LEM-onade for the CAR ride

by Robert Kruse

Scientists were buzzing last week with a Science paper featuring a previously unknown protein with key functions in the T cell response against infectious disease and cancer. The protein, LEM, regulates metabolism inside T cells. It was found through a genetic screen of for mutations that increased the T cell response to a chronic viral infection, LCMV, in mice. These mice were found to have a point mutation that led to increased stabilization of LEM mRNA and thus higher LEM protein levels. Interestingly, these mice also had improved immunity when inoculated with the B16 mouse melanoma line, resulting in weakened tumor formation.

The team at Imperial College London has filed two patents on the technology and established a startup called ImmunarT, revolving around adoptive immunotherapy. The startup looks to join the legions of Juno, Kite, Novartis, Cellectis, and more toward chasing adoptive T cell therapy. Given the cloudy IP situation around chimeric antigen receptors, it is possible the company can incorporate that technology and combine it with a vector overexpressing LEM inside T cells. Alternatively, this approach could also be applied to TILs or TCR-engineered T-cells. These T cells in theory should be more active than their normal counterparts. A key question will be whether long-term overexpression of LEM will be toxic to T cells, thereby nullifying the effect. Just because LEM is important at a defined step in T cell maturation and the immune response, doesn't mean that LEM would continue being beneficial. The researchers estimated human trials in 3 years, after more testing in mouse models

Beyond the discovery of LEM, this suggests other spheres of T cell optimization for therapy that aren't being targeted today. Currently, strategies to replace cytokines, guard against immunosuppresion, inhibit apoptosis, and help degrade extracellular matrix have been added to T cells to help improve performance. The LEM paper suggests optimizing cell metabolism as another route, merging biochemistry and immunotherapy. It is possible and likely that other metabolic targets exist, which may include proteins much more familiar in the field which could be overexpressed in T cells. A caveat of the LEM discovery is that it might be functionally redundant with existing improvement mechanisms mentioned above. For example, cytokine signaling could easily active expression at LEM's promoter, since cytokines are one of the master drivers of T cell activity. While an exciting target then, this story could be much ado about nothing. More microarray and pathway analysis is needed to define the effects of cytokines and TCR signaling on T cell metabolism, particularly in regards to LEM. If this research finds that LEM is upregulated by existing mechanisms, then the existing big-time CAR biotech companies should rest easy with their IP situation as is.