By Ana Espino | Published on March 4, 2026 | 3 min read
CAR-T cell therapy has transformed
the management of certain hematologic malignancies. Traditionally, however, its
development relies on a complex procedure: harvesting a patient’s T
lymphocytes, genetically modifying them in the laboratory, expanding the cells,
and reinfusing them. This lengthy, costly, and technically demanding process
limits access to treatment and creates major logistical constraints. In this
context, direct in vivo generation of CAR-T cells—without ex vivo
manipulation—emerges as an innovative strategy that could reshape cellular
immunotherapy.
A 2025 review published in Human
Vaccines & Immunotherapeutics examines recent advances in this emerging
approach. The authors aim to summarize gene-delivery platforms capable of
modifying T lymphocytes directly within the body, as well as the available
preclinical and clinical evidence.
Can CAR-T cells be created directly
in the body?
Unlike the conventional strategy, in
vivo CAR-T therapy involves administering vectors that can specifically
target T lymphocytes and deliver the gene encoding the chimeric antigen
receptor (CAR). Several systems are being explored:
- Viral
vectors,
especially lentiviruses and adeno-associated viruses (AAV), which offer
high transduction efficiency.
- Non-viral
vectors, such
as lipid nanoparticles (LNPs), polymers, or exosomes, enabling transient
and potentially more controllable expression.
The authors also describe the
evolution of CAR designs up to fifth-generation CARs, incorporating
co-stimulatory domains and cytokine-signaling modules intended to improve
persistence and antitumor activity.
Preclinical models have shown that
these approaches can generate functional CAR-T cells directly in vivo, with
significant antitumor activity, particularly in leukemia and lymphoma models.
Early clinical data, although limited, suggest promising efficacy with an
acceptable safety profile.
Toward simpler, more accessible
CAR-T
Despite meaningful progress, several
major challenges still determine large-scale clinical translation. The
safety
of gene-delivery vectors remains a top priority, particularly regarding the
risk of uncontrolled genomic integration associated with certain viral vectors.
Fine control over transgene expression, limiting off-target effects, and
managing the duration of activity of modified cells are key issues to ensure an
optimal benefit–risk profile.
Non-viral platforms such as LNPs
offer attractive safety prospects, but they still need improvements in
T-cell–specific targeting and intracellular delivery efficiency to reach yields
comparable to viral systems.
In addition, extending in vivo
CAR-T to solid tumors is a major biological challenge. The
immunosuppressive tumor microenvironment, antigen heterogeneity, and T-cell
functional exhaustion currently limit persistence and antitumor efficacy.
Combining strategies—precision genome editing, microenvironment modulation, and
AI-assisted optimization of vectors and antigen targets—could help overcome
these barriers.
Thus, while in vivo CAR-T therapy
is still in technological maturation, it represents a potentially
transformative evolution of cellular immunotherapy. By simplifying production,
reducing delays, and expanding accessibility, it could redefine therapeutic
standards—provided it is rigorously validated clinically and delivery platforms
are fully secured.
Read next: Immunotherapy on hold?
About the author – Ana Espino
PhD in Immunology, specialized in Virology
As a scientific writer, Ana is passionate about bridging the gap between research and real-world impact. With expertise in immunology, virology, oncology, and clinical studies, she makes complex science clear and accessible. Her mission: to accelerate knowledge sharing and empower evidence-based decisions through impactful communication.
