By Yifan Chen, MD, PhD, Medical Director, Novotech
Dr. Yifan Chen is a Medical Director at Novotech with extensive experience in clinical development and translational research across oncology, hematology, and advanced therapies. She is committed to bridging scientific progress and patient impact in the evolving field of advanced medicine.
CAR (Chimeric Antigen Receptor) T-cell therapy has reshaped what we expect from engineered immunity in cancer. The first wave demonstrated that with the right target and disease context, deep and durable responses in hematologic malignancies are achievable.
The question now is different. Control has become the most vital element of CAR technology. This next challenge asks if we can turn CAR therapies into a repeatable, scalable platform that works beyond the most tractable biology, into solid tumors and even non-oncology indications, without becoming unmanageable for sites, payers, and regulators?
I hear less awe and more pragmatism in conversations today. People ask whether we can treat patients faster, run studies reliably across centers, and expand beyond a narrow set of targets without building programs that only a few institutions globally can execute.
The pressures that define “next-generation” CAR
Behind the branding, the pressures are consistent.
Teams are trying to:
- Improve safety, particularly cytokine-driven toxicity
- Tackle solid tumors with hostile microenvironments and imperfect antigens
- Address antigen escape and T-cell exhaustion that limit durability
- Simplify manufacturing and logistics, which now shape timelines as much as biology
For me, a “next-generation” construct earns that label only if it changes at least one of these realities in a dependable way, not just in preclinical models and slides.
In vivo CAR: changing the operating model
In vivo CAR is one of the most disruptive concepts in the current pipeline because it alters the operating model, not just the molecule.
Instead of collecting cells, engineering them ex vivo, and reinfusing them, a payload is administered that induces CAR expression directly within immune cells inside the patient. If that process becomes controllable and consistent, it offers shorter time to treatment and fewer manufacturing bottlenecks.
That shift raises harder questions. Where does the payload go? How do we minimize off-target transduction or expression? How durable and controllable is CAR expression? What are the immunologic consequences of repeat dosing? In vivo CAR will not be judged on how complicated or streamlined it is, it will be judged on control.
Non-viral delivery platforms, including lipid nanoparticles carrying mRNA or DNA, are drawing significant attention due to their modular design and potential scalability. Viral vectors continue to play an important role, but in vivo applications can introduce challenges around repeat dosing, immunogenicity, and cost. The key inflection point will be robust human data showing that systemic delivery can reliably reprogram immune cells in vivo with an acceptable safety profile. Once demonstrated, the approach shifts from conceptual promise to a viable clinical development pathway.
CAR Success Story: Autoimmune Disease
If you want to see how far CAR thinking has expanded, look at autoimmune disease.
Most current therapies suppress or modulate activity rather than resetting the system. CAR approaches, particularly those that deplete pathogenic B cells deeply and selectively, offer the possibility of a more profound immunologic reset, followed by healthier reconstitution.
For this to be meaningful, two things need to be demonstrated:
- Depth of effect, biologically and clinically
- Durability beyond early follow-up
Autoimmune indications also force better thinking about endpoints and benefit–risk. Oncology conventions are not always applicable to chronic conditions, and sponsors need to design with that reality from first principles, rather than retrofitting later.
Beyond T cells: CAR as a toolkit
CAR-T will remain central, but it will not be sufficient on its own.
Work in CAR-modified NK cells, macrophages, dendritic cells, and regulatory T cells has moved beyond academic proof of concept. Each cell type brings distinct advantages and constraints: different safety patterns, tissue access, and alignment with disease biology.
Strategically, CAR is becoming a toolkit rather than a single modality. The task is to match effector cell type to indication, patient population, and operational reality.
Smarter targeting and logic gating
Solid tumors are unforgiving when targeting is blunt. That is why logic-gated CAR designs are increasingly a practical necessity rather than a niche curiosity.
By incorporating AND, OR, or NOT logic at the receptor or circuit level, these constructs aim to trigger activation only in the presence of a more specific antigen pattern. Combined with multi-target approaches, this offers a way to manage both safety and antigen heterogeneity. It is not a complete answer, but it is a meaningful step away from “one antigen, hope for the best.”
Keeping programs grounded
One change I see clearly is that operational realism now shapes platform choices from the beginning.
Teams are paying more attention to what centers can realistically deliver, how workflows behave under pressure, and what happens when a program moves beyond a small number of expert sites. Economics enters the conversation earlier, not as cost cutting, but because access and sustainability will determine whether these therapies change routine care or remain exceptional.
If in vivo CAR fulfills its promise clinically, it could alter cell therapy economics precisely because the workflow becomes more direct, with fewer handoffs and fewer points of failure.
Final Impressions
I spend much of my time at the intersection of science and execution, which is where promising programs either stay on track or quietly drift.
At Novotech, we supported the world’s first in vivo CAR clinical trial and have worked on more than 100 advanced therapy studies, including gene therapies and gene-modified cell therapies. We captured some of that experience in the report How In Vivo CAR-T May Reshape Cell Therapy Economics: https://novotech-cro.com/news/novotech-report-how-vivo-car-t-may-reshape-cell-therapy-economics
Those programs make me optimistic, but they also make me very specific about what matters. Site readiness, safety management, technology transfer discipline, and regulatory alignment are not implementation details. They are part of the innovation.
CAR is evolving from a set of breakthrough products into a way of running engineered immunity as an operating model. The groups that succeed will be the ones that pair bold science with platforms that centers, real patients, and real timelines can sustain.