Immune checkpoint therapy for thymic carcinoma

Immune checkpoint therapy for thymic carcinoma | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 14 May 2025 V1 Latest version Share on Immune checkpoint therapy for thymic carcinoma Authors : Jinhui Li 0009-0001-2803-7484 , Mao Fuling , Hongyu Liu , and Jun Chen [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.174724425.56401794/v1 Published Cancers Version of record Peer review timeline 395 views 156 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Thymic carcinoma (TC) is a malignant tumor that originates from the thymic epithelium. Compared to other thymic epithelial tumors, TC has distinctive immunological, morphological, and behavioral characteristics and is aggressive, which complicates its treatment. Currently, immune checkpoint–based immunotherapies have shown significant success in cancer treatment. Programmed cell death protein ligand 1 (PD-L1) is an immune checkpoint that is highly expressed in TC; several immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1/PD-L1 axis have been evaluated in advanced and metastatic TC. However, a very low tumor mutational burden and immune-related adverse effects continue to pose challenges for immune checkpoint blockade therapies in TC. The development and combination of other emerging ICIs may represent a future direction. This review explores the role of immunotherapy in TC as well as its future opportunities and challenges. Immune checkpoint therapy for thymic carcinoma Jinhui Li 1 , Fuling Mao 1 , Hongyu Liu 2* , Jun Chen 1,2* Author affiliations: 1 Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China 2 Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China *Co-correspondence: Jun Chen ( [email protected] )：https://orcid.org/0000-0001-9552-4429 Hongyu Liu ( [email protected] ) Abstract Thymic carcinoma (TC) is a malignant tumor that originates from the thymic epithelium. Compared to other thymic epithelial tumors, TC has distinctive immunological, morphological, and behavioral characteristics and is aggressive, which complicates its treatment. Currently, immune checkpoint–based immunotherapies have shown significant success in cancer treatment. Programmed cell death protein ligand 1 (PD-L1) is an immune checkpoint that is highly expressed in TC; several immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1/PD-L1 axis have been evaluated in advanced and metastatic TC. However, a very low tumor mutational burden and immune-related adverse effects continue to pose challenges for immune checkpoint blockade therapies in TC. The development and combination of other emerging ICIs may represent a future direction. This review explores the role of immunotherapy in TC as well as its future opportunities and challenges. Keywords: generation of immune checkpoints inhibitors, programmed cell death protein ligand 1, programmed cell death protein 1, thymic carcinomas, Immune-related adverse events Word Count: 7900 words (including references) Number of Tables/Figures: 3 tables, 1 figure Supporting Information: None Abbreviations CR Complete Response CTLA-4 Cytotoxic T-Lymphocyte-Associated Protein 4 DCR Disease Control Rate EMT Epithelial–Mesenchymal Transition ICIs Immune Checkpoint Inhibitors irAEs Immune-related Adverse Events OS Overall Survival PFS Progression-Free Survival MSI Microsatellite Instability MSS Microsatellite Stable MPR Major Pathologic Response NPR Non-Progression Rate ORR Objective Response Rate PD-1 Programmed Cell Death Protein 1 PD-L1 Programmed Cell Death Protein Ligand 1 PR Partial Response SD Stable disease TC Thymic Carcinoma TET Thymic Epithelial Tumor TILs Tumor-Infiltrating Lymphocytes TMB Tumor Mutational Burden Introduction Thymic epithelial tumors (TETs) are rare malignant tumors originating from the thymic epithelium that include thymomas, thymic carcinoma (TCs), and thymic neuroendocrine tumors (NETTs) 1 . Although the overall incidence is low, TET is the most common tumor of the anterior mediastinum. Of these, TC is particularly aggressive and has a poor prognosis 2 . The annual incidence of TETs is estimated to be 1.3–3.2 cases per million people globally. The most common TET subgroup is thymoma, accounting for nearly 50% of cases, followed by TCs (14–22%), and NETTs (2–5%). Compared to other subtypes, TCs exhibit unique morphological and behavioral characteristics 3 . Thymic squamous cell carcinoma (TSCC) is the most common subtype of TC and accounts for 72.4% of TCs and 7.2% of thymic tumors 3 . Thymic carcinoma shows high-grade histologic features, including marked cellular atypia, frequent mitoses, mature T and B cells, and the presence of vascular invasion and necrosis 4 . Among TETs, thymomas have a better prognosis with an overall 5-year survival rate of approximately 78%, while patients with TC have a poor prognosis with a 5-year survival rate of 36% for locally advanced TCs 1 . If metastasis occurs, the 5-year survival rate drops to 24% 2 . Treatment of TC has