In vivo CAR-T Therapy Challenges the Cancer Treatment Paradigm

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Adaeze Ekwe, MSc, PhD
Junior Associate Editor, ISCT Telegraft
Queensland University of Technology (QUT)
Australia

Joaquim Vives, PhD
Contributing Editor, ISCT Telegraft
Banc de Sang i Teixits (BST)
Spain

Topic Overview

Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized hematologic cancer treatment, yet its broad application is constrained by manufacturing complexity, time delays, and high costs due to reliance on ex vivo manipulation of patient-derived T cells. In vivo CAR-T is a transformative innovation that delivers directly into the patient to reprogram their own T cells inside the body. Enabled by nanoparticle, viral, and non-viral gene delivery systems, this approach bypasses apheresis and ex vivo GMP cell manufacturing. Recent clinical advances and strategic company consolidations underscore a rapidly maturing field poised to disrupt cell therapy logistics, economics, and accessibility.

Expert Perspectives

Dr. Chantal Martin, Capital BioVentures (Canada): “One of the hurdles of CAR-T therapy is balancing the centralized and decentralized components of manufacturing and testing. Centralized manufacturing is ideal for product quality, keeping processes and analytics consistent and comparable across lots because it's the same people and systems performing the work. Decentralized manufacturing, however, has been explored as a solution to keep vein-to-vein times down for CAR-T and to allow more patients to access the therapy by having manufacturing nearby. Maintaining the high quality and comparable process and analytics across myriad sites is complex and nearly ompossible. With in vivo CAR-T, this problem is resolved. We can manufacture a large lot of vector and perform all necessary release tests at a centralized industrial site, which can then be easily distributed to large and small clinical sites globally; there is no longer a need for patient-specific manufacturing. This decreases complexity, maintains comparability between lots, decreases costs, and minimizes vein-to-vein time."
Dr. Kerry Fisher, Univesity of Oxford, UK: "It is incumbent on all of us in the medical sciences to offer new therapeutic breakthroughs to everyone who needs them. For CAR-T therapies, this might be achieved through more research on in vivo gene transfer in order to bring treatment cost within reach of the global patient population."
Dr. Manel Juan, Hospital Clínic de Barcelona (Spain): “While in vivo CAR-T therapies could simplify access and reduce costs by circumventing the logistical and regulatory complexity of ex vivo manufacturing, there are undeniable limitations, starting with the fact that they remain experimental proposals. From a technical standpoint, since they are currently conceived as transient modifications using non-integrating mRNA, their efficacy is restricted to indications in which long-term persistence of the modified cells is not critical unlike in many cancers, where evidence demonstrates the importance of sustained CAR-T cell persistence. Overcoming this transient effect would require repeated dosing, with the added risk of immunogenicity, which could hinder clinical applications. Moreover, reductions in the cost of goods will not necessarily follow price reductions of the therapy, as illustrated by the high prices of commercial CAR-T products compared with academic CAR-Ts."

Insights Across the Ecosystem

For Patients: This new strategy addresses major limitations of traditional CAR-T cell therapies and could be transformative for patients in several important ways.

Impact: In vivo CAR-T promises much easier and faster treatment process with the elimination of lymphodepleting chemotherapy and dramatically reduced wait times for treatment (from weeks of manufacture to a simple injection).
Safety: Novel strategies aim to avoid cytokine release syndrome by preferential engineering of CD8+ T cells, enabling dose titration and targeting strategies. Temporary changes to T cells avoid the potential long-term risk of permanent gene-editing in traditional ex vivo CAR-T therapy.
Accessibility and availability: The removal of manufacturing bottlenecks may significantly lower the cost, making it viable for broader payer coverage. In addition, this new approach could make this therapy available at more hospitals and non-specialized treatment centers, especially in regions where healthcare systems lack the infrastructure for current CAR-T manufacturing.
Broader treatment options: While current CAR-T therapy is mainly used for certain blood cancers, this approach could open doors for solid tumors. There is also the potential for immune reset which may provide durable clinical benefits in autoimmune diseases. The temporary changes to immune cells could make this option ideal for patients who might not be suitable for current CAR-T cell therapy due to health concerns.

