Family Feud: T Cell Fratricide.

Before we really get into this, I need you to know that my relationship with my brother is just fine, thankyouverymuch. We get along great, in fact.

Anyway, fratricide.

As someone whose work centers around adoptive T cell therapies for cancer, T cell fratricide represents a nightmare scenario. The last thing you want is for your immunotherapeutic T cells to start killing each other, while the tumour chills out in the foreground.

There was a paper in The JCI in 2011 that showed that when T cells targeting survivin—an antigen experessed by tumour cells—were infused into a patient of a matching HLA type, those T cells died and the tumour thrived. So proliferating T cells make a lot of survivin themselves, and thus they became targets of their brother T cells who. There is seemingly no difference between survivin expressed by T cells (on the given HLA) and tumor-borne survivin, and this example is the very crux of target-dependent T cell fratricide.

Happily, this problem isn’t insurmountable. One strategy is outlined by Xiang et al in their paper where they pondered how to make non-fratricidal CAR Ts when attempting to take out CD2+ malignancies. This is a big ask of a CAR-T therapy. T cells are high expressors of CD2 given that it serves as a co-stimulatory molecule involved in all things from thymocyte development to immunological synapse formation. Ergo, a CAR directed to attack anything that expresses CD2 is very likely to cause carnage in the blood itself!

So, Xiang et al CRISPR’d out CD2 from their CAR and, predictably, found that these cells exerted poor tumor control: the IFNγ and Granzyme they had the potential to make (as determined by single-cell secretome analysis) wouldn’t fill a shot glass. This is…not great. However, these investigators decided to arm their ∆CD2 CARs with a long-acting recombinant IL-7, and they found that the functional impairment caused by CD2’s absence was reversed. The CAR Ts were in high cotton: good cytokine and cytolytic responses, and they weren’t killing each other!

It makes sense that IL-7 would set those CARs on the highway to directed cytolysis. After all, it’s a survival factor for T cells, especially CD8s, and also augments T cell cytolytic prowess. It was still a risk, though, to bring IL-7 into the picture, especially while treating a malignancy of T cell origin: IL-7 has been known to promote tumorigenesis.

But that’s a story for another time.

Peace!