Interferon Signature in Anti-CTLA-4 and Anti-PD-1/PD-L1-Treated Cancer Patients Compared With Systemic Autoimmune Disease Patients

This study aims to identify a way to predict the side effects that some people with cancer experience when receiving immunotherapy. These side effects, known as immune-related adverse events (irAEs), occur when the immune system mistakenly attacks healthy tissues, like certain autoimmune diseases. At present, clinicians lack reliable tests to determine who is most likely to develop these reactions. The goal of this study is to determine whether substances in the blood called interferons (IFNs) could serve as early warning markers. The study will include 300 people with cancer who are about to begin immunotherapy. To provide a meaningful comparison, the investigators will also enroll 40 individuals with autoimmune diseases such as lupus. Understanding how IFN levels differ between these groups may help clarify whether IFN patterns in cancer patients resemble those seen in autoimmune disease. Participants in both groups will be asked to provide small blood samples at predefined time points during their clinical care or treatment. Researchers will measure the levels of different IFN types in all samples to compare IFN levels between cancer patients and individuals with autoimmune diseases, and within the cancer group between patients who develop irAEs and those who do not. The long-term aim of the study is to develop a simple test that can help clinicians identify patients at higher risk of irAEs. Immune-related adverse events (irAEs) are a frequent complication in cancer patients treated with immune checkpoint inhibitors (ICIs), and they often resemble or exacerbate preexisting autoimmune diseases. Despite extensive research in the field, no validated predictive biomarkers of irAEs currently exist. Emerging evidence suggests that the IFN signature -long implicated in the pathogenesis of several systemic autoimmune diseases (SADs)- may also be upregulated in patients who develop ICI-induced irAEs, likely with substantial overlap among different IFN subtypes. Given these clinical and molecular similarities with SADs, it is plausible that IFN levels in peripheral blood carry predictive value for irAE risk, although the dominant IFN types in ICI-related toxicity remain unknown. The INTER-AUTENTIC project aims to determine whether baseline IFN levels and their dynamic changes, measured in peripheral blood using a dedicated panel, can predict the onset of irAEs in cancer patients receiving ICIs. Supported by the Medical Oncology departments of six university hospitals in Northern Spain, this multicenter, observational, prospective cohort study has been underway since 2021. Biobank samples have been collected from ICI-treated patients before treatment initiation, at protocol-defined time points, and at the moment of irAE diagnosis (ICI cohort). The study seeks to identify the IFN subtypes with the most pronounced differential expression between patients with and without irAEs, and to evaluate whether IFN levels enhance the predictive performance of a model incorporating other clinical variables potentially associated with immune-mediated toxicity. A sample size of 300 cancer patients has been estimated for this analysis. In addition, a second prospective cohort of 40 non-cancer patients with systemic lupus erythematosus, primary Sjögren's syndrome, systemic sclerosis, and/or idiopathic inflammatory myopathy (SAD cohort) will be included. Since IFNs play a well-established pathogenic role in these conditions, this cohort will allow characterization of the IFN signature at key follow-up points (baseline, remission, and disease flare) and comparison with the IFN profiles of ICI-treated patients, regardless of whether they develop irAEs.

Sex

All

Minimum age

18 Years

ICI cohort:

Inclusion Criteria:

* Initiation of treatment with a single ICI or dual ICI therapy in accordance with current clinical guidelines;
* Patients who are treatment-naïve to ICIs; and
* Age ≥18 years.

Exclusion Criteria:

* Estimated mortality of less than 3 months from the start of treatment;
* Current combination therapy with chemotherapy, tyrosine kinase inhibitors, or other tumor-specific treatments;
* Contraindication to treatment with ICIs (documented hypersensitivity, severe active autoimmune disease, Eastern Cooperative Oncology Group \[ECOG\] ≥3);
* Ongoing immunosuppressive therapy, including prednisone at doses \>10 mg/day or equivalent.

