Safety will be the key determinant of in vivo CAR T therapies, according to H.C. Wainwright’s Mitchel Kapoor, who noted that convenience and efficacy won’t be enough to impress investors in this space. Eli Lilly, AbbVie, AstraZeneca and more are up for the challenge.
Cell therapies have already proven their worth in the clinic, effectively turning the body’s immune system against cancer—and soon, potentially autoreactive immune cells, too. But manufacturing and cost challenges continue to plague the modality, keeping it out of reach of many patients who need it. Enter in vivo CAR T therapy.
Currently, CAR T therapies are produced ex vivo, or outside the body. A patient’s T cells are harvested and engineered in a lab to turn them into cancer killers. These new cells are then allowed to multiply before being injected back into the patient. An in vivo approach, meanwhile, enables the generation of CAR T cells inside the patient’s body.
This technology “can fundamentally change how healthcare practitioners administer cell therapy,” Mitchell Kapoor, senior biotech equity research analyst at H.C. Wainwright, told BioSpace in an email. “It could shorten time to infusion, cut the cost of cell therapy, and ultimately broaden access to hundreds of thousands of patients,” he said.
The ex vivo track was validated by Novartis’ Kymriah when it became the first CAR T therapy to win the FDA’s approval in 2017, paving the path for other medicines like Bristol Myers Squibb’s Breyanzi and Gilead’s Yescarta.
The problem with ex vivo CAR T is access, Kapoor said. “What it doesn’t do is scale,” he continued, adding that the process is time-consuming and expensive, and is often limited by the capabilities of the clinics dispensing the therapies.
In vivo CAR T, which involves delivering a piece of DNA into cells and transforming them into cancer-killers inside the body, circumvents these issues, explained Kostas Biliouris, managing director at Oppenheimer.
Such an approach, Biliouris said, eliminates the need to initially extract cells from patients and the preconditioning chemotherapy required to prevent an immune reaction to the implanted CAR T constructs, making for an overall shorter and smoother experience.
“In a sense, the body becomes the manufacturing site,” Kapoor added.
For all its potential upside, however, there remains a key question at the heart of in vivo CAR T therapy: safety.
“Moving manufacturing into the patient solves access and cost, but it takes the most complicated step—engineering the cells—out of a facility you can inspect and moves that process, and its quality control, into a patient who you can’t inspect,” Kapoor said.
An ex vivo approach gives companies high levels of control over their product, but with in vivo, “once the vector’s in, you’re committed,” he cautioned. Companies that can demonstrate precision and control even while inside the body will rise to the top of the field, Kapoor said, adding, “Convenience and efficacy won’t be enough to wow investors unless safety is pristine.”
Still, if this challenge can be solved, the allure of in vivo is strong for the pharma industry, which stands to gain a scalable therapeutic modality that lowers manufacturing costs while also expanding adoption to a broader market, Biliouris said.
This has led to what he called “growing FOMO”—fear of missing out—among large biopharma companies, he continued. Indeed, the past two years have seen high-profile and big-ticket deals in this space as industry giants, including Eli Lilly, AbbVie and AstraZeneca try to secure exposure to what Biliouris said could become the next major cell therapy platform.
Lilly leads space with deal spree
Arguably the biggest mover in the in vivo CAR T arena this year is Lilly, which in February paid $2.4 billion to acquire Orna Therapeutics, getting a clinical trial-ready asset that the pharma plans to develop for B cell–driven autoimmune diseases.
Orna’s design engine leverages circular RNA molecules, delivered using a lipid nanoparticle, to enable patients’ bodies to produce their own CAR T cells. Such an approach has shaken Lilly’s long-standing skepticism toward the CAR T space. In a 2019 interview with Reuters, Lilly CEO David Ricks called the data behind CAR T therapy “amazing” but lamented that “practically, it’s not reaching many people.”
Much of this apprehension, it turns out, was focused on ex vivo CAR T, which is “complex, confusing, inconvenient for patients,” a spokesperson told BioSpace in an email. “As a result of these complexities, only a fraction of patients who are eligible for ex vivo CAR-T therapies actually end up receiving them.”
An in vivo approach bypasses these problems, the spokesperson added, minimizing wait times and eliminating the need for additional infrastructure that ex vivo therapies otherwise require. In vivo CAR T, if successful, “could bring a therapy that’s currently out of reach to far more patients.”
The Indiana giant followed up its Orna buy with the up to $7 billion pickup of Kelonia Therapeutics in April. The deal, which as of publication has yet to close, will give Lilly the lentiviral KLN-1010, which targets the BCMA protein to treat multiple myeloma.