historically been challenging due to its rarity and aggressiveness. Surgical resection remains the mainstay of treatment for localized diseases, while systemic therapy is used in advanced or metastatic cases 5 . Carboplatin combined with paclitaxel chemotherapy has been the standard first-line treatment for advanced TC; compared with anthracycline-containing chemotherapy regimens, this regimen has shown significant efficacy in TC but still has a poor response rate 6 . In contrast, no standard second-line treatment exists for patients with advanced TC that has recurred or metastasized after first-line chemotherapy since the benefit is much less than that of a phase I chemotherapy regimen 7 . Due to the lack of unique targeting sites, targeted drugs are not widely used in the treatment of TCs 8 . This highlights the urgent need for novel therapeutic strategies to improve the prognosis of patients with TC. In recent years, immunotherapy, especially ICIs, has emerged as a promising approach for the treatment of various solid tumors. These drugs, especially those targeting programmed cell death protein 1 (PD-1) and its ligand, programmed cell death protein ligand 1 (PD-L1), have shown significant efficacy in a variety of solid tumors 9 . Given the limited treatment options and poor efficacy of conventional therapies, the potential application of ICIs in TC has attracted great interest. Several studies have reported high rates of PD-L1 expression in TC, ranging from 54% to 80% 10 11 . The high rate of PD-L1 expression suggests that the PD-1/PD-L1 axis may play a role in immune evasion in these tumors. However, although TCs typically exhibit a low tumor mutational load (TMB) compared to other solid tumors, paradoxically, they have a surprisingly high response rate to ICIs 12 . This observation challenges the conventional view that TMB is a reliable predictor of ICI efficacy and underscores the complex interplay between tumor biology and immune response in TC. High PD-L1 expression provides a rationale for using ICIs targeting the PD-1/PD-L1 inhibitors in TC therapy. As research in this area intensifies, interest has grown in identifying biomarkers that can predict the response to TC ICI therapy. While PD-L1 expression remains the most promising biomarker to date, other potential markers, such as tumor-infiltrating lymphocytes (TILs), T-cell receptor diversity, and novel immune checkpoints (e.g. TIM-3, B7-H4, and CD70), are also under investigation 12 . The use of ICIs in TC represents a promising new field for the treatment of this challenging malignancy. Although early clinical results are encouraging, further studies are needed to optimize therapeutic strategies, identify predictive biomarkers, and manage potential toxicities. This current review is to provide a comprehensive overview of the status of ICI for the treatment of TC and to explore future directions for improving the prognosis of patients. 1. Monotherapy with PD1/PD-L1 inhibitors for TC One of the most striking features of TC is the expression of PD-L1, which plays a crucial role in immune evasion and has become a target for immunotherapy. Several studies have investigated the expression of PD-L1 in TC and found this was higher in TC compared to thymomas 13 . A comprehensive analysis by Katsuya et al. 14 found that 70% of TCs expressed PD-L1, which was significantly higher, compared to 23% of thymomas. This finding was confirmed by another study 15 , which described PD-L1 expression in 61% of TETs, with TCs showing significantly higher expression than thymomas. The clinical significance of PD-L1 expression in TC has been a hot research topic. A study by Padda et al. 11 found that 68% of TET cases showed high PD-L1 expression and that PD-L1 expression correlated with advanced disease staging. This suggests that PD-L1 may be a potential prognostic marker for TC. The expression pattern of PD-L1 appears to be more heterogeneous in TC compared to thymoma. Notably, although PD-L1 expressions are usually higher in TC, the pattern may be different from that in thymomas. A study by Yokoyama et al. 16 found that median and mean PD-L1 expression was higher in B2 and B3 thymomas compared to TC. This scientific study emphasizes that the pattern of PD-L1 expressions in TC may be associated with the high biological heterogeneity of TC. The high rate of PD-L1 expression in TC provides a strong rationale for the use of ICIs that target the PD-1/PD-L1 axis. However, it is uncertain whether PD-L1 expression is associated with survival and prognosis in TC; more studies are still needed to determine this. Other factors, such as TMB and the presence of TILs, further illustrate the immune profile of TC. It was shown that all TET samples exhibited high levels of CD3 + and CD8 + TIL infiltration, with CD8 + lymphocytes accounting for approximately 82.8% ± 18.3% of CD3 + lymphocytes 17, 18 . In addition, 62% of patients with TC showed high PD-1 expression on TIL, suggesting the presence of an