SAD cohort:

Inclusion Criteria:

* Meeting classification criteria for Systemic Lupus Erythematosus (SLE) (ACR/EULAR 2019), Primary Sjögren's Syndrome (pSS) (ACR/EULAR 2016), Systemic Sclerosis (SSc) (ACR/EULAR 2013), and/or Idiopathic Inflammatory Myopathy (IIM) (ACR/EULAR 2017).
* Age ≥18 years old.

Exclusion Criteria:

* Estimated mortality less than 3 months from the start of follow-up.
* Active immunosuppressive treatment, including prednisone at doses \>10 mg/day or equivalent.
* Recent diagnosis (\<1 year) of cancer, with the exception of non-melanoma skin cancer, or currently receiving active oncology-specific treatment.

• BACKGROUNDLes I, Perez-Francisco I, Cabero M, Sanchez C, Hidalgo M, Teijeira L, Arrazubi V, Dominguez S, Anaut P, Eguiluz S, Elejalde I, Herrera A, Martinez M. Prediction of Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors With a Panel of Autoantibodies: Protocol of a Multicenter, Prospective, Observational Cohort Study. Front Pharmacol. 2022 Jun 1;13:894550. doi: 10.3389/fphar.2022.894550. eCollection 2022. PMID 35721217
• BACKGROUNDRiudavets M, Mosquera J, Garcia-Campelo R, Serra J, Anguera G, Gallardo P, Sullivan I, Barba A, Del Carpio L, Barnadas A, Gich I, Majem M. Immune-Related Adverse Events and Corticosteroid Use for Cancer-Related Symptoms Are Associated With Efficacy in Patients With Non-small Cell Lung Cancer Receiving Anti-PD-(L)1 Blockade Agents. Front Oncol. 2020 Sep 7;10:1677. doi: 10.3389/fonc.2020.01677. eCollection 2020. PMID 33014837
• BACKGROUNDHailemichael Y, Johnson DH, Abdel-Wahab N, Foo WC, Bentebibel SE, Daher M, Haymaker C, Wani K, Saberian C, Ogata D, Kim ST, Nurieva R, Lazar AJ, Abu-Sbeih H, Fa'ak F, Mathew A, Wang Y, Falohun A, Trinh V, Zobniw C, Spillson C, Burks JK, Awiwi M, Elsayes K, Soto LS, Melendez BD, Davies MA, Wargo J, Curry J, Yee C, Lizee G, Singh S, Sharma P, Allison JP, Hwu P, Ekmekcioglu S, Diab A. Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity. Cancer Cell. 2022 May 9;40(5):509-523.e6. doi: 10.1016/j.ccell.2022.04.004. Epub 2022 May 9. PMID 35537412
• BACKGROUNDBishu S, Melia J, Sharfman W, Lao CD, Fecher LA, Higgins PDR. Efficacy and Outcome of Tofacitinib in Immune checkpoint Inhibitor Colitis. Gastroenterology. 2021 Feb;160(3):932-934.e3. doi: 10.1053/j.gastro.2020.10.029. Epub 2020 Oct 21. No abstract available. PMID 33096100
• BACKGROUNDFernandez-Ruiz R, Niewold TB. Type I Interferons in Autoimmunity. J Invest Dermatol. 2022 Mar;142(3 Pt B):793-803. doi: 10.1016/j.jid.2021.11.031. Epub 2022 Jan 10. PMID 35016780
• BACKGROUNDUnger JM, Vaidya R, Albain KS, LeBlanc M, Minasian LM, Gotay CC, Henry NL, Fisch MJ, Lee SM, Blanke CD, Hershman DL. Sex Differences in Risk of Severe Adverse Events in Patients Receiving Immunotherapy, Targeted Therapy, or Chemotherapy in Cancer Clinical Trials. J Clin Oncol. 2022 May 1;40(13):1474-1486. doi: 10.1200/JCO.21.02377. Epub 2022 Feb 4.