The promise and peril of in vivo CAR-T therapy

The article presents “immune reset” as beneficial while ignoring that immunological memory loss is catastrophically dangerous. This is like claiming that amnesia is therapeutic because it prevents bad memories

https://www.nih.gov/news-events/nih-research-matters/engineering-immune-cells-within-body

״Because the changes in the T cells are temporary, they avoid potential long-term risks that more permanent gene-editing methods may pose”

Logical Fallacy: assuming temporary interventions can’t have permanent consequences.

The NIH’s July 2025 announcement about engineering immune cells within the body using lipid nanoparticles presents a compelling vision for democratizing CAR-T therapy. National Institutes of Health +2 However, comprehensive analysis of current evidence reveals substantial gaps between these optimistic claims and established medical reality. While the underlying Hunter et al. Science paper demonstrates technical feasibility in animal models, the translation to human therapeutic benefit faces formidable challenges that mirror historical patterns of premature immunotherapy enthusiasm.

The core innovation—using CD5-targeted lipid nanoparticles to deliver anti-CD19 CAR mRNA directly to T cells—achieved 90% engineering efficiency in non-human primates with B cell depletion lasting up to two weeks. Business Wire +3 Yet this transient effect required the longest follow-up period was merely seven weeks, providing no insight into long-term safety or durability. Capstan Therapeutics, despite securing a $2.1 billion acquisition by AbbVie, has only begun dosing healthy volunteers in Australia, not actual patients, Fierce Biotech +2 highlighting the cautious regulatory approach necessitated by this unprecedented technology. Fierce Biotech +4

Current CAR-T therapy sets a high efficacy bar

Traditional ex vivo CAR-T therapy has matured significantly since 2017, with seven FDA-approved products achieving remarkable clinical outcomes that any in vivo approach must match or exceed. Wikipedia Current therapies demonstrate 73-80% overall response rates in large B-cell lymphoma with 53-54% complete responses, Israeli Hospitals Bccresearch while B-cell acute lymphoblastic leukemia shows even more impressive 92.3% complete remission rates. Nature PubMed The recently approved Aucatzyl (November 2024) exemplifies continued innovation in the ex vivo space, Israeli Hospitals suggesting the technology remains far from obsolete. fda

Manufacturing challenges persist but are steadily improving. While traditional vein-to-vein times average 30-48 days, next-generation protocols have achieved 24-hour manufacturing Rockefeller University Press at academic centers like the University of Pennsylvania. Rockefeller University Press +2 Costs remain substantial at $350,000-500,000 per treatment, ScienceDirect Cell and Gene yet this represents known, manageable expenses within established healthcare systems. Medscape Frontiers The promise of in vivo approaches reducing these costs by over 50% remains entirely theoretical, lacking real-world economic validation.

Accessibility barriers extend beyond manufacturing. Geographic disparities mean 36% fewer patients receive therapy when living 2-4 hours from treatment centers, while Black patients remain less than half as likely as White patients to receive CAR-T therapy. Becarispublishing These systemic inequities will not be solved by technological innovation alone, regardless of manufacturing approach.

Safety profiles reveal concerning knowledge gaps

The safety landscape for B cell depletion therapies provides sobering context for evaluating in vivo approaches. Current CAR-T therapies cause hypogammaglobulinemia in 67-100% of patients, with 88% of responders requiring IVIG support beyond 90 days. PubMed Central +2 Infection rates reach 23-42% in the first month post-treatment, with infections representing the leading cause of nonrelapse mortality at 50.9% of deaths. American Society of Hematology +2 The NIH article’s casual mention of “immune reset” glosses over these serious immunological consequences.

Lipid nanoparticle safety data from COVID-19 vaccines and other applications raises additional concerns. Current LNPs achieve only 1-2% endosomal escape efficiency, with the vast majority accumulating in the liver causing ALT/AST elevation. C&EN Cell Press The Hunter paper’s novel L829 ionizable lipid claims reduced hepatotoxicity, but human safety data remains entirely absent. Anti-PEG antibodies causing accelerated blood clearance present another unaddressed challenge for repeated dosing strategies. ACS Publications

Cytokine release syndrome and neurotoxicity, while manageable in controlled ex vivo settings with 42-100% CRS incidence but less than 1% mortality, American Society for Transplantation and Cellular Therapy could present different profiles with in vivo generation. Journal of Experimental & Clinical Cancer Research +4 The inability to control or halt CAR-T production once initiated in vivo eliminates crucial safety mechanisms available with ex vivo approaches.

Regulatory framework remains undefined for in vivo approaches

The FDA’s comprehensive January 2024 CAR-T guidance explicitly addresses only ex vivo-manufactured products, leaving in vivo approaches in regulatory limbo. No precedent exists for approving in vivo CAR-T generation technologies, with companies reporting FDA’s “conservative attitude” toward these novel approaches. Frontiers The agency’s creation of a “super office” to handle cell and gene therapy workload suggests awareness of coming challenges but provides no clear pathway forward.

