The Next Evolution of Cell Therapy: The Rise of In Vivo Lentiviral CAR-T

Cell and Gene Therapy

9/22/20264 min read

a yellow substance with red dots in it
a yellow substance with red dots in it

Back in May, I wrote (and recently updated) a blog about in vivo CAR-T therapies using non-viral, mRNA-based treatments. Here I will focus on lentiviral-based in vivo CAR-T and the companies working on this approach.

First-generation Chimeric Antigen Receptor (CAR) T-cell therapies transformed hematological oncology by demonstrating that a patient’s own immune system could be reprogrammed to eradicate advanced malignancies. However, the classical ex vivo approach—harvesting T cells, shipping them to specialized manufacturing centers, genetically engineering them via viral vectors, and re-infusing them following toxic lymphodepleting chemotherapy—presents immense logistical bottlenecks, high costs, and treatment delays that many late-stage patients cannot afford.

The solution driving the next wave of cellular immunology is in vivo CAR-T therapy: generating tumor-hunting T cells directly inside the patient's body via a single intravenous injection. While transient mRNA-based platforms delivered by lipid nanoparticles (LNPs) have gained traction, lentiviral vector (LVV) platforms are rapidly emerging as the gold standard for applications requiring permanent genomic integration, sustained cellular persistence, and durable clinical remissions.

The Lentiviral Advantage: Stable Integration in Situ

Lentiviral vectors possess intrinsic biological properties that make them exceptionally suited for in vivo cell engineering:

  • Permanent Genomic Integration: Unlike non-integrating mRNA constructs that degrade over days, lentiviruses permanently integrate the CAR transgene into host T-cell genomes. This leads to stable CAR expression that is passed down to daughter cells upon clonal expansion, enabling long-term immunosurveillance against tumor recurrence.

  • Cell-Type Specificity via Tropism Engineering: Wild-type envelope glycoproteins (such as VSV-G) are detargeted and replaced with rationally engineered surface binders—such as single-chain variable fragments (scFvs), nanobodies, or viral fusogens. This ensures that the vector selectively transduces target T-cell subpopulations in the bloodstream while bypassing non-target tissues, macrophages, or circulating tumor cells.

  • No Preconditioning Required: By eliminating external cell manipulation and toxic lymphodepletion regimens, in vivo LVV platforms allow patient T cells to remain in their natural tissue microenvironments, preserving their fitness, central memory phenotypes, and proliferative potential.

High-Stakes M&A: Big Pharma Moves on In Vivo Lentiviruses

Recognizing that in vivo cellular engineering threatens to render centralized ex vivo manufacturing facilities obsolete, global pharmaceutical leaders have engaged in aggressive acquisition strategies to secure proprietary lentiviral platforms.

1. AstraZeneca’s $1 Billion Acquisition of EsoBiotec

AstraZeneca completed its acquisition of Belgian biotech EsoBiotec for up to $1 billion ($425 million upfront plus $575 million in milestone payments). EsoBiotec’s proprietary Engineered NanoBody Lentiviral (ENaBL) platform utilizes targeted lentiviruses engineered with single-domain antibody fragments (nanobodies) on their viral envelopes. This architecture selectively delivers CAR transgenes to specific T-cell subsets in situ, enabling off-the-shelf, single-IV infusion therapies that bypass lymphodepletion chemotherapy.

2. Gilead / Kite’s $350 Million Acquisition of Interius BioTherapeutics

Kite Pharma, a subsidiary of Gilead Sciences and commercial leader in traditional CAR-T therapies, announced the acquisition of Interius BioTherapeutics for $350 million in cash. Interius developed an integrating in vivo gene delivery platform using a second-generation detargeted viral fusogen. Its lead asset, INT-2104, utilizes a targeted lentivector to generate both CAR-T and CAR-NK cells in vivo, targeting B-cell malignancies through a single systemic administration without requiring preconditioning.

The Clinical and Preclinical Trailblazers

Beyond recent acquisitions, a select group of biotechnology companies is advancing proprietary lentiviral engineering architectures across clinical and preclinical stages.

