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Abstract
Background Immune related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). A prospective evaluation of the drivers of irAEs in a diverse pan-tumor cohort is needed to identify patients at greatest risk and to develop rational interception strategies.
Methods We prospectively collected clinical data and blood samples from patients with solid tumors at a single institution who received ICIs as standard of care. Blood samples were collected at baseline and early on treatment (month 1 or 2). We analyzed 32 circulating cytokines with Luminex multiplex assay and utilized Cytometry by Time-of-Flight (CyTOF) in an enriched cohort to investigate mechanisms of irAEs. Grade 2 or higher irAEs by CTCAE v5.0 were analyzed to enrich for clinically meaningful toxicities. Multi-testing adjustment utilizing false discovery rate (fdr) was performed for the primary cytokine time to irAE Cox analysis at baseline and early treatment.
Results 104 patients were prospectively enrolled. Reported race was 64.4% white, 28.8% black, and 2.9% Asian. 22.1% received combination anti-PD1/CTLA-4 therapy while 77.9% anti-PD1/PDL1 (monotherapy or in combination with other therapies). IrAEs occurred in 37.5% of the total patients with median onset of 2.1 months: 65.2% in anti-PD1/CTLA-4 (median 1.2 months) and 29.6% in anti-PD1/PDL1 groups (median of 2.9 months). Reported race was not associated with irAE development. No individual cytokine at baseline was associated with subsequent development of an irAE. In the Cox model, early fold changes in interleukin (Il)-6, Il-17f, Il-13, and Il-25 were significantly associated with the development of an irAE (table 1, adjusted p<0.05) and stratified patients by optimal cutoffs utilizing max log-rank statistics (figure 1, p<0.05). In the subgroup analysis, Il-6, Il-17f, and Il-25 were also significantly upregulated (figure 2, p<0.05) in patients who developed specific irAEs. To identify the cellular populations underlying these cytokine changes, we performed CyTOF on 15 irAE patients matched with 15 non-irAE patients by regimen and tumor type. Higher baseline proportions of two CD8+ T cell populations (CCR3+ and CCR4+), known to secrete type 2 cytokines,1 2 were associated with irAEs, while on-treatment persistent elevation of CD8+CCR4+ and peripheral expansion of effector memory Th17+ cells were associated with irAEs (figure 3, p<0.05).
Conclusions In a diverse, pan-tumor cohort, Il-6/Il-17f related Th17 and Il-13/Il-25 related CD8+ type 2 cytokine signatures are associated with the development of irAEs, serving as possible targets for monitoring and therapeutic interventions.
Acknowledgements The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, F. Hoffman-La Roche Ltd., and Genentech are members of the imCORE Network.
References
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Ethics Approval This study was approved by the Johns Hopkins institution’s Ethics Board #IRB00267960.
Significant cytokines in the adjusted time to irAE Cox model. HRs are reported per unit increase in fold change and were adjusted for treatment regimen used (combination anti-PD1/CTLA-4 treatment vs. anti-PD-1/PD-L1 groups). Abbreviations: HR = hazard ratio
Kaplan-Meier Curves of cumulative irAE stratified by early treatment cytokine fold changes. (A) IL-6 at cutoff 0.81, (B) II-17f at cutoff 1.4, (C) II-13 at cutoff of 1.1, (D) II-25 at cutoff of 1.6, (E) combined cytokine status. High combined cytokine status was defined as ≥2 cytokines were high, an intermediate status was defined when at least one cytokine was high, and a low status was when all four cytokines were low
transformed early treatment fold change between patients with no irAEs and specific types of irAEs: (A) II-6, (B) II-17f, (C) II-25
Proportion of cell populations. (A) Baseline, (B) On Treatment. Abbreviations: Tc_I = CD8+CCR3+,Tc_II = CD8+CCR4+, Thi7_EM = CD4+CD45RO+RORYT+Ki67+
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