Imaging Kv1.3 Expressing Memory T Cells as a Marker of Immunotherapy Response

Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer, however, only a relatively 33 small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding 34 tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated 35 with the generation of memory T cells. Effector memory T cells associated with tumour response to immune therapies are 36 characterized by substantial upregulation of the potassium channel Kv1.3 after repeated antigen stimulation. We have developed a 37 new Kv1.3 targeting radiopharmaceutical, [18F]AlF-NOTA-KCNA3P, and evaluated whether it can reliably differentiate tumours 38 successfully responding to immune checkpoint inhibitor (ICI) therapy targeting PD-1 alone or combined with CLTA4. In a syngeneic 39 colon cancer model, we compared tumour retention of [ 18F]AlF-NOTA-KCNA3P with changes in the tumour immune 40 microenvironment determined by flow cytometry. Imaging with [18F]AlF-NOTA-KCNA3P reliably differentiated tumours 41 responding to ICI therapy from non-responding tumours and was associated with substantial tumour infiltration of T cells, especially 42 Kv1.3-expressing CD8+ effector memory T cells.