In vivo cell therapy is emerging as a groundbreaking approach to reduce the cost and expand the availability of cell therapies. Unlike traditional ex vivo approaches where cells are extracted, modified externally, and then reinfused into the patient, in vivo cells therapies reprogrammed/engineer the cells within the subject, simplifying process and improving accessibility. In vivo cell therapies offer huge promise, particularly in the treatment of cancers, autoimmune diseases and genetic disorders. Technical and regulatory challenges to its widespread adoption remain, and there are interesting opportunities and strategic considerations from an intellectual property perspective.
The Promise of In vivo Cell Therapy
In vivo cell therapy represents a major shift in how we approach cell-based therapies. Traditionally, cell therapy has relied on ex vivo manipulation, as seen in contemporary approved chimeric antigen receptor (CAR) T-cell technologies. However, engineering of cells ex vivo can be labour-intensive, technically complex, time-consuming, and requires specialised facilities. The ex vivo processing procedures are prone to failure, and often yield products of poor quality and/or batch-to-batch consistency. In vivo engineering is a more streamlined, reliable and potentially cost-effective approach. Elimination of the need to extract and reinfuse cells simplifies the procedure for patients, while removal of the requirement to handle and modify cells ex vivo reduces costs and the risk of failure in production. In vivo cellular engineering could be key to unlocking what is still considered by many to be the biggest obstacle to widespread adoption of cell therapy: the per patient cost.
Changing Attitudes and Enabling Platform Technologies
So why haven’t cell therapies always been delivered in this way? Until recently, we didn’t have the necessary tools to reliably engineer cells in vivo with sufficient control.
In a recent interview, Prof. Carl June – often described as the ‘father’ of CAR-T – explained that the idea of engineering cells in patients in vivo has been around for many years, but that “10 years ago, the field to a person…said we would never be able to really give an integrating virus in vivo”. There were concerns that engineering cells in vivo could result in insertional mutagenesis and oncogenesis, particularly after leukemia-like outcomes were observed in recipient patients in early gene therapy trials. Ex vivo engineering provided more control, with the opportunity to screen and then select, expand and administer only the cells that had been modified as desired.
However, in recent years there has been significant technical progress in the ability to target delivery of modifying nucleic acids only to cell types of particular interest, the control that can be exercised over sites of genomic integration, engineering of cells with non-integrating payloads, and in the regulation of expression of such modifying nucleic acids in vivo.
New viral vectors – particularly novel adeno-associated viruses (AAVs) and lentiviruses – and also lipid nanoparticles (LNPs) have been developed that offer precise control of delivery of exogenous nucleic acid only to cell types of interest. We’ve also seen significant innovation in genetic elements of integrating viruses for controlling integration into specific regions of target cell genomes, while the maturation of AAV and LNP delivery systems and the rapid emergence of mRNA-based platforms provide a growing array of non-integrating alternatives. Novel regulatory elements for fine control of expression of modifying nucleic acids have also been developed, including novel tissue/cell-type specific promoters/enhancers and genetic ‘switches’ for turning expression on/up or down/off.
Challenges Remain
Despite significant progress, technical challenges remain. Innovators are working to develop vectors and elements to improve specificity and thereby further reduce off-target engineering and associated side effects. There’s also work to address the issue of elimination of vectors and engineered cells by the host immune system, e.g. through transient expression and/or immune cloaking, while balancing safety considerations of engineering vectors in this way. Novel systems for regulating expression in vivo are also in development, with the aim of improving the stability and durability of therapeutic effects.
Of course, innovative technologies also present new challenges from a regulatory perspective. In vivo cell therapies combine the complex regulatory considerations of both cell therapies and gene therapies, and will require rigorous safety evaluations and the development of novel manufacturing standards.
Intellectual Property – Opportunities and Strategic Considerations
With the emergence of in vivo cell therapy, there are clear opportunities to secure patent protection for novel delivery platforms, vectors, and procedures. As the field evolves, innovators are working to overcome shared technical challenges, and history suggests that certain breakthroughs could prove transformative, i.e. unlocking new possibilities for the entire space. Securing strong IP protection for these enabling innovations could be particularly valuable.
Given that the in vivo cell therapy movement is in its infancy, IP strategies should account for the likely long road to regulatory approval. Patent portfolios should be structured with a long-term view, ensuring that exclusivity is maintained throughout clinical development and beyond.
IP strategies should also align with the broader commercial landscape. Bringing these therapies to market will likely require collaboration between organisations with complementary expertise in technical and clinical development. Companies looking to establish a strong position in this space should ensure that their IP portfolios are structured to support strategic partnerships, licensing, and potential acquisitions.