immunosuppressive microenvironment that could potentially be reversed by ICI therapy 18 . Tumor mutational load and microsatellite instability (MSI) are important biomarkers for predicting the efficacy of ICIs in various cancers 19 20 . However, in TET, including TC, these biomarkers show unique features that may influence the efficacy of immunotherapy. Several studies have investigated TMB and MSI in TET and found that these tumors typically exhibit lower TMB and microsatellite stability (MSS) 21 22 . A comprehensive review by Rajan et al. 17 emphasized that TETs have a lower TMB compared to other solid tumors. This low mutational load may limit the efficacy of ICIs, as a higher TMB is usually associated with a better immunotherapy response in other cancer types. Despite its low TMB, TC has responded to ICI therapy in clinical trials. For example, a study by Giaccone et al. 23 reported an objective response rate (ORR) of 22.5% in patients with TC treated with pembrolizumab, although TMB was generally low. A case report by Chen et al. 24 further explored the relationship between TMB and response to TC treatment. They described two patients with metastatic TC after first-line treatment with pembrolizumab + chemotherapy. Unexpectedly, both patients achieved durable clinical responses despite low TMB and MSS status. Although no evidence exists suggesting that TMB and MSI are likely to be suitable predictive markers in TC, these characteristics may contribute to the response of TC to ICIs. Such an observation challenges the conventional understanding of TMB as a predictive biomarker of ICI efficacy and suggests that other factors may play a more important role in determining therapeutic response in TC. PD-1/PD-L1 Monotherapy Table 1 Summary of clinical trials of immune checkpoint inhibitors in thymic carcinoma Pembrolizumab TC 40 57 28/12 22.5 75 4.2 24.9 ORR 15 Giaccone et al., 2018 Pembrolizumab TC 26 57 18/8 19.2 73.1 6.1 14.5 ORR 15.4 Cho et al., 2019 Nivolumab TC 15 55 12/3 0 73.3 3.8 14.1 ORR 14.3 Katsuya Y., 2019 Nivolumab T and TC 10/43 58 35/20 12 67 6.2 21.3 PFS 59 N. Girard., 2023 Avelumab T and TC 7/1 53 5/3 0 100 NA NA DLT 83.3 Arun Rajan., 2019 TC Thymic carcinoma, T Thymoma, ORR Overall Response Rate, DCR Disease Control Rate, mPFS median Progression-Free Survival, mOS median Overall Survival, DLT Dose-Limiting Toxicities, irAEs immune-related Adverse Events Pembrolizumab Giaccone et al. conducted a single-arm phase II study 23 of pembrolizumab in patients with recurrent TC after chemotherapy. A total of 40 patients with TC were enrolled ( Table 1 ). After 20 months of follow-up, one patient was in complete remission and eight patients were in partial remission, with an overall remission rate of 22.5%. Approximately 53% of patients had stabilized diseases, and the disease control rate (DCR) was 75%. At the cutoff date, the median progression-free survival (PFS) averaged 4.2 months, the median overall survival (OS) was about 25 months, and the 1-year OS rate was 71%. In this trial, patients with high PD-L1 expression showed longer PFS than patients with low or no expression (median 24 vs. 2–9 months). Overall survival was also longer in patients with high expression than in those with low or no expression (median not reached vs. 15–5 months). Subsequently, Giaccone et al. updated a phase II study of pembrolizumab in patients with advanced TC who had failed prior therapy 25 and who found a plateau in the survival curve, suggesting that the sustained therapeutic effect of pembrolizumab extends beyond drug discontinuation. Similar results were reported in another phase II study 26 conducted in Korea, in which 26 of 33 enrolled patients with refractory or recurrent TC had disease progression after failure of at least one platinum-based chemotherapy, with the following final outcomes: a partial remission rate of 19.2%, stabilization rate of 53.8%, and DCR of 73.1%. The PFS for TC was approximately 6 months and the OS was 14.5 months. ( Table 1 ) Both clinical studies demonstrated that pembrolizumab had better anti-tumor activity and a durable response in the treatment of TC. Additionally, it was found that in TET, the responsiveness to pembrolizumab showed a significant correlation with tumor PD-L1 expression. In the Giaccone team’s genomic and transcriptomic analysis of TC samples from patients receiving pembrolizumab monotherapy, it was found that PD-L1 expression and alterations in related genes or pathways ( CYLD and BAP1 ) may be potential predictors of the response to immunotherapy in patients with advanced diseases. In such patients, CYLD mutations showed a positive correlation with the expression of PD-L1. Further studies are needed to confirm whether BAP1 mutations decrease PD-L1 expression 27 . In addition, the role of PD-L1 expression as a predictive biomarker of treatment response needs to be further validated to optimize the selection of pembrolizumab therapy for patients with TC. Nivolumab The PRIMER study 