Abstract
Immune checkpoint inhibitors (ICIs) block checkpoint receptors that tumours use for immune evasion, allowing immune cells to target and destroy cancer cells. Despite rapid advancements in immunotherapy, durable response rates to ICIs remains low. To address this, combination clinical trials are underway assessing whether adjuvants can enhance responsiveness by increasing tumour immunogenicity. CpG-oligodeoxynucleotides (CpG-ODN) are synthetic DNA fragments containing an unmethylated cysteine-guanosine motif that stimulate the innate and adaptive immune systems by engaging Toll-like receptor 9 (TLR9) present on the plasmacytoid dendritic cells (pDCs) and B cells. Here, we have assessed the ability of AlF-mNOTA-GZP, a peptide tracer targeting granzyme B, to serve as a PET imaging biomarker in response to CpG-ODN 1585 in situ vaccine therapy delivered intratumourally (IT) or intraperitoneally (IP) either as monotherapy or in combination with αPD1. [18F]AlF-mNOTA-GZP was able to differentiate treatment responders from non-responders based on tumour uptake. Furthermore, [18F]AlF-mNOTA-GZP showed positive associations with changes in tumour-associated lymphocytes expressing GZB, namely GZB+ CD8+ T cells, and decreases in suppressive F4/80+ cells. [18F]AlF-mNOTA-GZP tumour uptake was mediated by GZB expressing CD8+ cells and successfully stratifies therapy responders from non-responders, potentially acting as a non-invasive biomarker for ICIs and combination therapy evaluation in a clinical setting.
Highlights
IntroductionThere are a lack of specific biomarkers capable of providing a readout of in situ immune responses to different treatment strategies, complicating interpretation of clinical trials combining different treatment strategies, such as in situ vaccines and Immune checkpoint inhibitors (ICIs). Numerous studies have demonstrated that tumour-associated immune infiltrates are required for immune therapy efficacy, and numerous imaging biomarkers have been developed to quantify immune cell infiltrates, such as the T lymphocyte populations CD3 and CD8
We have evaluated whether [18 F]AlF-mNOTA-GZP, can be used for the stratification of response to CpG-ODN in situ vaccine therapy combined with the immune checkpoint inhibitor αPD1 in a syngeneic mouse model of colon cancer
We explored whether different routes of administration of CpG-ODN could influence different tumourassociated immune responses, correlating tumour uptake of [18 F]AlF-mNOTA-GZP to differences in tumour-infiltrating immune cells using Fluorescence-Assisted Cell Sorting (FACS)
Summary
There are a lack of specific biomarkers capable of providing a readout of in situ immune responses to different treatment strategies, complicating interpretation of clinical trials combining different treatment strategies, such as in situ vaccines and ICIs. Numerous studies have demonstrated that tumour-associated immune infiltrates are required for immune therapy efficacy, and numerous imaging biomarkers have been developed to quantify immune cell infiltrates, such as the T lymphocyte populations CD3 and CD8. We have evaluated whether [18 F]AlF-mNOTA-GZP, can be used for the stratification of response to CpG-ODN in situ vaccine therapy combined with the immune checkpoint inhibitor αPD1 in a syngeneic mouse model of colon cancer. We explored whether different routes of administration of CpG-ODN could influence different tumourassociated immune responses, correlating tumour uptake of [18 F]AlF-mNOTA-GZP to differences in tumour-infiltrating immune cells using FACS
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