Eli Lilly Leads In Vivo CAR T Space with Strategic Acquisitions

Eli Lilly Accelerates In Vivo CAR T Development with Key Acquisitions

Eli Lilly has emerged as a frontrunner in the in vivo CAR T therapy landscape, making significant investments to overcome the manufacturing and cost challenges associated with traditional ex vivo CAR T. The company acquired Orna Therapeutics for $2.4 billion in February, gaining a clinical trial-ready asset utilizing circular RNA molecules delivered via lipid nanoparticles to generate CAR T cells within the patient's body for B cell-driven autoimmune diseases. This was followed by the up to $7 billion acquisition of Kelonia Therapeutics in April, adding the lentiviral KLN-1010, which targets BCMA for multiple myeloma. Early Phase 1 data for KLN-1010 showed a 100% overall response rate in 18 patients with multiple myeloma, reinforcing Lilly's commitment to this scalable therapeutic modality.

• Strategic Acquisitions for In Vivo CAR T Expansion: Eli Lilly has aggressively entered the in vivo CAR T space through two major acquisitions. The $2.4 billion acquisition of Orna Therapeutics in February provided a platform leveraging circular RNA and lipid nanoparticles to enable in-body CAR T cell production for B cell-driven autoimmune diseases. This was complemented by the up to $7 billion deal for Kelonia Therapeutics in April, securing the lentiviral KLN-1010 asset targeting BCMA for multiple myeloma, demonstrating Lilly's comprehensive strategy to build a robust in vivo CAR T pipeline.
• Promising Early Clinical Data for KLN-1010: The lentiviral asset KLN-1010, acquired through Kelonia Therapeutics, has shown compelling early results in the Phase 1 inMMyCAR study. Data presented at ASCO 2026 revealed a 100% overall response rate among all 18 treated patients with multiple myeloma. Furthermore, bone marrow samples tested negative for minimal residual disease one month post-treatment, with four patients showing no signs of disease after at least four months of follow-up, indicating strong initial efficacy.
• Addressing Ex Vivo CAR T Limitations: Lilly's pivot to in vivo CAR T therapy is driven by the aim to overcome the significant access, cost, and manufacturing complexities of traditional ex vivo CAR T. By enabling CAR T cell generation inside the patient's body, this approach seeks to shorten time to infusion, reduce costs, and broaden patient access, potentially transforming how cell therapies are administered and making them available to a much larger population currently underserved by existing modalities.

Addressing Limitations in B Cell-Driven Autoimmune Disease

Current management of B cell-driven autoimmune diseases remains constrained by the broad, non-specific nature of existing immunosuppressive and B cell-depleting therapies, which struggle to balance efficacy with safety. While anti-CD20 monoclonal antibodies such as rituximab have transformed treatment paradigms, significant gaps persist in mechanistic understanding, long-term safety data, and durability of response—challenges that emerging cellular immunotherapies are only beginning to address.

• Broad immunosuppression and safety concerns: General immunosuppressants remain only partially effective while causing significant, often serious adverse effects due to their lack of specificity; similarly, B cell-depleting monoclonal antibodies eliminate both pathogenic and non-pathogenic B cell populations rather than selectively targeting disease-driving clones.

• Immunogenicity and infusion-related issues: Rituximab, a murine-human chimeric antibody, frequently induces anti-drug antibodies and infusion-related reactions, highlighting the need for improved antibody engineering and delivery approaches.

• Incomplete B cell targeting: Treatment failure can occur due to persistence of CD20-negative plasmablasts in peripheral blood, which evade anti-CD20 therapy, and autoreactive B cells often persist within lymphoid tissues and inflammatory sites despite systemic depletion—limiting efficacy in certain autoimmune diseases.

• Insufficient evidence base: There is a paucity of literature on the safety of continuous, long-term B-cell depletion, and clinical effectiveness has often been assessed only in small pilot studies rather than large randomized controlled trials. In the absence of robust trial data, anti-CD20 therapy use in refractory patients must be guided by individualized risk/benefit assessment.

• Unresolved mechanistic and comparative questions: The precise mechanisms underlying B-cell depletion's therapeutic effect in autoimmunity remain incompletely defined, and important questions persist regarding its value in autoimmune diseases beyond rheumatoid arthritis. Additionally, how newer anti-CD20 agents compare with rituximab in efficacy, safety, convenience, and cost remains an open question critical to guiding future clinical management.

• Emerging cell-based therapy limitations: Novel platforms—including CAR-T cells, CAAR-T cells, CAR-Tregs, tolerogenic dendritic cells, and mesenchymal/hematopoietic stem cells—face their own translational hurdles, including manufacturing complexity and scale-up, short- and long-term safety uncertainties, limited in vivo persistence, and high costs associated with personalized cell manufacturing.

• Innovation still maturing: While CAR-T therapies targeting CD19 have shown encouraging durable remissions in treatment-resistant systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myopathies, refinements such as logic-gated CARs, inducible suicide switches, and universal CAR constructs are still under active investigation to improve safety, control, and clinical accessibility before these approaches can achieve broader adoption.

Lilly's Bold Bet on In Vivo CAR T Reshapes Cell Therapy

Eli Lilly's recent acquisitions of Orna Therapeutics and Kelonia Therapeutics signal a profound strategic shift, positioning the company at the forefront of in vivo CAR T-cell therapy development. This innovative approach seeks to overcome the inherent challenges of traditional ex vivo CAR T, which, despite its revolutionary efficacy in hematologic malignancies, is plagued by complex, time-consuming manufacturing, exorbitant costs, and logistical hurdles that limit patient access. By engineering CAR T cells directly within the patient's body using advanced delivery systems like lipid nanoparticles for circular RNA or lentiviral vectors, in vivo therapy promises immediate administration and enhanced scalability.

This strategy holds significant implications for the broader cell therapy landscape. Lilly is not only targeting multiple myeloma, a challenging hematologic malignancy where CAR T has shown remarkable promise, but also venturing into B-cell driven autoimmune diseases. This expansion into autoimmune conditions represents a substantial opportunity, potentially offering long-term remission for diseases like systemic lupus erythematosus, though it also introduces new considerations regarding patient eligibility and the long-term safety of B-cell depletion.

However, this ambitious endeavor is not without its risks. The impressive 100% overall response rate observed in early Phase 1 data for Kelonia's multiple myeloma candidate, KLN-1010, while encouraging, is based on a small patient cohort. The translation of such efficacy and the management of potential toxicities like cytokine release syndrome and neurotoxicity in larger, later-stage trials will be critical. Furthermore, the in vivo platform itself, while addressing manufacturing bottlenecks, is still largely unproven at scale regarding its long-term safety, potential off-target effects, and the sustained persistence of engineered T cells. The competitive landscape, with several established ex vivo CAR T products and a pipeline of emerging therapies, means Lilly will need to demonstrate a clear superior benefit-risk profile and cost-effectiveness to secure broad market acceptance. This bold move by Lilly could redefine the future of cell therapy, making these transformative treatments more accessible, but the journey from early promise to widespread clinical adoption will require rigorous validation.