Following its $2.4 billion acquisition of Orna Therapeutics earlier this year, Eli Lilly is once again betting heavily on in vivo CAR-T therapy.

Recently, Eli Lilly announced its acquisition of Kelonia Therapeutics for $7 billion, pushing the valuation of transactions in the in vivo CAR-T field to a new high. This means that by 2026, Eli Lilly will have invested nearly $10 billion in the in vivo CAR-T field alone.

It's worth noting that this acquisition doesn't involve mature assets. Kelonia's core drug, KLN-1010, is still in Phase I, with only early validation completed in four patients. Orna's core asset, ORN-252, is in the clinical trial preparation stage.

Clearly, Eli Lilly is not betting on a single molecule, but rather on two differentiated in vivo CAR-T technology pathways.

Orna uses an LNP delivery + circular RNA system, which has advantages in in vivo stability and sustained protein expression, making it more suitable for long-term treatment scenarios such as autoimmune diseases; Kelonia, on the other hand, is based on lentivirus delivery, continuing the technical logic of traditional CAR-T in the field of oncology.

Not only Eli Lilly, but also many MNCs, from AstraZeneca to AbbVie, Gilead and BMS, have made huge investments in acquiring their own CAR-T companies in the past year, setting off a wave of mergers and acquisitions in the industry.

The collective heavy investment from MNCs has not only boosted the value of in vivo CAR-T assets but also confirmed the core value and broad potential of the field. However, it is important to recognize that in vivo CAR-T is still in its early stages, and key issues such as efficacy stability and safety have not yet been fully verified.

This wave of mergers and acquisitions is an early positioning for "next-generation" cell therapy. Whether it can deliver on expectations in the next few years remains to be seen.

01
Valuation rises

Eli Lilly's latest acquisition has broken the record for transactions in the field of in vivo CAR-T therapy.

Prior to this, the sector had seen a flurry of high-profile deals. AstraZeneca acquired EsoBiotec for $1 billion, Gilead's Kite acquired Interius Bio Therapeutics for $350 million and signed a collaboration agreement with Pregene worth up to $1.6 billion; AbbVie also made two moves, partnering with Umoja for $1.44 billion and then acquiring Capstan Therapeutics for $2.1 billion, while BMS acquired Orbital Therapeutics for $1.5 billion.

Comparing acquisition prices alone, Eli Lilly's $7 billion acquisition is indeed not cheap. The overall value of CAR-T cells in vivo is also trending towards increasing prices, driven by clinical data.

Kelonia's core pipeline, KLN-1010, is an in vivo CAR-T therapy targeting BCMA for the treatment of relapsed/refractory multiple myeloma, and is currently in Phase I clinical trials.

One of the core reasons Eli Lilly was willing to pay a hefty sum to acquire it was the efficacy potential shown by its early clinical data.

At the 2025 ASH Annual Meeting, Kelonia presented the first data on KLN-1010: four patients with relapsed/refractory multiple myeloma achieved minimal residual disease (MRD) negative remission one month after receiving a single KLN-1010 infusion, and the two patients with the longest follow-up maintained MRD negativity for three months. During the longest follow-up period of five months, all patients maintained a response, showing some degree of persistence.

Its in vivo expansion capacity is close to that of commercially available in vitro CAR-T cells. Without lymph node depletion chemotherapy, the proportion of CAR-T cells in circulating T cells can reach 85%.

In terms of safety, KLN-1010 also performed well. No patients with grade ≥3 CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), or delayed neurotoxicity were observed after KLN-1010 treatment. Furthermore, cytopenia was significantly reduced, which is something that cannot be achieved with in vitro CAR-T.

Based on the above data, in January 2026, KLN-1010 received FDA approval for its IND application for the treatment of relapsed/refractory multiple myeloma.

Jacob Van Naarden, Head of Oncology Business Development at Eli Lilly, said: “Autologous CAR-T therapy has significantly improved treatment outcomes for patients with a variety of cancers, but due to numerous barriers in terms of manufacturing, safety, and accessibility, only a small percentage of eligible patients are actually able to receive the treatment. Kelonia’s in vivo platform promises to change this, providing rapid and durable efficacy in a simpler and more convenient way.”

Therefore, the high premium supporting this round of transactions is the therapeutic potential of the CAR-T platform in Kelonia, and although the data from these four patients is limited in scale, it provides the most direct evidence of efficacy.

In the future, as more clinical data is released, we may see a continued rise in the valuation of CAR-T in vivo.

02
Betting on both ends of the technology

Since 2024, in vivo CAR-T therapy has developed rapidly, sparking a technological arms race among multiple MNCs. Although Eli Lilly entered the market late, it has completed its layout in the two core areas of in vivo CAR-T through the acquisitions of Orna Therapeutics and Kelonia Therapeutics: oncology and autoimmune diseases.

In February 2026, Eli Lilly acquired Orna Therapeutics, whose core asset ORN-252 is an in vivo CAR-T product targeting CD19, primarily used to treat B-cell driven autoimmune diseases such as systemic lupus erythematosus (SLE), and is currently in the IND preparation stage.

