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Naive-biased in vivo CAR-T cell therapy

Jinjiao Wang , Haopeng Wang

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.02.0014
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Naive-biased in vivo CAR-T cell therapy

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In vivo CAR-T therapy offers a scalable, off-the-shelf alternative to complex ex vivo CAR-T manufacturing, yet the field struggles to achieve efficient T-cell transduction in the human body without inducing systemic T-cell activation-induced toxicity. In a study published in Vita, Ma and colleagues demonstrate that AAV6-M2, a capsid variant targeting CD62L+ naive T cells, achieves high transduction of T cells with durable CAR expression, reverses pathology in a humanized model of systemic lupus erythematosus, and exhibits markedly reduced liver tropism compared to wild-type AAV6.

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Ex vivo CAR-T cell therapy has transformed the treatment of hematologic malignancies and autoimmune diseases, achieving remarkable complete remission rates in refractory B-cell leukemias and enabling drug-free remissions in systemic lupus erythematosus (SLE)1,2. However, both autologous and allogeneic CAR-T therapies face substantial translational barriers. Autologous manufacturing requires individualized leukapheresis, multi-week ex vivo expansion in specialized GMP facilities, and treatment costs in the hundreds of thousands of dollars per patient3. Allogeneic strategies circumvent personalized manufacturing but introduce risks of graft-versus-host disease and exhibit limited in vivo persistence. Critically, both modalities require lymphodepleting chemotherapy prior to cell infusion, thereby restricting patient eligibility and limiting institutional accessibility4. These constraints underscore an urgent need for simplified CAR-T generation strategies that bypass ex vivo manipulation while preserving therapeutic efficacy.
In vivo CAR-T therapy represents a paradigm shift addressing these limitations. By delivering CAR-encoding vectors directly to patients' circulating T cells, this strategy eliminates ex vivo manipulation and converts cellular immunotherapy into an “off-the-shelf” gene therapy product5. Manufacturing complexity and costs are substantially reduced, treatment timelines compress from weeks to hours, and lymphodepletion becomes unnecessary — preserving patients' intact immune systems.
Current in vivo CAR-T strategies employ viral and non-viral delivery platforms, each with critical limitations6. Non-viral vectors (e.g., lipid nanoparticles, polymeric nanoparticles) offer scalable manufacturing but produce transient CAR expression (days) and trigger innate immune responses and potential antibody-mediated rejection, which constrain the frequency and feasibility of repeat administrations. Lentiviral vectors with T cell-targeting ligands achieve reasonable transduction and durable expression through genomic integration, yet pose insertional mutagenesis risks and critically, require broad T cell activation for efficient transduction — triggering cytokine release syndrome, organ toxicity, and hemophagocytosis.
In this issue of Vita, Ma and colleagues report the development of an in vivo CAR-T delivery platform based on engineered adeno-associated viral (AAV) vectors7. AAV vectors offer compelling advantages for in vivo gene delivery: episomal persistence minimizes insertional mutagenesis risk; multiple FDA-approved therapies (Luxturna, Zolgensma, Hemgenix) establish a clinical safety precedent; and compact packaging capacity accommodates CAR constructs8. However, traditional AAV serotypes exhibit poor tropism for T cells, limiting their application for in vivo CAR-T generation. Ma and colleagues overcome this barrier through AI-guided directed evolution of AAV6 capsid VP3 libraries, identifying AAV6-M2, a variant that enables efficient, safe, and durable in vivo CAR-T therapy.
This study demonstrates four critical translational innovations (Fig. 1). First, the AI-guided capsid engineering platform establishes a generalizable pipeline for developing tissue- and cell-specific AAV variants. Systematic screening of VP3 mutant libraries enables the generation of vectors targeting any immune cell subset or organ system beyond T cells, representing a scalable framework for precision gene delivery. Second, AAV6-M2 selectively transduces CD62L+ naive and central memory T cells, populations with superior proliferative capacity and self-renewal potential9. These engineered cells generate functional CAR-T products that sustain therapeutic levels for 6 weeks in humanized mouse models, representing the first successful in vivo reprogramming of quiescent human T cell subsets. Third, AAV6-M2 achieves high transduction efficiency in primary human T cells without requiring scFv-mediated targeting or T cell activation, thereby circumventing activation-associated toxicities inherent to conventional delivery systems. Fourth, capsid surface charge engineering confers cross-species hepatic de-targeting, reducing liver tropism by > 100-fold in both mice and cynomolgus macaques compared to wild-type AAV6. This modification significantly mitigates hepatotoxicity risk while enhancing vector bioavailability at target lymphoid compartments.
In humanized SLE models, single-dose AAV6-M2 administration demonstrates profound disease-modifying efficacy, reversing lupus nephritis and systemic pathology. These findings validate therapeutic potential for autoimmune disease intervention and collectively position AAV6-M2 as a clinically viable off-the-shelf in vivo CAR-T platform, warranting human trials to assess safety, immunogenicity, optimal dosing, and therapeutic durability across diverse disease contexts.
Despite these advances, several translational challenges warrant further investigation. A fundamental limitation across all in vivo CAR delivery platforms is achieving T cell-selective transduction. The absence of truly T cell-specific surface receptors creates risk of off-target toxicity, wherein even low-level transduction of non-T cells expressing the targeting ligand could trigger unintended immune dysregulation or functional impairment. For AAV6-M2, CD62L expression extends beyond T cells to include NK cells, monocytes, and B cell subsets, necessitating additional safeguards. Incorporation of T cell-restricted promoters represents one strategy to confine CAR expression exclusively to T lineages, mitigating off-target risk while preserving broad T cell transduction. A second challenge involves therapeutic durability and redosing constraints. Recent studies suggest that certain genetically driven forms of SLE require sustained CAR-T persistence for long-term disease control, whereas transient B cell depletion by CAR-T therapy can lead to disease relapse in these SLE cases10. However, episomal AAV genomes dilute with cell division and preexisting anti-capsid antibodies preclude repeat dosing in seropositive individuals. An AAV system utilizing compact genome editors such as AsCas12f for site-specific CAR integration offers a potential solution. This approach combines AAV6-M2's in vivo delivery efficiency with stable chromosomal insertion to achieve heritable, dilution-resistant expression. Beyond AAV6-M2 itself, this study provides a conceptual blueprint for alternative in vivo T cell engineering strategies: CD62L nanobody-conjugated lipid nanoparticles, alternative naive/memory markers (CCR7, IL-7Rα), or other capsid variants may leverage similar principles to preferentially target quiescent T cells, collectively advancing the development of next-generation off-the-shelf cellular immunotherapies.

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Wang, J., Wang, H. Naive-biased in vivo CAR-T cell therapy Vita https://doi.org/10.15302/vita.2026.02.0014 ()
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