Fate Therapeutics Inc (FATE)

[jondoeuk]

Trogocytosis has been documented for other leukocytes, including T-cells. In this paper, CAR-T cells were also shown to exhibit it when co-cultured with different types of cancer cells, including CARs that used the high-affinity CD19 binding domain FMC63 (most CAR-T therapies use it) https://www.nature.com/articles/s41586-019-1054-1

Similarly, it can be triggered by engagement of the CD16 receptor on NKs with mAbs leading to reduced efficacy https://ashpublications.org/blood/article/125/5/762/34055/Fc-receptor-mediated-trogocytosis-impacts-mAb https://aacrjournals.org/clincancerres/article/22/21/5211/79645/Checkpoint-Inhibition-of-KIR2D-with-the-Monoclonal

In this, they investigated if it contributed to (anti-CD19) CAR-NK cell fratricide and tumour progression in patients with lymphoid malignancies treated in a previously reported trial https://www.nature.com/articles/s41591-022-02003-x

Using blood samples collected at multiple time points after CAR-NK cell infusion, patients were divided into two groups based on the overall trogocytosis expression on CAR-NK cells [high (n=4) vs. low (n=7)]. It was found that acquisition of trogocytosised CD19 expression on CAR-NK cells was associated with a reduction in CD19 expression on B-cells and a higher probability of relapse (3 of 4 patients) compared to patients in the low group (0 of 7 patients). Also, expression was associated with improved clinical response. Those with a lower level had improved responses (100% ORR vs. 25% ORR).

They hypothesised that an inhibitory CAR, which incorporated an scFv directed to an NK-specific antigen linked to a inhibitory signal might overcome it. To determine that, they synthesised a CAR that recognised an NK self antigen. This was done by fusing the transmembrane and intracellular domains of a CAR with an scFv targeting CS1, a co-receptor that is expressed on all normal NKs, but absent on most CD19+ lymphoid-derived malignancies.

While this did not impact the extent of trogocytosis, they observed less trogocytosis-mediated in vivo fratricide (NK self killing), as evidenced by the better cell viability, higher persistence and improved effector functions compared with control groups.

So, companies should be able to address it, but I'm not aware of any that currently are.