28 was a two-stage, single-arm phase II trial investigating the activity of the PD-1 inhibitor nivolumab in 15 patients with TC (13 presenting with squamous carcinoma) who had received prior platinum-based chemotherapy and whose disease had progressed, with a final DCR of 73% (11/15). Stable disease (SD) was observed in 33% (5/15) for 24 weeks or longer. The final DCR was 73% (11/15), SD was observed in 33% (5/15) for 24 weeks or longer, median OS was 14.1 months, and median PFS was 3.8 months in a subgroup of patients with squamous cell carcinoma, which had to be terminated due to a lack of responders in a cumulative phase I cohort of 15 patients. The ORR and PFS in this trial were not as significant as those observed with pembrolizumab, suggesting variability in the response of TC to different PD-1 inhibitors. Notably, the efficacy of nivolumab in TC still needs to be validated using larger sample sizes and longer-term studies ( Table 1 ). NIVOTHYM 29 was an international, multicenter, phase II, dual-cohort, single-arm trial that enrolled 43 (78%) patients with advanced or recurrent TC after platinum-based chemotherapy ( Table 1 ). The primary endpoint was 6-month PFS (PFSR-6) in patients treated with nivolumab alone or in combination with ipilimumab. The overall remission and DCRs in this trial were 12% and 63%, respectively, and the locally assessed median PFS was 6 months. Although the safety and objective activity of this trial proved manageable, the primary objectives of the trial were not met, and therefore nivolumab should not be given in the first instance without a full assessment of the possible benefits versus the risks. However, nivolumab alone or in combination with other therapies is a potential treatment for patients with advanced TC. The results of this II trial, which is evaluating the efficacy of the combination of nivolumab plus ipilimumab, have not been released. A retrospective study 30 evaluated 8 patients with unresectable or recurrent thymic epithelial tumors who received low dose nivolumab due to toxicity and financial concerns. The cohort included 3 TC, 4 thymoma, and 1 mixed histology cases, with three patients having controlled myasthenia gravis. Moderate or severe immune-related adverse events occurred in four patients, including two severe events after the first 40 mg dose leading to permanent discontinuation. The median number of doses was four (range 1–18). The best response was partial remission, with the longest response durations of 9 and 14 months in TC and thymoma, respectively. The median overall survival was 7.4 months. Despite some clinical benefit, the high rate of severe toxicity highlights the need for predictive biomarkers. Interestingly, a review of ICIs for TETs noted that nituzumab may be particularly effective in patients with high PD-L1 expression 14 . This emphasizes the potential importance of PD-L1 expression as a biomarker for predicting response to PD-1 inhibitors in TC patients. Avelumab In a phase I study of seven patients with thymoma and one patient with TC treated with avelumab monotherapy 31 , two patients with thymoma vs. one patient with TC had SD; the median PFS for the patients with TC was 14.7 months ( Table 1 ). The efficacy of avelumab in advanced TC was not conclusive due to the small sample size used. A recent trial of avelumab in patients with advanced TET is evaluating its safety and clinical efficacy (NCT03076554). In conclusion, avelumab is a promising new addition to the arsenal of drugs for the treatment of TC. However, the use of avelumab must be carefully weighed against the risk of immune-related adverse events, especially in patients with a history of autoimmune disease. Further studies are needed to optimize patient selection and management strategies for avelumab therapy in TC. Atezolizumab A phase II, open-label basket study (NCT02458638) 32 recruited patients with a wide range of stage III or IV solid tumors; 12 patients with TC were enrolled. In this study, an NPR (Non-progression Rate) ≥40% was defined as the threshold for patient benefit. The median 18-week NPR for TC was 41.7 with an ORR of 8.3 months. These patients crossed the intermediate benefit threshold for survival time with atezolizumab treatment, suggesting that atezolizumab also shows some efficacy in advanced TC. A recent phase II, open-label, single-arm, multicenter study to evaluate the efficacy and safety of atezolizumab in patients with advanced thymic cancer who have failed prior systemic therapy is ongoing (NCT04321330). 