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438 Interrogation of immune toxicity in patients with thymic epithelial tumors (TETs)
  1. Meredith McAdams,
  2. Shannon Swift,
  3. Madison Ballman,
  4. Abigail Wong-Rolle,
  5. Renee Donahue,
  6. Claudia Palena,
  7. Jeffrey Schlom,
  8. James Gulley,
  9. Arun Rajan and
  10. Chen Zhao
  1. National Cancer Institute, Bethesda, MD, United States


Background Immune checkpoint inhibitors (ICIs) are well tolerated and clinically active against a wide variety of cancers. However, the risk of immune toxicity in patients with thymic epithelial tumors (TETs), especially thymomas, remains unacceptably high due to underlying defects in immune tolerance.1-3 Mechanisms of immune toxicity remain poorly understood and the mainstay of treatment is immunosuppression with systemic corticosteroids, which can potentially impact the anti-tumor activity of ICIs.

Methods To understand mechanisms of organ-specific immune toxicity, we evaluated blood and tissue samples from patients with TETs enrolled in an ongoing NIH IRB-approved clinical trial (NCT03076554; NCI protocol number: 17C0066) of avelumab, an anti-PD-L1 antibody who developed multi-organ immune-related adverse events (irAEs) following treatment. Participants received avelumab 10 mg/kg IV every two weeks until disease progression or development of intolerable AEs. Toxicity was assessed with CTCAE 5.0. Immune profiling was conducted using one or more of the following methods: evaluation of biopsies with routine hematoxylin and eosin staining and immunohistochemistry (IHC), peripheral blood immune cell subset analysis by flow cytometry, RNAscope for IL-6, IL-8 and TGF-ß1 mRNA expression, and spatial transcriptomics using the nanoString Digital Spatial Profiler platform to investigate T-cells’ transcriptional profiles at tumor and irAE sites.

Results Between April 2017 and February 2022, 32 participants were enrolled (median age: 55 years; 16 female; 16 thymoma;). Five (16%) participants developed multiple irAEs during treatment. Objective anti-tumor responses were observed in 2 (40%) of 5 participants. table 1 includes clinical characteristics and results of immune analyses. Histopathology and IHC were notable for a T-cell infiltrate and paucity of B cells across irAE sites. IL-6 and TGF-ß1 mRNA expression was variable in cases of upper gastrointestinal inflammation. Spatial transcriptomic analysis of 1811 genes in tumor and irAE samples (bone marrow) from subject 3 revealed distinct T-cell activation profiles in the bone marrow compared with tumor infiltrating T cells (figure 1).

Conclusions Organ-specific heterogeneity in mechanisms of ICI-related immune-mediated toxicity in individuals with TETs needs further evaluation. If confirmed, these findings highlight the need to tailor immunosuppressive treatments to specific irAEs and develop strategies for primary or secondary prophylaxis to decrease the risks associated with immunotherapy while maintaining clinical benefit in this population.

Acknowledgements This research was supported in part by the Intramural Research Program of the National Cancer Institute (Center for Cancer Research) and through a Cooperative Research and Development Agreement between the National Cancer Institute and EMD Serono (CrossRef Funder ID: 10.13039/100004755), as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany and Pfizer.


  1. Ballman M, Zhao C, McAdams MJ, Rajan A. Immunotherapy for Management of Thymic Epithelial Tumors: A Double-Edged Sword. Cancers. 2022 Apr 20;14(9):2060. doi: 10.3390/cancers14092060. PMID: 35565190; PMCID: PMC9105984.

  2. Rajan A, Heery CR, Thomas A, Mammen AL, Perry S, O'Sullivan Coyne G, Guha U, Berman A, Szabo E, Madan RA, Ballester LY, Pittaluga S, Donahue RN, Tsai YT, Lepone LM, Chin K, Ginty F, Sood A, Hewitt SM, Schlom J, Hassan R, Gulley JL. Efficacy and tolerability of anti-programmed death-ligand 1 (PD-L1) antibody (Avelumab) treatment in advanced thymoma. J Immunother Cancer. 2019 Oct 21;7(1):269. doi: 10.1186/s40425-019-0723-9. PMID: 31639039; PMCID: PMC6805423.

  3. Cho J, Kim HS, Ku BM, Choi YL, Cristescu R, Han J, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial. J Clin Oncol. 2019 Aug 20;37(24):2162–2170. doi: 10.1200/JCO.2017.77.3184. Epub 2018 Jun 15. PMID 29906252.

Ethics Approval Samples used in this study were derived from an ongoing NIH IRB-approved clinical trial [NCT03076554; NCI protocol number: 17C0066]. Participants gave informed consent for participation in the clinical trial.

Abstract 438 Table 1

Clinical Characteristics and Results of Immune Analyses

Abstract 438 Figure 1

Volcano plot of T-cell genes enriched in primary tumor site versus organs affected by immune toxicity

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