Scientists create CAR-T cells directly inside the body for the first time: a new method in mice eliminated leukemia, multiple myeloma, and sarcoma
For years, one of the biggest problems of modern cancer immunotherapy has not been only medical, but also logistical. CAR-T therapy, one of the most powerful treatment methods for certain hematologic malignancies, is currently generally manufactured separately for each patient: doctors first isolate the patient’s T lymphocytes, cells of the immune system that can attack the disease, then send them to a specialized laboratory where they are genetically re-engineered, after which the prepared cells are returned to the body. Such a procedure can save a life, but it takes weeks, is very expensive, and is not equally accessible to all patients. That is precisely why a new paper by scientists from the University of California, San Francisco, published on March 18 in the journal Nature, has attracted great attention: the researchers claim they succeeded in doing what until recently seemed like a distant goal, namely creating antitumor CAR-T cells directly inside the body.
In experiments on mice with humanized immune systems, the new approach led to the elimination of aggressive leukemia, multiple myeloma, and sarcoma. This is a preclinical study, which means the method has not yet been tested in humans and still has a long road ahead before any possible clinical application. But the importance of the results lies in the fact that the team showed it is possible to insert a larger DNA sequence very precisely into an exactly defined place in the genome of human T cells, without removing those cells from the body. In the field of cell and gene therapy, this is considered one of the key technical challenges, which is why interest from the professional community is high even beyond oncology itself.
Why CAR-T therapy has so far been powerful, but hard to access
CAR-T therapy is based on a simple idea with a very complex implementation. T lymphocytes are genetically given instructions to create the so-called chimeric antigen receptor, or CAR. This receptor enables T cells to recognize precisely defined targets on the surface of tumor cells and then destroy them. The U.S. National Cancer Institute states that since 2017, CAR-T therapies have become an important part of treatment for certain leukemias, lymphomas, and multiple myeloma, while the U.S. Food and Drug Administration currently lists seven CAR-T products for various hematologic malignancies among its approved cell and gene therapies. At the same time, the FDA reminds that these therapies are still administered with strict safety monitoring because of potentially serious side effects, including cytokine storm, neurological complications, and long-term monitoring of the risk of secondary malignancies.
Despite impressive clinical results, the current production model has serious limitations. Each preparation is made individually from the patient’s own cells, and the entire process requires specialized centers, laboratory infrastructure, and time that is often not an ally in aggressive diseases. An additional problem is that before infusion, patients usually undergo preparatory chemotherapy to make room for the new cells, and some cannot tolerate that well. That is why interest has grown strongly in recent years in so-called in vivo CAR-T, an approach in which T cells are not re-engineered outside the body but inside it. Back in 2024 and 2025, Nature warned that such a direction of development could radically change the accessibility of therapy, but also open up an entirely new generation of precise gene interventions in specific cells.
What exactly the UCSF team did
The team led by Justin Eyquem at UCSF developed a system of two particles. The first carries the CRISPR-Cas9 gene-editing tool, often described as a kind of molecular scissors, and delivers it to T lymphocytes circulating through the body. The second carries a new DNA instruction for an antitumor CAR. According to the available descriptions of the work, the key to the entire system is not only delivering the genetic material to the right cell, but also inserting it into a predetermined place in the genome, instead of letting it end up at a random location.
This is important for at least two reasons. The first is safety: with random integration, there is a possibility of affecting a part of the genome that should not be touched, which in rare cases can create additional problems, including secondary malignant changes. The second is functionality: when CAR is inserted at a precisely selected site, its expression can be regulated more naturally, which potentially improves the behavior of the cells obtained in this way. In a statement published by Azalea Therapeutics, a company created on the basis of this research platform, it is stated that the promoterless CAR is inserted into the TRAC locus, that is, into the genomic location associated with the alpha chain of the T-cell receptor, thereby achieving physiologically regulated CAR expression. In other words, the researchers did not only try to produce as many re-engineered cells as possible, but also to make them behave more closely to what the immune system could maintain in a stable and long-term way.
The researchers also had to solve an additional problem of selectivity. When cells are edited in the laboratory, it is possible to verify whether exactly the cells intended to be changed were changed. In the body, such control is significantly harder. That is why the approach was designed from the beginning so that the particles target T lymphocytes and avoid rapid elimination from the body. According to the description of the preclinical results, precisely the ability of the system to reach the right cells without affecting unwanted targets is one of the main advantages of this platform compared with earlier attempts at an in vivo approach.
Results in mice: rapid tumor clearance and an unexpected plus
In models of aggressive leukemia, a single injection of the two-component system eliminated every measurable trace of cancer in almost all mice within two weeks, according to the description of the study and accompanying reports. CAR-T cells created inside the body made up a substantial share of immune cells in certain organs and eliminated the disease from the bone marrow and spleen. The same approach also showed an effect in multiple myeloma, a malignant disease of plasma cells, but also in sarcoma, which attracted particular attention because solid tumors have so far generally represented a much more difficult terrain for CAR-T therapy than hematologic malignancies.
An important detail is that the cells produced inside the body, according to the authors, in some characteristics appeared even higher-quality than those produced in the laboratory. The researchers’ assumption is that during manipulation outside the body, T cells may lose part of their so-called stemness and proliferative potential, that is, their capacity for longer-term expansion and maintenance of the antitumor effect. If that impression is confirmed in further research, it would not only be a simplification of production, but perhaps also a biological advantage of the approach itself. This is precisely one of the most striking messages of the work: the new technology promises not only faster and cheaper therapy, but potentially a functionally better one as well.