1.2 B3 Thymoma: Bridging Thymoma and Thymic Carcinoma B3 thymoma is a distinct subtype of TET, histologically characterized by sheets of epithelial cells with mild to moderate atypia and relatively sparse lymphocytic infiltration. It is considered an intermediate entity between WHO type A–B2 thymomas and TC, exhibiting greater cytological atypia and invasive potential compared to lower-grade thymomas, but lacking the fully malignant features of TC 33 . Clinically, B3 thymomas demonstrate more aggressive behavior than A–B2 subtypes, with reported 10-year OS rates around 72%, compared to 75%–97% for types A–B2 thymomas and approximately 48% for TC 34 . B3 tumors also have a higher risk of recurrence and extrathymic spread, often necessitating more aggressive treatment strategies similar to those used for TC. Despite their histological aggressiveness, B3 thymomas have shown limited responsiveness to ICI therapy. Several factors may contribute to this paradox. First, while PD-L1 expression can be detected in B3 tumors, it is generally lower and more heterogeneous than in TC 14 35 . Second, B3 tumors typically exhibit a low TMB and preserve elements of normal thymic architecture, features less favorable for inducing a robust anti-tumor immune response. Third, the presence of immature T-cell populations within the tumor microenvironment may promote immune tolerance rather than effective immune activation 17 . Although thymomas of types AB, B1, and B2 are rich in lymphocytic aggregates and are most frequently associated with autoimmune disorders such as myasthenia gravis and pure red cell aplasia, B3 thymomas and thymic carcinomas typically exhibit fewer lymphoid infiltrates 36 . Nevertheless, B3 thymomas are still associated with a significant incidence of autoimmune diseases, particularly myasthenia gravis and pure red cell aplasia, albeit at a lower frequency compared to earlier-stage thymomas 37 . This underlying autoimmune predisposition reflects impaired central immune tolerance caused by disruption of the thymic epithelial architecture, particularly affecting the positive and negative selection of T lymphocytes. As a result, patients with TETs often harbor autoreactive T-cell populations. When treated with ICIs, which release inhibitory pathways such as PD-1/PD-L1, not only tumor-specific T cells but also these autoreactive T cells may become activated ( Figure 1 ). Consequently, patients with B3 thymoma, especially those with a history of autoimmune disease, are at increased risk of developing severe irAEs, including myositis, myocarditis, pure red cell aplasia, and neurological complications 38 . These irAEs tend to occur more frequently and with greater severity compared to patients with other malignancies. Clinical studies, including trials conducted by Giaccone et al., have confirmed that pre-existing or latent autoimmune disease significantly increases the risk of high-grade irAEs in patients with B3 thymoma receiving ICIs 25 . Figure 1 Anti-PD-1/PD-L1 and CTLA-4 antibodies enable T cells to recognize and destroy tumor cells but activated T cells can also attack normal body organs, resulting in immune-related adverse events (irAEs). CTLA-4, cytotoxic T-lymphocyte associated protein 4; PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand 1 1.3 IrAEs in clinical trials Immune-related adverse events (irAEs) of varying severity have been observed in all clinical trials of immunotherapy with TETs. Although the probability is much lower than that of thymoma, immunotherapy-associated side effects are still inevitable in the treatment of TC with immunologic agents. Even severe immunologic side effects pose a great challenge to the life and health of patients. The incidence of serious irAEs in immune checkpoint blockade (ICB) treated patients with TC is about 15% compared with 71% of patients with thymoma 26 . Expert teams suggest that thymoma patients should refrain from using immune checkpoint inhibitor therapy to avoid potential severe adverse reactions. For patients with thymic carcinoma, after evaluating their individual conditions, immunotherapy can be incorporated into the treatment plan, but comprehensive and continuous health monitoring is required throughout the treatment. Serious irAEs most commonly include impaired liver function, elevated alanine, and elevated aspartate aminotransferase levels 23 . Some patients show symptoms of muscle damage such as myositis or myalgia; patients’ heart, blood, and eyes are also affected to varying degrees 26 28 ( Table 2 ). Most patients experiencing irAEs recover with high-dose corticosteroids or other treatments. Interestingly, the prognosis of patients who experience severe irAEs appears to be better than those who do not. For example, four of nine patients who experienced severe irAEs achieved partial remission in a clinical trial conducted by Giaccone et al. 23 , which was a higher proportion than that of patients who did not experience irAEs. Similar results have been reported in several other trials, which may be related to a patient’s inherent sensitivity to immunosuppressive agents 31 39 . In trial settings, the true risk of a drug in a broad population may not be fully reflected due to limitations such as entry criteria. The international pharmacovigilance database, which covers a wider patient population, is important for the detection of rare but serious adverse reactions, such as an increased risk of TET