Cell and gene therapy continues to reshape oncology, with chimeric antigen receptor (CAR) T-cell therapies delivering striking results in hematologic malignancies while facing ongoing access, manufacturing and real-world performance challenges.
Two development pathways are now prominent: next-generation ex vivo CAR T programs entering randomized trials against approved products, and in vivo CAR T platforms that engineer T cells inside the patient. Both approaches raise strategic questions for clinical trial design, regulatory strategy and payer engagement.
Ex vivo CAR T therapies have established efficacy in B-cell leukemias and lymphomas and have moved into earlier lines of therapy. Next-generation candidates include allogeneic, off-the-shelf products and dual-target CARs (for example CD19/CD20 or CD19/CD22) intended to reduce relapse from antigen escape. Efforts to extend CAR T to solid tumors focus on overcoming suppressive tumor microenvironments through checkpoint inhibition, chemokine receptor engineering and other approaches to improve tumor infiltration and persistence.
As approved CAR Ts expand use, new ex vivo trials face a higher evidentiary bar. Sponsors must plan comparator strategies that reflect regulator and health technology assessment expectations, prioritizing randomized head-to-head or add-on designs where feasible and relying on rigorously constructed external control arms only when direct comparison is impractical. Trials should report comprehensive endpoints beyond response rates, including minimal residual disease negativity, time-to-next-treatment and patient-reported outcomes, to align with reimbursement requirements. Transparent manufacturing metrics—vein-to-vein times, product success rates and bridging therapy exposure—are essential for regulators and payers, as are plans for expanded access to out-of-spec products.
In vivo CAR T represents a paradigm shift by delivering CAR constructs directly to immune cells in the body, removing leukapheresis and patient-specific ex vivo manufacturing. This model promises greater operational scalability, reduced treatment delays and potential suitability for frail patients by avoiding intensive lymphodepletion in some designs.
Two in vivo approaches are in early clinical testing. Engineered viral vectors (lentiviral or gamma-retroviral) aim to integrate CAR genes into T cells in vivo and may provide durable expression comparable to ex vivo products, but require long-term monitoring for insertional mutagenesis in line with gene therapy guidance. Targeted RNA–lipid nanoparticle systems deliver CAR-encoding RNA for transient expression, enabling controlled dosing and potential re-dosing; these avoid genomic integration but introduce platform-specific safety considerations such as LNP toxicity, immunogenicity and hypersensitivity, along with standard CAR T risks like cytokine release syndrome and neurotoxicity.
Early-phase in vivo trial design benefits from conventional drug-trial elements but must account for novel biology and safety. Key considerations include selection of endpoints that capture pharmacodynamic signals (progression-free survival, MRD, circulating CAR cells and circulating tumor DNA), dose and schedule optimization for RNA therapeutics, and long-term follow-up for delayed adverse events. Although in vivo platforms can broaden site participation by removing apheresis requirements, early studies should include centers experienced in managing CAR T toxicities. Adaptive designs and careful country selection can help with enrollment and dose-finding when CAR T–naïve patients are scarce.
Regulatory expectations for in vivo programs increasingly emphasize biodistribution studies to demonstrate targeted delivery and minimize off-target effects, along with stringent chemistry, manufacturing and controls to ensure vector consistency and potency. These requirements are especially pertinent when RNA-based in vivo approaches are considered for healthy volunteer studies or non-oncology indications.
Both ex vivo and in vivo CAR T programs are advancing toward solid tumors, combination regimens and applications beyond oncology, including B-cell–mediated autoimmune diseases. Ex vivo efforts are testing armored CARs and checkpoint inhibitor combinations, while in vivo platforms are exploring multi-receptor constructs and localized delivery to overcome tumor microenvironment barriers.
If validated, in vivo CAR T could reduce cost and complexity and accelerate global scalability and access. Realizing that potential will require rigorous safety and biodistribution data, robust comparator and endpoint strategies for regulatory and payer acceptance, and trial designs that support timely evaluation of efficacy and long-term safety. Together, these innovations have the potential to broaden the impact of CAR T therapies across cancer and other immune-mediated diseases.
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