Trafficking T cells – how to get cells to their target destination

After being in the shadow of its famous relative, the antibody-producing B cell, for many decades, the time has come for the T cell to shine. Last year, we wrote about the world’s first approval for an allogeneic “off-the-shelf” T cell immunotherapy by the European Medicines Agency (EMA). Earlier that same year, 13-year old Alyssa became the first patient to receive a different type of allogeneic T cell therapy as treatment for her T-cell acute lymphoblastic leukaemia. And with the FDA swamped by next-generation cell therapy applications, there’s seemingly no stopping T cells from showing off their diverse therapy potential.

T cells are key players in the adaptive immune response and are capable of directly killing infected or malignant cells. Cell therapies use healthy, living cells, in this case T cells, to treat many diseases, including cancers. T cells can be engineered to express synthetic receptors that function to redirect T cells to recognise and eliminate cells expressing a particular target antigen, and these are referred to as chimeric antigen receptor (CAR) T cells.

For these therapies to work effectively, cells need to be able to reach their end destination successfully. T cells are phenomenal at treating haematological diseases such as leukaemia, and this has been partly due the easy accessibility of blood. However, one of the major challenges in the field is effective and targeted delivery of cells to specific tissue locations, in particular solid tumours.

Tissue homing, the cellular process that enables cells to get to a specific location within the body, is complex and difficult to replicate in situ. The stroma of solid tumours effectively forms a physical barrier preventing T cell penetration into the tumour, which poses additional difficulties for effective cell delivery.

One strategy that improves T cell trafficking to the tumour involves further engineering CAR T cells expressing chemokine receptors on their surface that home to specific tumour-derived chemokines. In addition, CAR T cells can be engineered to express specific enzymes that break down components of the stroma.

Perhaps a more holistic approach to solving the problem of effective cell delivery of next-generation cell therapies has been developed by researchers from the Wyss Institute, and coined “SomaCode”. Somacode uses high-throughput, in vivo pooled genetic screens to identify unique molecular signatures of disease followed by engineering therapeutic cells that are able to reliably home to that signature. The researchers have likened this process to “a car following directions to a specific zip code using a GPS system”.

It is exciting to see how decades of research and development have culminated in the first T cell therapies now reaching the market. While challenges remain, it is clearly only a matter of time before innovative scientists solve them.