myocarditis. Of the 141,630 reports of adverse drug reactions associated with ICIs in the VigiBase database, ICI cardiomyopathy was reported more frequently in TET (22/139, 16%) than in other cancer types (1,473/141,491, 1%), with a ratio of reports (rOR) = 17.9 and 95% confidence interval (CI). Checkpoint inhibitor myositis showed similar results, with a higher proportion of TET (19/139, 14%) compared to other cancer types (1,539/141,491, 1%), a rOR = 14.4, 95% CI: 8.9 – 23.4, P < 0.0001. Of the 24 evaluated irAEs, the association of TET with irAEs was specific to ICI myotoxicity. Outside of myocarditis and myositis, only myasthenia gravis-like syndrome and hepatitis were associated with TET 40 . Although immunosuppressive agents have produced promising results in the treatment of TC, more evidence is needed to assess their effect on patient care. Table 2 irAE,n(%) Pembrolizumab Nivolumab Katsuya et al.， 2019(N=15) Giaccone et al., (N=40) Cho et al.，（N=26） Grade 3 4 3-4 3-4 Fatigue 3(8%) 0 0 0 Hepatitis 0 0 2(7.7%) 0 AST increased 3(8%) 2 (5%) 0 1(6.7%) ALT increased 4(10%) 1(3%) 0 0 Arthralgia 1(3%) 0 0 0 Anemia 2(5%) 0 0 0 Dyspnea 3 (8%) 0 0 0 Myalgia or myositis 3 (8%) 0 0 0 subacute myoclonus 0 0 1(3.8%) 0 Creatine phosphokinase increased 1 (3%) 2 (5%) 0 0 Blurred vision 1 (3%) 0 0 0 Myocarditis 0 2 (5%) 0 0 Hyperglycemia 0 1 (3%) 0 0 Hypoalbuminemia 0 0 0 1(6.7%) Lipase increased 1 (3%) 0 0 0 Thrombocytopenia 1 (3%) 0 0 0 Myasthenia gravis 0 0 2(7.7%) 0 Lymphocyte count decreased 0 0 0 1(6.7%) \crefname equationبرابریequations \crefnamechapterفصلchapters \crefnamesectionبخشsections \crefnameappendixپیوستappendices \crefnameenumiموردitems \crefnamefootnoteزیرنویسfootnotes \crefnamefigureشکلfigures \crefnametableجدولtables \crefnametheoremقضیهtheorems \crefnamelemmaلمlemmas \crefnamecorollaryنتیجهcorollaries \crefnamepropositionگزارهpropositions \crefnamedefinitionتعریفdefinitions \crefnameresultنتیجهresults \crefnameexampleمثالexamples \crefnameremarkنکتهremarks \crefnamenoteیادداشتnotes \crefnameasumفرضAssumption N number, AST aspartate transaminase, ALT alanine aminotransferase, irAE immune-related Adverse Event 2. Combination Therapy Strategies Next-Generation Immune Targets CD70 is highly expressed in TSCC, the most common TC subtype, and its expression is positively correlated with PD-L1 41 . CD27–CD70 agonists promote T-cell activation and survival, as well as enhance NK cell and B cell activation 42 43 . Combined with CTLA-4 or PD-1/PD-L1 blockers, CD27 agonists may produce a synergistic antitumor effect 42 . CD70-targeted therapies, including antibody–drug conjugates and CAR-T cell therapies, are under development in various cancers, and the high CD70 expression in TSCC makes it a promising target for future TC trials 42 43 . TIM-3 (CD366; HAVCR2) is an inhibitory transmembrane protein that negatively regulates Th1 responses. 44 . Blocking TIM-3 increases interferon-γ secretion, which is involved in Th1-driven autoimmune diseases 45 . While there is no strong correlation with high PD-L1 expression, moderate to high TIM-3 expression is common in TC 15 . TIM-3 is a promising therapeutic target, potentially synergizing with anti–PD-1/PD-L1 or CTLA-4 blockade, making its high expression rate relevant for future drug development 46 . B7-H4 (VTCN1) is a negative regulator that inhibits T-cell activation, proliferation, cytokine production, and cytotoxicity, playing a role in cancer immunity 47 . A study by Wang et al. found that 78.75% of TET patients expressed B7-H4, with expression levels correlating with clinicopathologic features. The co-expression of PD-L1 and B7-H4 may predict clinical progression in TET, suggesting the potential of combination therapies targeting multiple immune checkpoints in TC 48 . Non-T-cell–associated inhibitory molecules Indoleamine-2,3-dioxygenase (IDO) is an enzyme that metabolizes tryptophan into kynurenine, creating an immunosuppressive tumor environment by depleting tryptophan and accumulating metabolites that induce T-cell dysfunction 49 . A study on TC found that IDO is highly expressed in TETs and that low IDO levels correlate with survival 50 . Targeting IDO1 may be a promising strategy to enhance anti-tumor immunity. TGF-β, a multifunctional cytokine, plays a key role in development, tissue repair, and inflammation. Its overexpression causes metabolic disturbances, epithelial–mesenchymal transition (EMT), immune dysfunction, fibrosis, and cancer 51 . In TC, TGF-β inhibits CD8 T-cell expansion, potentially contributing to TC progression and immune suppression. High TGF-β expression is associated with poor OS in TC, making it a potential therapeutic target for advanced cases 52 . Other therapeutic targets Calmodulin-like protein 5 (CALML5) is a potential therapeutic target. A study showed that overexpression of CALML5 in the TC cell line ThyL-6 accelerated cell proliferation and increased cisplatin sensitivity. Gene set enrichment analysis revealed upregulation of the E2F gene set in