncology to autoimmune diseases and competitor biologics (e.g., T-cell engagers) enter the clinic and market. This market growth demands smart indication selection, as well as product differentiation to best compete.
Weinberg is also quick to note that “autoimmune” is not one market. B cells drive dozens of distinct diseases — lupus, myositis, systemic sclerosis, myasthenia gravis — each with its own patients, endpoints, and tolerance for side effects. “There’s room for many drugs, each tailored to a specific patient population,” he said.
As such, there still is plenty of room to play in the RNA space, seeing as many candidates are conventional linear mRNA molecules that require high and frequent doses.
“Many of the RNA candidates in development are all slightly different flavors of the same thing,” he said. In turn, this leaves room for mRNA players to innovate on the molecule itself, particularly to reduce dosage amounts and frequency.
As he went on to explain, we saw a great case study emerge earlier this year at ASGCT. The first clinical data for an mRNA-based in vivo CAR-T, which was published in September 2025 in the NEJM, demonstrated first and foremost that the mRNA-based in vivo CAR-T technology works in humans.
“You can make CAR-T cells in the body, and the B cells in the blood are immediately depleted,” Weinberg explained.
However, his biggest takeaway from the data was the field’s need for a more potent, more durable molecule, especially considering we’re still not seeing complete depletion of B-cells in the lymph nodes.
“Lymph nodes are the hardest to deplete,” he contextualized; “That’s why the bar for efficacy is complete B-cell depletion in the lymph nodes. The preclinical and clinical data for conventional mRNA so far shows we’re not getting complete lymph-node depletion in every subject, even with relatively high and frequent doses.”
For example, in vivo CAR-T candidates today typically require repeat dosing — often several infusions spaced across consecutive days. In turn, Weinberg hypothesizes that candidates capable of reducing the dosing burden stand to be more competitive for a number of different reasons, including safety and patient centricity.
“This data — especially the dosing regimens that the field is working with today — suggests there’s still an opportunity for a better mRNA to come in and address this unmet need,” he concluded — “particularly if we’re able to reduce to one or two short infusions.”
So, what does a better mRNA look like? ParcelBio’s answer, APEXm™, is an mRNA engineered to produce more protein for longer while keeping the modified linear format the field already knows how to make and dose safely. In the in vivo CAR-T setting, that means more CAR and a longer expression window from each dose — the levers needed to reach residual B cells in the lymph nodes while easing the dosing burden.
“Our goal is durable, drug-free remission through deep depletion, with a regimen that’s simple for patients and with an RNA that’s simple to make,” Weinberg said. “That’s what a competitive mRNA looks like.”
Miss part 1? You can check it out here!