At ASCO 2026, data from the Phase 1 inMMyCAR study showed a 100% overall response rate in all 18 patients treated with KLN-1010, with bone marrow samples testing negative for minimal residual disease at one month after treatment. Four patients who had been followed for at least four months showed no signs of disease.
Legend stands among giants
A standout on this list is Legend Biotech, which is ushering an in vivo CAR T asset through the clinic without the typical deep pockets and entrenched infrastructure of Big Pharma.
Legend’s candidate LB2501 targets both the CD19 and CD20 proteins found on B cells. The therapy, which is designed to enable the patient to produce their own CAR T cells after a single intravenous infusion, is in Phase 1 testing for relapsed or refractory B cell malignancies.
Phase 1 data disclosed last month demonstrated a 100% response rate in patients with non-Hodgkin lymphoma (NHL)—findings that “point to a potentially best-in-class profile in the in vivo CART space and best-in-disease profile in NHL,” Oppenheimer analysts told investors in a June 2 note.
LB2501 also had an overall favorable safety profile, with no documented cases of deaths, serious adverse events or dose-limiting toxicities.
Overall, the asset’s Phase 1 performance “strengthens chances” of Legend being acquired, Oppenheimer added, pointing to the Lilly acquisitions as sign that in vivo CAR T is becoming “a very active M&A space.” LB2501’s Phase 1 study is ongoing with a primary completion date in mid-2027.
Legend inked a CAR T collaboration with Johnson & Johnson in 2017, and together the companies developed the ex vivo therapy Carvykti. It won its first FDA approval in February 2022, for relapsed or refractory multiple myeloma.
“We view in vivo CAR-T as a natural extension of our leadership in cell therapy” and a key next step in the cancer field, Legend CEO Ying Huang told BioSpace over email. Legend’s early clinical findings for LB2501, Huang added, “reinforce our belief that in vivo approaches have the potential to complement existing cell therapy modalities.”
AbbVie, the early believer
Illinois-based AbbVie was an early believer in the promise of in vivo CAR T therapies. The pharma in January 2024 bet up to $1.4 billion in a pair of deals to partner with Umoja Biopharma, gaining access to the biotech’s VivoVec platform, which uses a lentiviral vector to deliver a gene construct that allows the patient’s body to produce its own CAR T cells.
The main asset under the collaboration is UB-VV111, a CD19-targeting in vivo candidate in Phase 1 development for B cell cancers driven by the mutation. The study is recruiting participants with a primary completion date in March 2029. In the second deal, AbbVie secured the option to leverage VivoVec for up to four other in vivo CAR T candidates.
But AbbVie wasn’t done. In June 2025, the company made another hefty investment in its in vivo CAR T portfolio, earmarking up to $2.1 billion to acquire Capstan Therapeutics. Capstan’s tech uses lipid nanoparticles to deliver RNA molecules that can reprogram the patient’s cells to produce CAR T constructs.
The biotech’s lead asset was CPTX2309, which has since been renamed ABBV-619 and is in Phase 1 development for B cell–mediated autoimmune diseases.
Death clouds AstraZeneca’s path
Like AbbVie, AstraZeneca entered the in vivo CAR T space by acquiring a smaller developer with promising tech.
In March 2025, the company picked up Belgium-based EsoBiotec and its proprietary ENaBL platform that enables the in vivo programming of immune cells, retooling them to target and attack tumors or self-targeting cells in autoimmune disease. ENaBL allows cell therapies “to be administered through a simple [intravenous] injection” and eliminates the need for the usual immune depletion preparatory step, AstraZeneca said at the time.
For this bounty, the pharma paid $425 million upfront plus the possibility of $575 million more in milestones.
That investment has started to pay off. Phase 1 data published in Nature Medicine in March showed that an investigational in vivo asset, dubbed ESO-T01, eradicated cancer in three of five enrolled patients with relapsed or refractory multiple myeloma. Four of the treated participants responded to the cell therapy and tested negative for minimal residual disease at 60 days.
One patient died, however, after grade 1 immune effector cell-associated neurotoxicity (ICANS), a severe complication associated with cancer immunotherapies in which immune cells attack and damage neurons.
The study wasn’t sponsored by AstraZeneca.
“Every death on a trial is a tragedy,” a company spokesperson told BioSpace over email. Patients enrolled in the early-stage study were refractory to prior treatments, had aggressive disease and had relapsed several times, the spokesperson continued, adding that the ESO-T01 study showed that an in vivo approach is “feasible without lymphodepletion.”
“AstraZeneca is now working to further develop in vivo treatments based on these results,” the spokesperson said.