At the ASH conference in 2025, Orna presented early in vivo data for ORN-252. In a humanized lupus model, ORN-252 effectively cleared B cells and significantly reduced dsDNA antibody levels at doses as low as 0.03 mg/kg, demonstrating superior efficacy compared to rituximab treatment. In non-human primate studies, a dose of only 0.1 mg/kg was required to achieve complete clearance of B cells in peripheral blood and spleen, while simultaneously inducing transient expansion of CAR-T cells.

More importantly, it exhibits controllable persistence: after B cell regeneration, the immune system rebuilds to immature B cells, suggesting its potential for immune reset.

Beyond its indications, Eli Lilly has also made two bets on different technological approaches.

ORN-252 was developed based on the LNP delivery + circular RNA (panCAR™) platform. Circular RNA significantly improves stability and expression efficiency and reduces immunogenicity risk by self-circulating linear RNA. Furthermore, the cap-free, tail-free, and nucleoside-free nature of circular RNA, compared to traditional mRNA, offers a longer half-life, higher protein expression, and easier large-scale production, making it suitable for encapsulation into the LNP system.

Its delivery-dependent LNP avoids complex ligand modifications, thereby reducing the risk of immunogenicity. Specifically, it exhibits short-term attenuation, supporting repeated dosing. Its controllable long-term efficacy also makes it more suitable for autoimmune diseases.

In contrast, Kelonia represents a different approach. Based on the iGPS® platform, Kelonia uses engineered lentiviruses to directly modify T cells in vivo, achieving stable integration and long-term expression of the CAR gene.

Lentiviral delivery follows the technical logic of traditional CAR-T in the field of oncology, namely, using lentiviral vectors to stably integrate the CAR gene into the T cell genome, which has stronger persistence and is expected to achieve "functional cure".

Furthermore, its in vivo gene localization system (iGPS) achieves selective recognition and targeted delivery to T cells by removing the virus's natural receptor binding capacity and incorporating anti-CD3 single-chain antibody fragments (scFv) into the envelope structure, thereby improving the cell specificity of in vivo transduction. This allows for lower dosage and has the potential to be applied to more patients.

Prior to the acquisition, Kelonia's technology platform had already partnered with several MNCs. In early 2025, Kelonia entered into an in vivo CAR-T development collaboration with Xyphos Biosciences, a subsidiary of Astellas; in October, Johnson & Johnson announced a strategic collaboration with Kelonia to jointly develop next-generation in vivo CAR-T therapies based on the iGPS® platform.

After completing these two transactions, Eli Lilly became the only company globally with two in vivo CAR-T technology platforms: autoimmune and oncology. This also reminds us that in this cutting-edge field, there is no winner-takes-all; the ultimate validation of technology and clinical trials is the core factor determining the direction of the field.

03
Caution and optimism coexist

Despite the promising technological prospects and substantial progress made in in vivo CAR-T research over the past two years, attracting significant investment from multinational corporations (MNCs), its clinical efficacy and safety profile, as a novel in vivo gene therapy, still require careful consideration.

After all, disruptive potential cannot mask the risks of research and development.

Take ESO-T01, the in vivo CAR-T product acquired by AstraZeneca through its acquisition of EsoBiotec, as an example. In a Phase I clinical trial for the treatment of relapsed/refractory multiple myeloma, ESO-T01 showed strong early efficacy signals: 80% (4/5) of patients achieved objective response, including 3 cases that achieved complete response in the strict sense.

However, along with the signs of therapeutic efficacy, there are also safety concerns that cannot be ignored.

In March of this year, the journal Nature Medicine published the complete clinical data of ESO-T01. Behind the safety conclusion of "generally well tolerated", there are worrying side effects.

CRS, a common symptom of in vitro CAR-T therapy, also occurred in patients treated with ESO-T01; four out of five patients developed CRS, with three of them experiencing grade 3 CRS. Furthermore, the study also observed two patients developing grade 2 herpes simplex virus infection within 30 days and one patient developing a lung infection six months after infusion. This suggests that during the window of immune system remodeling, patients still experience some degree of immunosuppression or immune imbalance.

More seriously, one patient developed ICANS and ultimately died from spinal cord compression due to the progression of extramedullary lesions. Although this event had overlapping factors with disease progression itself, it also exposed the uncontrollable risks of CAR-T therapy in vivo.

Hongxin Bio's HN2301 points to another constraint of in vivo CAR-T: persistence.

HN2301 is an LNP-based CD19 in vivo CAR-T for SLE. In a phase I clinical trial for SLE patients, a decrease in SLEDAI 2000 scores was observed in 5 patients 3 months after treatment. Regarding safety, no ICANS or ≥3 grade CRS occurred.

However, the duration of action of this drug is relatively short. It reaches its peak rapidly about 6 hours after administration, but the overall duration in vivo is only maintained for 2–3 days, which is significantly shorter than that of lentiviral integration or LNP expression systems.

Of course, despite the numerous challenges and the long road to clinical validation, in vivo CAR-T, as a disruptive innovation in the treatment of tumors and autoimmune diseases, will continue to reconstruct the underlying logic of cell therapy through technological innovation.

With continued investment from global pharmaceutical companies and ongoing clinical validation, this cutting-edge technology will eventually break through existing limitations and open a new treatment window for countless patients with intractable diseases.

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