Historical context offers cautionary lessons. The cancer vaccine field provides numerous examples of promising preclinical and early-phase results failing in larger trials. Canvaxin’s dramatic Phase II survival improvements in melanoma collapsed in Phase III testing after consuming $34 million in NCI funding. Wikipedia +2 The pattern—strong animal models, encouraging small studies, premature enthusiasm, Phase III failure—has repeated across multiple immunotherapy platforms over decades.

Expert commentary reflects cautious optimism tempered by technical concerns

Leading CAR-T researchers express measured enthusiasm while highlighting significant challenges. Michel Sadelain, director of Columbia’s Initiative in Cell Engineering and Therapy, identifies the core challenge: “How do you get it to the right cell, the right place, right time?” Nature nature Carl June, despite co-founding Capstan, acknowledges the “daunting task that’s never been attempted in humans” of evading immune detection while achieving targeted delivery. Nature BioPharma Dive

Stephen Gottschalk’s Science perspective piece, while generally supportive, carefully notes the technology “could” move immunotherapy to wider use—conditional language reflecting appropriate scientific caution. Science The absence of published letters, rebuttals, or corrections to the Hunter paper suggests acceptance of the technical achievement while reserving judgment on clinical translation.

Industry validation through AbbVie’s acquisition and investments from major pharmaceutical companies indicates commercial interest but not clinical certainty. BMO Capital Markets explicitly characterized the acquisition as “high-risk, high-reward,” acknowledging the speculative nature of the investment despite the substantial price tag. BioSpace +2

Critical gaps between claims and evidence persist

The NIH article’s framing of in vivo CAR-T as a near-term solution for accessibility issues contradicts available evidence. Capstan’s Phase 1 trial in healthy volunteers, not patients, represents the global state of clinical development—far from the transformative therapy implied by the announcement. Business Wire +3 The claimed “immune reset” lacks rigorous immunological validation, borrowing terminology from autoimmune applications without establishing relevance to cancer treatment. Synapse Patsnap Synapse

Manufacturing scalability, presented as a key advantage, remains entirely theoretical. No data exists on commercial-scale production of CD5-targeted LNPs with consistent quality attributes. The complex multi-component nature of these delivery systems may present their own manufacturing challenges distinct from, but not necessarily simpler than, cellular manufacturing. Thermo Fisher Scientific Cell and Gene

Long-term safety represents perhaps the most glaring knowledge gap. The longest follow-up in non-human primates extends only seven weeks, providing no insight into risks of secondary malignancies, sustained immunosuppression, or other late effects. American Association for Cancer Research The FDA’s requirement for 15-year monitoring of gene therapy recipients underscores the timeline needed for proper safety evaluation. FDA

Technical hurdles require years of development to overcome

Multiple technical challenges must be resolved before in vivo CAR-T can rival established therapies. Targeting specificity remains imperfect, with risk of CAR expression in unintended cell populations including potentially tumor cells themselves. Journal of Translational Medicine The transient nature of mRNA expression may require repeated dosing, each carrying risks of immune sensitization and adverse reactions. MedPath +2 Duration of therapeutic effect, cost-effectiveness at scale, and optimal patient selection criteria all remain undefined.

The competitive landscape reveals diverse approaches—lentiviral, AAV, and mRNA platforms—each with distinct advantages and limitations. Interius BioTherapeutics’ lentiviral approach achieved first-in-human dosing ahead of Capstan, while Umoja Biopharma’s collaboration with AbbVie predates the Capstan acquisition. Fierce Biotech +2This proliferation of technologies suggests the field remains in exploratory phases rather than converging on optimal solutions.

Conclusion: Promise requires patience and rigorous validation

In vivo CAR-T generation represents genuine scientific progress with potential to address current therapy limitations. However, the gap between the NIH article’s optimistic framing and clinical reality spans years of necessary development and validation. Historical patterns of premature immunotherapy claims, combined with absent regulatory frameworks and unresolved technical challenges, mandate measured expectations. Wikipedia ScienceDirect

Medical professionals evaluating these claims should recognize that while seven FDA-approved ex vivo CAR-T therapies deliver proven clinical benefits today, Israeli Hospitals PubMed Central in vivo approaches remain entirely investigational with no established efficacy or safety profile in humans. fda The transformation from revolutionary concept to clinical reality typically requires 8-12 years of rigorous development—a timeline that even breakthrough technologies rarely circumvent.

The most appropriate stance combines recognition of legitimate scientific achievement with insistence on comprehensive evidence before accepting claims of imminent clinical transformation. Until randomized controlled trials demonstrate superiority or even equivalence to current standards, in vivo CAR-T generation remains an intriguing possibility rather than an impending revolution in cancer and autoimmune disease treatment.