Kelonia Therapeutics

Kelonia Therapeutics is leveraging its iNSight (In Vivo Specific Integration) platform to produce replication-incompetent, self-inactivating lentiviral vectors. Their lead candidate, KLN-1010, is designed for relapsed or refractory multiple myeloma. In early phase 1 clinical evaluation (the inMMyCAR study), single-dose administration of KLN-1010 without preconditioning chemotherapy generated robust in vivo CAR-T cell expansion, achieving minimal residual disease (MRD)-negative complete responses in heavily pretreated patients while demonstrating a manageable toxicity profile.

Legend Biotech

Known for co-developing the commercial autologous CAR-T therapy Carvykti, Legend Biotech is expanding into in vivo modalities with its TaVec platform. Legend advanced LB2501, a dual CD19/CD20-targeted lentiviral in vivo CAR-T therapy, into first-in-human clinical trials for non-Hodgkin lymphoma. Early clinical findings demonstrated complete responses in patients receiving the therapeutic dose without chemotherapy preconditioning, validating the feasibility of viral-mediated in vivo targeting in human subjects.

Umoja Biopharma

Umoja Biopharma’s VivoVec platform reimagines the viral surface by pseudotyping lentiviral particles with the Cocal fusion glycoprotein alongside surface-anchored anti-CD3 scFvs and costimulatory ligands. Rather than merely delivering a gene payload, next-generation VivoVec particles simultaneously deliver signal 1 (TCR engagement) and signal 2 (costimulation) to host T cells at the moment of vector binding. This simultaneous activation drives superior viral transduction efficiency and generates CAR-T cells displaying less-differentiated, stem-cell memory phenotypes capable of durable serial tumor killing.

Sana Biotechnology

Sana Biotechnology focuses on precision targeting via its proprietary fusogen platform. Sana utilizes paramyxovirus-derived viral fusogens embedded within third-generation lentiviral vectors (such as its SG295 program targeting CD8+ T cells). By decoupling vector attachment from cell fusion and engineering strict CD8 receptor specificity, Sana’s vectors prevent off-target transduction into phagocytic macrophages or antigen-presenting cells, minimizing vector clearance and avoiding unintentional gene delivery to malignant host cells.

Future Outlook

The field of cell and gene therapy is undergoing a fundamental realignment. By combining the persistent, durable expression of integrating viral vectors with precision surface targeting and fusogen biochemistry, in vivo lentiviral CAR-T platforms are bridging the gap between bespoke living drugs and scalable biological therapeutics. As ongoing clinical trials continue to yield human safety and efficacy data, lentiviral in vivo reprogramming is positioned to define the next generation of off-the-shelf oncology and autoimmune medicines.

References

  1. AstraZeneca. (2025). Acquisition of EsoBiotec completed. Press Release. Retrieved from https://www.astrazeneca.com/media-centre/press-releases/2025/acquisition-of-esobiotec-completed.html

  2. Gilead Sciences / Kite Pharma. (2025). Kite to acquire Interius BioTherapeutics to advance in vivo platform. Press Release. Retrieved from https://www.gilead.com/news/news-details/2025/kite-to-acquire-interius-biotherapeutics-to-advance-in-vivo-platform

  3. Gardner, J. (2026). Legend surges on early data for 'in vivo' lymphoma cell therapy. BioPharma Dive.

  4. Ho, P. J., et al. (2025). In vivo generation of CAR T cells using KLN-1010 in patients with relapsed/refractory multiple myeloma: Initial clinical observations from the inMMyCAR trial. Presented at American Society of Hematology (ASH) Annual Meeting.

  5. June, C. H., et al. (2025). In vivo chimeric antigen receptor (CAR)-T cell therapy. Nature Reviews Drug Discovery.

  6. Nicolai, C., et al. (2022). VivoVec lentiviral vector particles surface-engineered with T cell activating and co-stimulatory ligands enhance in vivo CAR T cell generation and antitumor activity. Society for Immunotherapy of Cancer (SITC).

  7. Sana Biotechnology. (2024). CD8-targeted paramyxo fusogen for in vivo CAR-T shows potent and highly-specific T cell delivery in non-human primates. American Society of Hematology (ASH) Poster Session.