Cell and gene therapy is reshaping oncology, with chimeric antigen receptor (CAR) T-cell therapies delivering marked benefits in hematologic malignancies while facing persistent obstacles around access, manufacturing complexity and inconsistent real-world outcomes.
Two development paths are emerging. Ex vivo CAR T programs are moving into randomized trials against approved therapies, and in vivo CAR T platforms aim to engineer T cells inside the patient, eliminating personalized manufacturing and potentially improving scalability and access.
Ex vivo CAR T therapies have established efficacy in B-cell leukemias and lymphomas, and approved products are moving into earlier lines of therapy. Next-generation approaches include off-the-shelf allogeneic products and dual-target CARs such as CD19/CD20 or CD19/CD22, designed to reduce relapse from antigen escape. Progress in solid tumors remains limited, driven by suppressive tumor microenvironments; strategies under study include checkpoint inhibition and chemokine receptor engineering to enhance tumor infiltration and activity.
Sponsors of ex vivo programs face a higher evidence bar as approved therapies become standards of care. Trial designs increasingly require randomized comparators or rigorously constructed external control arms using high-quality real-world data. Endpoint sets should extend beyond response rates to include minimal residual disease, time-to-next-treatment and patient-reported outcomes to meet payer and health technology assessment expectations. Transparent manufacturing metrics—vein-to-vein timelines, product success rates and details on bridging therapies—are essential for regulators and payers, along with plans for expanded access to out-of-spec products.
In vivo CAR T approaches represent a paradigm shift by delivering CAR constructs directly to patients, removing leukapheresis and ex vivo manipulation. Two platform types have reached first-in-human trials: engineered viral vectors that aim for durable CAR expression and targeted RNA–lipid nanoparticle systems that produce transient CAR expression amenable to repeat dosing. Viral-vector approaches require long-term monitoring for insertional mutagenesis under gene therapy guidance; RNA–LNP strategies avoid genomic modification but raise concerns about LNP toxicity, immunogenicity and hypersensitivity alongside standard CAR T toxicities such as cytokine release syndrome and neurotoxicity.
Early-phase in vivo trials resemble traditional drug studies and can enable faster enrollment and broader site participation, but they demand tailored design elements. Protocols should incorporate translational biomarkers (circulating CAR T cells, circulating tumor DNA), MRD assessments and appropriate efficacy endpoints. Dose and schedule optimization, robust safety monitoring for both platform-specific and CAR T–related toxicities, and selection of sites experienced in managing immune-effector adverse events are critical. Adaptive designs can accelerate dose finding and account for evolving endpoints and extended follow-up needs. Regulators will require rigorous biodistribution data and strong Chemistry, Manufacturing and Controls for vector consistency and potency.
Both ex vivo and in vivo programs are extending toward solid tumors, combination regimens and non-malignant B-cell–mediated diseases. Ex vivo efforts are exploring armored CARs and immune checkpoint combinations; in vivo work focuses on multi-receptor constructs and localized delivery to overcome the tumor microenvironment. Demonstrating differentiation will require robust comparator strategies and meaningful clinical endpoints.
If validated, in vivo CAR T could lower costs and simplify logistics, enabling broader global access and faster scalability. Realizing that potential will depend on addressing novel safety and regulatory challenges and generating the comparative evidence needed by clinicians, payers and health authorities. Trials will remain the critical proving ground for safety, efficacy and real-world applicability as CAR T technologies evolve.
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