In vivo CAR: Answering Persistence Questions

Author: Joe Moss, Market Analyst, Hanson Wade Intelligence

A breakthrough year

The close of 2022 saw a landmark moment for allogeneic cell therapies, with the approval of the world’s first donor-derived T cell therapy, Atara Bioherapeutics’ Ebvallo. However, this milestone has not hindered the development of the next wave of off-the-shelf drugs, as researchers continue to find ways to overcome concerns surrounding allogeneic approaches, namely the persistence of T cells and hence the duration of therapeutic response. A ground-breaking study by Rurik et al. at the University of Pennsylvania showed that in vivo reprogramming of T cells to express a chimeric antigen receptor (CAR) restores cardiac function in a mouse model of heart failure. This proof-of-concept study paved the way for further in vivo CAR investment in 2022, as competition in the space heightened in the race to enter the clinic.

Viral delivery

A significant benefit of in vivo CAR is the opportunity to leverage clinically proven technologies born out of other therapeutic classes. Most current programs use viral vectors to transport genetic cargo to target cells, delivery systems that have proven effective in ex vivo gene therapies. Lentivirus is the vector of choice due to its high rate of genome integration, ensuring long-term CAR expression and hence more durable responses. Nonetheless, valid concerns remain around significant immunogenicity and the ability to administer multiple doses, which might be required for a true long-term cure. One potential solution is vector surface engineering to target specific cell subtypes, such as central memory T cells (Tcms), which have increased persistence. Umoja Biopharma is employing this strategy via surface expression of the SupraMolecular Activation Complex (SMAC).

Expanding LNP potential

Other key players, Capstan, Orna, and Carisma Therapeutics, prefer using lipid nanoparticles (LNPs), a well-established system following use in approved COVID-19 vaccines. Interestingly, of all in vivo CAR developers, these three companies have attracted the most venture capital over the last six months, highlighting the appeal of leveraging LNPs for this modality. This perhaps stems from their low immunogenicity compared to lentiviral vectors, offering the most straightforward and safest route to re-dosing and making off-the-shelf cell therapy a reality. Furthermore, delivery of mRNA (Capstan and Carisma Therapeutics) or circRNA (Orna Therapeutics) via LNPs induces transient CAR-T production, decreasing the risk of cytokine release syndrome and further enabling safer subsequent dosing.

The inherent infancy of this space means that limited data exists to evidence improved safety and persistence. However, announcements of planned INDs for 2023 suggest that these questions will soon be answered with first-in-human studies on the horizon.