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Imaging Effector Memory T-Cells Predicts Response to PD1-Chemotherapy Combinations in Colon Cancer
Julian L Goggi1, Shivashankar Khanapur1, Siddesh V Hartimath1
1Institute of Bioengineering and Bioimaging (IBB), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #01-02 Helios, Singapore 138667, Singapore.
Abstract:
Often, patients fail to respond to immune checkpoint inhibitor (ICI) treatment despite favourable biomarker status. Numerous chemotherapeutic agents have been shown to promote tumour immunogenicity when used in conjunction with ICIs; however, little is known about whether such combination therapies lead to a lasting immune response. Given the potential toxicity of ICI-chemotherapy combinations, identification of biomarkers that accurately predict how individuals respond to specific treatment combinations and whether these responses will be long lasting is of paramount importance. In this study, we explored [18F]AlF-NOTA-KCNA3P, a peptide radiopharmaceutical that targets the Kv1.3 potassium channel overexpressed on T-effector memory (TEM) cells as a PET imaging biomarker for lasting immunological memory response. The first-line colon cancer chemotherapies oxaliplatin and 5-fluorouracil were assessed in a syngeneic colon cancer model, either as monotherapies or in combination with PD1, comparing radiopharmaceutical uptake to memory-associated immune cells in the tumour. [18F]AlF-NOTA-KCNA3P reliably separated tumours with immunological memory responses from non-responding tumours and could be used to measure Kv1.3-expressing TEM cells responsible for durable immunological memory response to combination therapy in vivo.
Insights
A novel PET imaging agent, [18F]AlF-NOTA-KCNA3P, can identify lasting immune responses in colon cancer patients receiving combination therapy. This biomarker helps predict durable efficacy for immune checkpoint inhibitor (ICI) treatments.
Area of Science:
- Oncology
- Immunology
- Radiopharmaceutical Science
Background:
- Immune checkpoint inhibitor (ICI) therapy efficacy is limited by patient non-response, even with favorable biomarkers.
- Chemotherapy can enhance tumor immunogenicity with ICIs, but lasting immune responses are not well understood.
- Predicting durable responses to combination therapies is crucial due to potential toxicities.
Purpose of the Study:
- To evaluate [18F]AlF-NOTA-KCNA3P as a PET imaging biomarker for lasting immunological memory.
- To assess the peptide radiopharmaceutical's ability to detect T-effector memory (TEM) cells in a colon cancer model.
Main Methods:
- Utilized a syngeneic colon cancer model treated with oxaliplatin and 5-fluorouracil, alone or combined with PD1 blockade.
- Administered the Kv1.3-targeting peptide radiopharmaceutical [18F]AlF-NOTA-KCNA3P for PET imaging.
- Correlated radiopharmaceutical uptake with memory-associated immune cells in tumors.
Main Results:
- [18F]AlF-NOTA-KCNA3P successfully differentiated tumors with immunological memory from non-responding tumors.
- The PET tracer effectively measured Kv1.3-expressing TEM cells associated with durable responses.
- Demonstrated the potential for in vivo assessment of TEM cell populations crucial for combination therapy efficacy.
Conclusions:
- [18F]AlF-NOTA-KCNA3P serves as a reliable PET imaging biomarker for detecting durable immune responses to ICI-chemotherapy combinations.
- This approach can identify patients likely to achieve long-lasting benefits from immunotherapy.
- The study highlights the importance of targeting TEM cells for predicting treatment success in oncology.
