LAUSR

Simple Summary Cancer immunotherapy has shown huge potential in the fight against cancer but few patients respond durably to treatment. Durable immunological responses are associated with the generation of memory T cells. A subset of memory T cells, effector memory T cells, have been shown to be associated with tumours responding to immune checkpoint inhibitor therapy in a range of cancer types. These effector memory T cells overexpress the potassium channel, Kv1.3, on the cell surface. In the current manuscript, we have developed a new Kv1.3 targeting peptide radiopharmaceutical, [18F]AlF-NOTA-KCNA3P, and characterised its in vivo biodistribution and ability to stratify response to immune checkpoint inhibitor therapy, correlating tumour uptake to changes in tumour associated immune cell populations. Overall, [18F]AlF-NOTA-KCNA3P successfully predicted response to immune checkpoint inhibitors in a murine model of colon cancer where tracer uptake in the tumour correlated well with changes in tumour associated memory T cell populations. Abstract Immune checkpoint inhibitors have shown great promise, emerging as a new pillar of treatment for cancer; however, only a relatively small proportion of recipients show a durable response to treatment. Strategies that reliably differentiate durably-responding tumours from non-responsive tumours are a critical unmet need. Persistent and durable immunological responses are associated with the generation of memory T cells. Effector memory T cells associated with tumour response to immune therapies are characterized by substantial upregulation of the potassium channel Kv1.3 after repeated antigen stimulation. We have developed a new Kv1.3 targeting radiopharmaceutical, [18F]AlF-NOTA-KCNA3P, and evaluated whether it can reliably differentiate tumours successfully responding to immune checkpoint inhibitor (ICI) therapy targeting PD-1 alone or combined with CLTA4. In a syngeneic colon cancer model, we compared tumour retention of [18F]AlF-NOTA-KCNA3P with changes in the tumour immune microenvironment determined by flow cytometry. Imaging with [18F]AlF-NOTA-KCNA3P reliably differentiated tumours responding to ICI therapy from non-responding tumours and was associated with substantial tumour infiltration of T cells, especially Kv1.3-expressing CD8+ effector memory T cells.