Still, this remains a preclinical finding. Mouse models, even those with humanized immune systems, cannot fully predict what will happen in humans. The history of drug development is full of examples in which encouraging results in animals were only the first step, and later it turned out that safety, dosing, durability of effect, or side effects in humans opened entirely new questions. Because of this, it is necessary to avoid an excessively triumphalist tone: this is a serious scientific advance, but not a therapy ready for routine clinical use.
Why precise gene insertion matters more than speed alone
In previous CAR-T approaches, much of the attention was focused on how to produce therapy quickly enough for a severely ill patient. This paper shifts the discussion one step further, toward the question of how to do it more precisely and safely. CRISPR-Cas9 was not used here only as a tool for "cutting" the genome, but as part of a system by which a large DNA sequence is introduced into an exactly planned location. In the field of gene therapy, such control is crucial because the difference between random and targeted integration can mean the difference between a variable and a more predictable biological response.
This is also the reason why this result has broader significance than oncology alone. If it turns out that larger genetic payloads can be selectively and stably inserted into desired cells inside the body, similar concepts could one day be adapted to other diseases in which immune or other cells need to be re-engineered without a complex laboratory process. Nature and other expert sources have for some time described in vivo cellular engineering as a possible new frontier of cell and gene therapies, precisely because it combines the precision of molecular biology with the ambition to transform complex personalized procedures into more broadly available medical platforms.
Could this really mean cheaper and more accessible therapy
One of the most important reasons why this publication resonated so strongly is not only its medical potential, but also the question of accessibility. Today’s CAR-T procedures are tied to large oncology centers and expensive manufacturing chains. This creates a difference between patients who can get therapy in time and those who, because of geography, finances, logistics, or their general physical condition, do not have that possibility. In the summer of 2025, when abolishing the mandatory REMS program for part of autologous CAR-T therapies, the FDA openly said it wanted to reduce the administrative and organizational burden and speed up access to potentially curative treatments. But even without that regulatory easing, the fact remains that the production of current CAR-T preparations is itself complex and expensive.
That is why researchers and companies working on the in vivo approach often use the comparison with ready-made, "off-the-shelf" therapies. The idea is not that such a procedure would literally become as simple as a vaccine tomorrow, but that a standardized system could be applied without individual multi-week manufacturing for each patient separately. If that goal were achieved, it would theoretically shorten waiting times, reduce costs, and open up the possibility for therapy to be offered by hospitals that currently do not have the full infrastructure for the classic CAR-T process. In healthcare systems with limited resources, that would represent more than technological progress: it would be a possible step toward fairer access to advanced cancer treatment.
Experts’ caution: the road to humans is only beginning
As impressive as the results sound, the next phase will be the hardest. The transition from a preclinical model to trials in humans opens several groups of questions. The first is safety: it must be shown that the system truly does not alter unwanted cells and does not cause harmful immune or genetic consequences. The second is dose control: it matters how many new CAR-T cells will be created, how long they will persist, and whether their activity will be strong enough to destroy the tumor without causing excessive toxicity. The third is reliability: a preclinical model may be neatly optimized, while in real patients there will be great diversity of tumors, prior therapies, and immune system conditions.
It is already known that the platform is being translated toward clinical development through Azalea Therapeutics, a company that, according to publicly available data, was co-founded by some of the authors of the paper, including Justin Eyquem, Jenny Hamilton, and Jennifer Doudna. This is a common path in biomedicine: an academic discovery moves into biotechnology development in order to secure the capital, regulatory work, and manufacturing infrastructure needed for clinical trials. Such a model can accelerate the arrival of a technology to patients, but it also increases the need for careful, independent monitoring of results in later stages of development, especially when it comes to a platform that affects the genetic regulation of living immune cells.
What this paper means for the future of cancer treatment
The most important message of the new paper is not that cancer has suddenly become an easily solvable problem, but that the boundaries of what is technically feasible in immunotherapy are shifting again. CAR-T therapies have already changed the outlook for some patients with leukemias, lymphomas, and multiple myeloma, but they have remained therapies of high complexity, high cost, and limited accessibility. If it turns out that T cells can be precisely programmed directly in the body, without individual laboratory manufacturing, then a new era of cell therapy could open in which top-tier personalized biology would be combined with significantly simpler administration.
It is particularly interesting that the authors also showed an effect in a sarcoma model, because solid tumors continue to represent one of the biggest obstacles for CAR-T platforms. That in itself does not mean the problem has been solved, but it suggests that the in vivo approach may not remain limited exclusively to hematologic malignancies. In the best possible scenario, this paper could one day be remembered as the moment when CAR-T therapy began to move out of the narrow framework of a complex hospital "handcrafted" procedure and toward a more broadly applicable precision medicine platform. For now, however, this is a promising scientific step whose real value will have to be confirmed through strict clinical trials, regulatory oversight, and reproducibility of results outside laboratory conditions.
Sources:- Nature – news about the development of an approach by which CAR-T cells could be created directly inside the body, with an overview of the scientific and clinical context link
- Nature – expert overview of the development of in vivo CAR-T approaches and the entry of such platforms into clinical trials link
- National Cancer Institute – explanation of how CAR-T therapy works and for which hematologic malignancies it is used link
- FDA – official list of approved cell and gene therapies, including approved CAR-T products in the United States link
- FDA – announcement on regulatory changes for autologous CAR-T immunotherapies and a reminder on the safety monitoring of those therapies link
- FDA – approval of a new indication for Breyanzi from December 2025, as an example of the further expansion of CAR-T use in hematologic malignancies link
- Azalea Therapeutics – announcement about the paper published on March 18, 2026, and the technical features of the platform for precise in vivo insertion of CAR into the TRAC locus link
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