Clinical development of lead NEOantigen-specific T cell receptors for Adoptive T cell Therapy of solid tumors (NEO-ATT)

Targeting cancer mutations by reactivating neoepitope-specific T-cells using checkpoint blockade has shown therapeutic success in solid cancers with high mutational load but is hampered in patients with tumors carrying lower numbers of mutations. Here, targeting mutations by T-cell receptor (TCR) gene therapy may be a more appropriate strategy. 

Exemplarily, for the activating mutation in the GTPase Rac1, the 3rd most common mutation in melanoma, we found that heterologous targeting Rac1P29S mutant cancer cells with TCR-modified T-cells generated against the isogenic mutation Rac2P29L elicits efficient tumor rejection upon adoptive T-cell therapy.

On the other hand, we found that high-affinity H3.3K27M-specific HLA-A2 restricted TCR-modified T-cells against glioma were unable to recognize tumor cells naturally expressing the H3.3K27M mutation.  This points to the cautionary note that in silico predicted (neo)antigens should first be validated by testing for presence of the expected HLA ligands on the relevant cells, either by T-cell assays or by mass spectrometry, before an extensive (and expensive) development program towards clinical use is started.