Background The availability of immune checkpoint inhibitors (ICI) has radically changed the prognosis of patients (pts) with metastatic melanoma. More recently, PD-1 inhibitors have also become the standard of care as adjuvant therapy in high-risk and resected melanoma.1–7 However, 65–80% of patients treated with ICI experience immune-related adverse events (irAEs)8 causing morbidity and a potential decrease in clinical benefit. Currently, there are no biomarkers that can predict which patients are at risk of developing irAEs. Aim of this study is to recognize patients who will develop toxicity to anti-PD1 treatment.
Methods Gene profiling analysis was performed using NanoString IO360 panel from basal PBMCs of patients treated with anti-PD1 in both setting (adjuvant and first line therapy). Patient’s characteristics are reported in (table 1). To identify the best genes signature the Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) was applied. Differences in characteristics of patients with and without toxicity were tested by t-test or Wilcoxon test (according to their distribution) and Pearson chi-squared test for continuous and categorical variables, respectively. ROC curves were used to determine the best cut off which defines the border line between absence and presence of toxicity (table 2).
Results Among 161 pts included, 75 received anti-PD1 as adjuvant therapy (AT) and 86 as first line therapy (FLT). Arthralgia and fever were observed in the 27% and 14% of total population (12% and 9% respectively in AT; 15% and 4% respectively in FLT). A specific gene signature for predicting the onset of arthralgia has been identified and characterized by the most representative genes such as: ZEB2, TNFS13, RPTOR, NFKBIE, GNLY, CCNB1. In particular, we observed that genes involved in the mTORC/NF-κB pathway correlate with arthralgia. Differently, the gene signature for predicting the onset of fever is mainly characterized by humoral immunity genes such as: HLA-F, CD8B, CD45RA, CD27. In both cases, the increase of signature value is associated with a greater probability of toxicity onset.
Conclusions In this retrospective study, we found a gene signature model able to predict the onset of toxicities (arthralgia and fever) related to anti-PD1 treatment. Further investigations are needed to get additional information.
Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet. 2021;398(10304):1002–14. https://doi.org/10.1016/S0140–6736(21)01206-X.
Jiang YZ, Liu YR, Xu XE, Jin X, Hu X, Yu KD, Shao ZM. Transcriptome analysis of triple-negative breast cancer reveals an integrated mRNA-lncRNA signature with predictive and prognostic value. Cancer Res. 2016;76(8):2105–14. https://doi.org/10.1158/0008–5472.CAN-15–3284.
Gandhi S, Pandey MR, Attwood K, Ji W, Witkiewicz AK, Knudsen ES, Allen C, Tario JD, Wallace PK, Cedeno CD, Levis M, Stack S, Funchain P, Drabick JJ, Bucsek MJ, Puzanov I, 2021
John SP, Sun J, Carlson RJ, Cao B, Bradfield CJ, Song J, Smelkinson M, Fraser IDC. IFIT1 exerts opposing regulatory effects on the inflammatory and interferon gene programs in LPS-activated human macrophages. Cell Rep. 2018;25(1):95–106.e6. https://doi.org/10.1016/j.celrep.2018.09.002.
Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1. https://doi.org/10.1056/NEJMc1509660.
Li JW, Zhou J, Shi ZT, Li N, Zhou SC, Chang C. Sonographic features of triple-negative breast carcinomas are correlated with mRNA-lncRNA signatures and risk of tumor recurrence. Front Oncol. 2021;10: 587422. https://doi.org/10.3389/fonc.2020.587422.
Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000 Prime Rep. 2014;6:13. https://doi.org/10.12703/P6–13.
Bertrand A, Kostine M, Barnetche T, Truchetet ME, Schaeverbeke T. Immune related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. BMC Med. 2015 Sep 4;13:211. doi: 10.1186/s12916–015-0455–8.
Ethics Approval This study was approved by the Ethics Committee of Istituto Nazionale Tumori - IRCCS - Fondazione ‘G. Pascale’, Naples, Italy, protocol number 33/17 oss. All patients provided their written informed consent to participate in this study.
Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal
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