CALML5-overexpressing cells 53 . These findings suggest that CALML5 plays a key role in TC development and may be a new therapeutic target. Mucin 1 (MUC1) is highly expressed in TETs and correlates with tumor malignancy, angiogenesis, and p53. Its overexpression is a poor prognosis marker. MUC1 expression is significantly higher in TC than in B3 thymomas (94% vs. 0%) and may help differentiate TC from B3 thymomas 54 . MUC1 also has signaling functions, participates in cellular metabolism, and aids the immune system targeting cancer cells. MUC1-based vaccines, including glycopeptide and DNA vaccines, are under development, making it a promising therapeutic target for TC 55 . SRY-box transcription factor 9 (SOX9) is a key factor in various diseases, including cancer, and induces EMT during invasion and migration 56 . A study on TET tissues found an association between SOX9 expression and clinicopathological features and prognosis. Bioinformatics analysis confirmed gene expression differences in TC based on SOX9 levels, suggesting its significant role in TC development and its potential as a therapeutic target 57 . Trophoblast cell surface antigen 2 (Trop-2), part of the GA733 gene family, plays a role in cell proliferation, apoptosis, adhesion, EMT, and tumor progression 58 . It is highly expressed in TC compared to normal thymic tissues 59 . Studies have emphasized Trop-2’s potential as a therapeutic target, with clinical trials showing promise for targeted therapies, especially in cancers lacking traditional targets like triple-negative breast cancer 60 . Combination therapy with ICIs As research in this area intensifies, new combination strategies are being explored to improve the efficacy of ICIs in TC. These approaches include combining ICIs with antiangiogenic drugs and dual immune checkpoint blockade 61 ( Table 3 ). Table 3 Ongoing clinical trials evaluating combination therapies in thymic carcinoma Bintrafusp Alfa （M7824） NCT04417660 PD-L1 and TGF-β 2 ORR Pembrolizumab and Sunitinib NCT03463460 PD-L1, PDGFR, RTK and VEGFR 2 PR and CR Pembrolizumab and chemotherapy NCT04554524 PD-L1 4 ORR Pembrolizumab and chemotherapy NCT03858582 PD-L1 2 Major pathologic response rate Pembrolizumab, Lenvatinib and chemotherapy NCT05832827 PD-1 and VEGFR/FGFR 2 RR RXC004 and Nivolumab NCT03447470 Wnt and PD-1 1 DLT Toripalimab and chemotherapy NCT04667793 PD-1 2 Safety and MPR Vorolanib and nivolumab NCT03583086 PD-1 and VEGFR/PDGFR 1/2 Escalation and Dose Expansion KN046 NCT04925947 PD-1 and CTLA-4 4 ORR Pembrolizumab and Lenvatinib NCT04710628 PD-1 and VEGFR/FGFR 2 PFS \crefname equationبرابریequations \crefnamechapterفصلchapters \crefnamesectionبخشsections \crefnameappendixپیوستappendices \crefnameenumiموردitems \crefnamefootnoteزیرنویسfootnotes \crefnamefigureشکلfigures \crefnametableجدولtables \crefnametheoremقضیهtheorems \crefnamelemmaلمlemmas \crefnamecorollaryنتیجهcorollaries \crefnamepropositionگزارهpropositions \crefnamedefinitionتعریفdefinitions \crefnameresultنتیجهresults \crefnameexampleمثالexamples \crefnameremarkنکتهremarks \crefnamenoteیادداشتnotes \crefnameasumفرضAssumption ORR Overall Response Rate, PR Partial response, CR Complete response, DLT Dose-Limiting Toxicities, MPR major pathologic response, PFS Progression-Free Survival 5.1 Combination therapy with ICIs and anti-angiogenic drugs Vascular endothelial growth factor promotes immune evasion by inhibiting T-cell function and dendritic cell maturation. It promotes the development of an immunosuppressive tumor microenvironment by increasing intertumoral regulatory T cells and myeloid-derived suppressor cells 62 . Combining ICIs with antiangiogenic drugs has shown promise, especially in patients who have not previously received antiangiogenic therapy 63 64 . CAVEATT 65 was a single-arm, multicenter, phase II trial, conducted by Conforti et al., that evaluated the efficacy of avelumab in combination with the antiangiogenic drug axitinib in the treatment of advanced B3 thymoma and TC in patients. Twenty-seven of the 32 participants were patients with histologically confirmed TC who had progressed after platinum-based chemotherapy. The overall response rate was 34%, with median PFS and median OS of 7.5 and 26.6 months, respectively; disease control was achieved in more than 90% of patients, which was better than that with avelumab monotherapy. 