Navigating New Frontiers in Cell and Gene Therapy: In Vivo CAR T Opportunity and The Role of Investigator-Initiated Trials

Cell and gene therapies (CGT) are redefining how we treat disease. Driven by innovations and improvements in the field of CAR-T therapies, CRISPR gene editing and mRNA technologies, combined with better ways to deliver these treatments to patients, the market is expected to achieve tremendous growth. Indeed, the global CGT industry is entering a reported scale-up phase, with market forecasts projecting growth worth billions of dollars, with a CAGR between 17% to 22%, depending on source.

This growth is reflected in an expanding pipeline, increasing approvals, and maturing platforms across viral and nonviral delivery systems, particularly for CAR-T therapies that reprogram immune cells to attack disease at the biological root. While ex vivo CART has transformed outcomes for patients, its complex personalized manufacturing process, time to therapy and cost, have limited its potential.

In vivo CAR-T offers an exciting alternative path. In vivo CAR-T therapy engineers the patient’s own immune cells, to target and destroy cancer cells, inside their body. This eliminates the need for some of the complex and costly elements of ex vivo CAR-T, such as cell manufacturing, simplifying production, reducing costs, and allowing patients more accessible and timely treatment options.

Strategic investment and collaborations are on the rise for vivo CAR-T therapies. Kelonia Therapeutics recently announced the first patient dosing for anti-BCMA in vivo CAR-T (KLN-1010) and Vivacta Bio announced promising in-human results for GT801, an in vivo CAR-T therapy for Non-Hodgkin’s Lymphoma. In addition, numerous companies can be seen to be investing in their pipelines, services, and products to support the growing market.

Considerations for Manufacturing In Vivo CAR-T Therapies

In vivo CART delivers genetic payloads via viral vectors, such as lentivirus (LVV) and adeno-associated virus (AAV), and nonviral carriers such as targeted lipid nanoparticles (tLNPs). LNPs deliver mRNA encoding the CAR construct directly into T cells in vivo, where the mRNA is translated into CAR protein, but does not integrate into the genome. LVVs deliver DNA encoding the CAR construct, which integrates into the T-cell genome.

The consideration of which delivery system to use will depend on several factors:

Safety and Immunogenicity

tLNPs enable the integration of RNA into immune cells by transient expression, providing a shorter expression of days to weeks, depending on mRNA stability and immune clearance. Viral vector delivery enables a more stable integration, with long-term expression (years) and carries higher risks due to genomic integration. Primary investigations have suggested that tLNPs have potential for autoimmune disease, whilst LVV offers potential for treating cancer.

Targeting Efficiency

LNPs can be engineered to target specific tissues; however, this does require optimization of the LNP formulation to avoid adverse effects on non-targeted tissues. The LNP is conjugated with a targeting antibody which binds to the T cell receptor. Viral vectors are highly efficient at delivering genes into cells, with precise regulation achievable. The viral vector envelope is modified to de-target first, followed by another plasmid coding targeting antibody to retarget T cells.

Manufacturability

The LVV manufacturing process is mature but still faces CMC challenges. mRNA-tLNP is a new modality with the advanced project, in clinical stages, so it is difficult to compare at this stage. Lipid nanoparticles (LNPs) currently dominate due to scalability, faster turnaround, and consistency, particularly in oncology and immunology, though technical challenges remain around targeting, conjugation, and QC. Specialization in advanced QC testing for targeted LNPs with high-end analytics and comprehensive QC panels is critical. Assays for potency, lipid composition, and endosomal escape profiling are increasingly recognized as necessary for clinical success.

Although viral delivery markets are well established, non-viral delivery is seeing fast growth and innovation, with more standard offerings driving towards platformization and broader adoption.

The Role of Investigator-Initiated Trials for In Vivo CAR-T

In vivo CAR-T offers promise to expand into treating solid tumors and autoimmune diseases, an area where ex vivo CAR-T has not been able to fully realize potential due to scalability and accessibility issues. Investigator initiated trials (IITs) may offer a way of helping fulfil that promise.

IITs are clinical studies conceived, designed, and led by independent investigators, usually academic centers. These centers can leverage academic infrastructure and ethics processes, often reducing start-up time and cost. Because of their position outside a corporation, they can focus on exploratory work and early-stage innovation, to enable rapid testing. This offers a time advantage for emerging innovative therapies, bringing them to patients more quickly.

An example of IITs driving innovation was shown recently by EsoBiotec, a small startup working on an immune shielded lentiviral BCMA in vivo CART (ESOT01). EsoBiotec worked with Chinese doctors to run an investigator lead-initiated trial, compressing lab-to-clinic timelines, showing positive results quickly. Indeed, China is very attractive for IITs for numerous reasons such as its large patient population, regulatory flexibility at early innovation stages, academic structure and expertise, cost efficiency and government and institutional support.

The move to in vivo CAR-T is redefining the CGT landscape. To deliver on its promise, manufacturers will need to have expertise in many areas of advanced therapy manufacturing, providing flexible, scalable platforms, support from cell line development to CMC and guidance through regulatory frameworks.