For Clinicians/Researchers:

Applicability: Promising results have been reported in animals models of cancer and autoimmune diseases & cardiac fibrosis, and from first-in-human studies for patients with B-cell non-Hodgkin’s lymphoma and relapsed or refractory multiple myeloma. Recently, Kelonia Therapeutics started a phase 1 study of anti-BCMA in vivo CAR-T therapy for patients with relapsed and refractory multiple myeloma in Australia. As a platform technology, this could be adapted for multiple targets and clinical indications, providing a versatile new tool for immune engineering studies.
Evidence Needs: Validation of durability, target specificity, and immune escape mitigation in comparison with autologous CAR-T is ongoing. While pre-clinical data shows reduced off-target delivery and improved safety and tolerability profile, extensive studies for long-term safety and efficacy will be required.
Practice-Changing Implications: The model removes the need for T-cell harvest or specialized handling in complex and expensive GMP facilities, shifting administration into outpatient settings. The simpler delivery method opens possibilities for combining this approach with other treatments (something much harder to do with current CAR-T protocols that require intensive pre-conditioning).

For Developers/Industry: This represents a high growth opportunity with potential for global scaling

Market Expansion: The development of novel platform technologies means CAR-T cell therapies can be expanded beyond B cell malignancies to a vast new market across multiple diseases broadening patient populations.
Technical Hurdles: Optimizing vector tropism, gene delivery efficiency, and minimizing off-target effects remain major R&D frontiers.
Regulatory Strategies: Regulatory Authorities are adapting guidance for in-vivo gene-modified cell products, drawing parallels to gene therapy frameworks to accommodate gene-editing and in-vivo delivery platforms. However, approval pathways are still evolving.
Manufacturing Scalability: mRNA-LNP, AAV vectors, and synthetic delivery systems (e.g., Verve Therapeutics, GenEdit) enable centralized GMP vector production with distribution akin to traditional drugs.

For Regulators/Payers/Policy Makers:

Decision Frameworks: Need to reassess value frameworks for CAR-Ts that are not manufactured products but functionally “therapeutic procedures.” New regulatory frameworks are likely to emerge as more data from clinical trials become available. This will need to consider pre-clinical and clinical data, as well as long-term monitoring for genotoxicity, off-target effect and secondary malignancies. As most of this is already included in the current regulatory landscape for traditional CAR-T therapies, expedited review pathways may be considered.
Assessment Tools: Real-world evidence and adaptive licensing may support early adoption while robust safety data accumulate. Unlike ex vivo CAR-T in vivo therapies cannot be tested before infusion raising safety concerns. Thus, new ways to measure safety of treatment, real-time tracking of CAR-T cells and monitoring of immune activity are essential. Although manufacturing is not required, GMP compliance for delivery systems (viral and non-viral) remains critical.
Reimbursement: Novel payment models may emerge for in vivo gene delivery-based therapies, potentially bundled with diagnostics and follow-up monitoring, also considering anticipated lower manufacturing costs compared to ex vivo CAR-T. The reduction in cost could make this therapy more appealing for broader coverage and reimbursement. However, payers will need clear data on the durability of clinical response as well as long term safety profile.

Global Viewpoint

While this treatment approach is promising and represents a major step towards more accessible, safer, and effective treatments, key questions and considerations remain. Key data from ongoing and future clinical trials will be needed to determine optimal dosage and regimen, immunogenicity and adverse effects.

Regional trends: The US leads with volume of clinical trial studies, stronger platform technologies and global commercialization networks
Emerging markets: China is the fastest growing market with regulatory flexibility, strong clinical trial and infrastructure. Other countries in the Asia Pacific region are also developing domestic nanoparticle delivery systems
Harmonization efforts: Cross-border partnerships and global harmonization will be limited by regulatory differences. The new scenario opens opportunities for international scientific societies like ISCT to propose consensus
Partnerships: Industry momentum is high with strategic partnerships (AbbVie-Umoja) and recent acquisitions (EsoBiotec by Astrazeneca, Capstan by AbbVie and Interius by Gilead’s Kite). EU Horizon funding and collaborations between biotech startups and academic centers are driving innovation.

What to Watch

Milestone trials or datasets

Upcoming conferences

European Society of Gene and Cell Therapy annual congress (October 7-10, FIBES, Sevilla, Spain)

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