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

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, [(18)F]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, [(18)F]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, [(18)F]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 [(18)F]AlF-NOTA-KCNA3P with changes in the tumour immune microenvironment determined by flow cytometry. Imaging with [(18)F]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.