Rachel Mumby and Nick Michelmore
CAR-T cell therapy remains an exciting area in healthcare, and a potentially very lucrative one - a recent market study has estimated the value to be $2.9 billion by 2023 worldwide. Celyad, a biopharmaceutical company specialised in CAR-T therapies announced last month that the FDA has accepted its Investigational New Drug application for the “world’s first” non-gene edited, allogeneic CAR-T clinical program. This latest CAR-T candidate, CYAD-101, is for the treatment of colorectal cancer. We have reviewed below some potential advantages and disadvantages of allogeneic vs autologous CAR-T therapies as well as gene-edited vs non-gene-edited allogeneic therapies.
Allogeneic vs Autologous
Autologous CAR-T therapies, where the cells are sourced from the patient, are further down the developmental pipeline than allogeneic CAR-T therapies, with Novartis’s Kymriah, and Kite Pharma’s Yescarta already approved by the FDA for certain indications, and with positive opinions from the EMA for marketing authorisations in the EU. In comparison, allogeneic CAR-T’s, where the cells are collected from a healthy donor, have so far lagged behind. This is not least because, unlike autologous CAR-T treatments, there is the potential and significant risk of Graft versus Host Disease (GvHD) - a medical complication that can arise following receipt of transplanted cells or tissue from a genetically different person, whereby the donor’s T-cells attack the recipient’s own tissues. A key hurdle for allogeneic CAR-T therapy development therefore is to overcome this safety issue.
However, allogeneic CAR-Ts may have advantages over autologous therapies. For example, in situations when it is either not possible or not suitable to extract healthy T-cells from the patient. Additionally, a universal ‘off-the-shelf’ allogeneic CAR-T cell product would cut the significant costs and time of having to undergo individual cell manufacturing for each patient. Allogeneic CAR-Ts could also allow for greater reproducibility, which would be beneficial when re-dosing is required.
To gene-edit or not to gene-edit?
There are other allogeneic CAR-T clinical programs preceding Celyad’s, such as Allogene and Servier’s UCART19 program. However, Celyad’s claims to be the first that is “non-gene edited”. After the T-cells are transduced with a CAR-encoding viral vector, they often go through a second manufacturing step, whereby the cell genome is edited. Allogeneic CAR-T cells are commonly gene edited to reduce the T cell receptor signalling that leads to GvHD. Celyad’s new technology program aims to reduce or eliminate the T cell receptor signalling responsible for GvHD using a peptide which is encoded alongside the CAR construct. The advantage, they say, is that these allogeneic CAR-T cells can then be produced through a single transduction step, using a manufacturing process that is highly similar to the more well-established process for producing Celyad’s clinical autologous CAR-T cell product – CYAD-01. Celyad state that this will offer significant advantages over gene edited approaches
There is clearly a long way to go before any such non-gene edited allogeneic therapy could reach the market. However, if shown to be safe and effective, CAR-T technologies such as CYAD-101 have the potential to offer significant advantages.