The company was the first to dose a patient without LD chemo as part of a PhI trial in Australia. Interius, which is studying INT2104 (anti-CD20) in R/R B-cell malignancies, has also received approval to start testing its therapy in Spain and Germany. Before the deal, the company was expected to report its first data later this year (likely ASH). Interius has dosed six patients to date, and the company shared the data it has so far as part of the deal making process.
The abstract shows that all patients (N=3) experienced an MRD-negative response at month one. The patient with the longest follow-up to date maintained the MRD negativity at month three. All achieved a partial response at month one that deepened over time; the best response was a very good partial response (VGPR) at month three. All remain in response without disease progression.
Also, CAR-positive cells comprised 35%, 22%, and 72% of CD3+ lymphocytes on day fifteen showing expansion before. CAR-T cells were detected in the BM and peripheral blood through month three and were comprised predominantly of a memory-phenotype.
A T-LNP/mRNA–based in vivo CAR-T candidate targeting CD19.
''The Phase 1 investigator-initiated study is evaluating the safety, tolerability, and preliminary efficacy of repeat GT801 dosing in patients with relapsed or refractory CD19-positive B-cell malignancies. As of the November 30, 2025 data cutoff, two patients with non-Hodgkin's lymphoma had completed multiple GT801 administrations without lymphodepleting chemotherapy, demonstrating the feasibility of generating functional CAR-T cells in vivo in the absence of cytotoxic conditioning.
Patient 1 received three doses of 0.5 mg, and Patient 2 received four doses of 1.5 mg. GT801 was generally well tolerated. Both patients showed high CAR expression within circulating T cells. Durable and repeatable CAR-T expansion was observed following each GT801 administration. No CAR expression was detected in peripheral blood monocytes, suggesting negligible off-target delivery of GT801 and supporting high selectivity of the T-LNP platform.
''The trial enrolled just five patients, all of whom experienced SAEs. Notably, 100% of participants developed grade 3 or higher toxicities, underscoring the intensity of the treatment’s side effects. Cytokine release syndrome (CRS)—a potentially life-threatening inflammatory reaction—occurred in four out of five patients. Three cases were severe. Symptoms included high fever, low blood pressure, and hypoxia, requiring aggressive medical intervention.
One patient experienced a dramatic hyperacute reaction within hours of infusion, with dangerously elevated inflammatory markers and cardiovascular instability. This event was so severe that it prompted a mid-trial protocol change to include preemptive steroid treatment for subsequent patients. Although this adjustment reduced the intensity of early reactions, it did not eliminate high-grade CRS. Neurological toxicity was also observed, and all patients developed significant hematologic abnormalities, including severe reductions in white blood cells and platelets.
A treatment-related death raises alarms Most concerning was the death of one participant during the study. The patient developed rapid neurological deterioration and ultimately died following spinal cord compression caused by an expanding tumor mass.
While investigators attributed the death primarily to disease progression, the timing—coinciding with peak CAR T expansion and immune activation—raises unresolved questions about whether the therapy may have contributed indirectly, for example, through inflammatory swelling or so-called pseudoprogression. This case highlights a key risk of in vivo CAR T approaches: once the therapy is administered, it cannot be easily controlled or withdrawn.
The study was ultimately stopped in 2025, with no further patients enrolled. Although the official reason cited was sponsor restructuring, the combination of severe toxicities, complex immune reactions, and a fatal outcome underscores the challenges facing this therapeutic strategy. With only five patients treated and short follow-up, the trial was insufficient to establish a clear safety profile or determine whether benefits outweigh risks.
Unpredictable immune responses One of the most striking findings was the unusual pattern of immune activation. Unlike conventional CAR T therapies, which typically trigger immune responses after engineered cells expand, ESO-T01 caused an immediate inflammatory surge within 24 hours—before CAR T cells were even detectable.
This early “innate” immune reaction, the authors suggest, is likely driven by the viral vector itself, introducing a layer of toxicity absent from traditional approaches. A second wave of immune activation happened a few days later. This two-phase response complicates both monitoring and management, as standard CAR T toxicity frameworks may not fully apply.
Although four patients showed tumor responses, including deep remissions in some cases, these results are difficult to interpret given the study’s limitations and safety concerns. The small sample size, early termination, and lack of long-term follow-up mean that any apparent efficacy remains preliminary. Moreover, rapid biomarker changes observed shortly after infusion may reflect transient immune effects rather than durable tumor control.
A cautionary step forward The research is a blow to AstraZeneca, which acquired all outstanding equity of EsoBiotec for a total consideration of up to $1 billion, on a cash- and debt-free basis, last May. This includes an initial payment of $425 million and up to $575 million in contingent consideration based on development and regulatory milestones.
The ESO-T01 trial illustrates both the promise and the peril of in vivo CAR T therapy. By eliminating manufacturing, the approach could theoretically expand access and speed treatment—but it also introduces new biological risks.
Delivering gene-modifying vectors systemically exposes the entire immune system to activation, potentially triggering severe inflammation before therapeutic benefits emerge. In addition, the inability to fine-tune or halt CAR T production once initiated raises safety concerns, particularly in patients with complex or high-risk disease.
Researchers emphasize that further development will require careful redesign, including strategies to reduce innate immune activation, improve targeting, and enhance safety controls. Larger trials with more rigorous monitoring will be needed to determine whether the approach can be made viable. For now, the study serves as a cautionary example: simplifying CAR T therapy by moving it inside the body may not be as straightforward or safe as hoped.''
''Two new startups have begun testing their in vivo CAR-T therapies for autoimmune disease in people.
China-based Immorna recently treated a systemic sclerosis patient with an in vivo CAR-T therapy, and the patient’s peripheral B cells were undetectable at two weeks. It’s an early signal suggesting that the therapy removed disease-causing immune cells, but far more data are needed to show whether the treatment improves the patient’s disease long-term.
Massachusetts-based Orna Therapeutics, which Eli Lilly is buying, also started recruiting for a healthy volunteer study in Australia, according to a US clinical trials database.
At least one other biotech from China, Therorna, is also studying in vivo CAR-T for autoimmune conditions in the clinic, according to ClinicalTrials.gov, along with several Chinese academic institutions.
Large US pharma companies including Eli Lilly and Bristol Myers Squibb have bought biotechs working on mRNA-based in vivo CAR-T treatments for autoimmune conditions, but have provided few public updates on their programs. Last year, Bristol Myers Squibb bought Orbital Therapeutics for $1.5 billion. Then in February, Lilly said it was planning to buy Orna for up to $2.4 billion.
Also last year, AbbVie bought Capstan as part of a $2.1 billion deal. Capstan in 2025 started a Phase 1 study in Australia for healthy volunteers as well as patients with rheumatoid arthritis and systemic lupus erythematosus. Meanwhile, Orna began a healthy volunteer study of a CD19-targeted in vivo CAR-T therapy in March. Both trials are running in Australia.
Immorna said last week that the first patient received “low doses” of its mRNA-based in vivo CAR-T, called JCXH-213, which targets CD19. The patient’s “peripheral B-cell counts dropped to undetectable levels” and remained undetectable through a two-week treatment period. It appears the patient received several doses over the treatment period, but Immorna did not provide specifics.
A biopsy showed B cell depletion in lymph node tissue and the patient did not experience cytokine release syndrome or liver toxicity, Immorna reported.
More data are needed to see whether the treatment was effective. In MagicRNA’s case, patients saw some improvement in their lupus disease activity, but did not achieve the level of disease clearance and “immune reset” that has been seen with conventional CAR-T therapy over a three-month period.
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