5.2 Combination therapy with ICIs and chemotherapy Recent studies have explored the efficacy of combining pembrolizumab with chemotherapy in the treatment of metastatic TC. A case report 24 described two patients with metastatic TC who achieved durable clinical responses to first-line pembrolizumab combination chemotherapy. One patient achieved complete remission for more than three years and the other maintained partial remission for more than 20 months. This suggests that combining pembrolizumab with chemotherapy may be an effective strategy for the first-line treatment of metastatic TC, even for patients with a low TMB and MSS. In addition, the Marble 66 study, a multicenter, single-arm, open-label, phase II trial, investigated the safety and efficacy of atezolizumab in combination with carboplatin and paclitaxel for the treatment of metastatic or recurrent TC. A total of 47 patients with TC were enrolled in the study, which is ongoing with promising results. A phase IV, single-arm, multicenter study (NCT04554524) is currently underway to evaluate the first-line combination of pembrolizumab with platinum-based chemotherapy in patients with advanced TETs, including TC. This study addresses a critical therapeutic gap by assessing whether adding immunotherapy to standard chemotherapy (e.g., carboplatin and paclitaxel) improves response rates, progression-free survival, and potentially overall survival. The trial, which enrolls patients without prior systemic therapy, uses ORR as the primary endpoint, and includes secondary endpoints like safety, DCR, and duration of response to provide a comprehensive picture of efficacy. The design of this trial holds significant potential clinical impact. By integrating ICIs earlier in the treatment course, the study aims to enhance therapeutic outcomes, particularly in patients with high PD-L1 expression or chemotherapy-sensitive histology. Additionally, biomarker analysis within this trial may inform the development of predictive indicators and establish pembrolizumab plus chemotherapy as a new first-line standard for advanced TC. 5.3 Dual ICI therapy Dual immune checkpoint blockade strategies aim to enhance anti-tumor immune responses by simultaneously targeting multiple inhibitory pathways 61 . A phase II trial (NCT04925947) of the dual blockade of PD1 and CTLA-4 against pembrolizumab-treated recurrent TC is ongoing with KN046, a bispecific antibody against both targets. In this study, KN046 was evaluated for efficacy and safety in patients with advanced TC that had progressed after at least one prior checkpoint inhibitor therapy. Ten patients with TC will be enrolled in phase I of this study, with the program initiated in 2021. 5.4 Neo-adjuvant therapy with ICIs A phase II single-center, open-label, single-arm neoadjuvant therapy study (NCT03858582) is ongoing in patients with unresectable TETs (Masaoka stage III, IVA). Patients receive pembrolizumab 200 mg, docetaxel 75 mg/m², and cisplatin 75 mg/m² every 3 weeks for three cycles, followed by surgical reassessment. Based on surgical resection status: R0 resection: pembrolizumab monotherapy for 32 cycles. R1 resection: pembrolizumab plus radiotherapy (52.8 Gy/24 Fx) for 32 cycles. R2 resection: pembrolizumab plus radiotherapy (59.4 Gy/27 Fx) for 32 cycles. The primary endpoint is the major pathological response rate, defined by ≤ 10% of tumor composed of viable tumor. This trial is of relevance as it tests the hypothesis that immune priming via neoadjuvant ICI-chemotherapy can improve operability and long-term tumor control in borderline resectable or locally advanced TETs. Its design integrates immunotherapy not just as a systemic agent but also in combination with surgery and radiotherapy in a stage-adapted approach. If successful, it could pave the way for risk-adapted multimodal protocols in locally advanced thymic tumors. 5.5 Future combination therapy The future of ICI therapy for TC also includes the development of novel immunotherapeutic agents. Bintrafusp alfa, a bifunctional fusion protein targeting PD-L1 and TGF-β 67 , is currently being studied in patients with TET 68 . This innovative approach aims to enhance anti-tumor immunity by simultaneously blocking two key immunosuppressive pathways. Other emerging immunomodulatory agents, such as epacadostat (an IDO1 inhibitor) in combination with pembrolizumab, are also being evaluated for their potential to improve the prognosis of patients with TC (NCT02364076). 5.6 Clinical recommendations and optimization of therapeutic strategies With the growing use of ICIs in TC, selecting appropriate patients and determining the optimal timing for treatment have become key challenges. Studies suggest that patients with high PD-L1 expression (>50%), abundant TILs, or mutations in CYLD or BAP1 are more likely to benefit from ICIs 27 . Those with good performance status and no severe autoimmune disease may also be suitable for ICI monotherapy or combination regimens. First-line ICI plus chemotherapy has shown durable responses in advanced TC with high PD-L1 expression, as ongoing trials (e.g., NCT04554524) continue to explore. While sunitinib remains a standard second-line option, emerging evidence, including from the CAVEATT trial, supports a sequencing strategy: in patients with “cold” tumors (low PD-L1 and sparse TILs), initiating anti-angiogenic therapy (e.g., sunitinib or axitinib) may enhance ICI response by reshaping the tumor microenvironment. Conversely, patients with “hot” tumors may benefit from starting ICIs directly. Future studies should focus on biomarker-defined subgroups to optimize ICI and anti-angiogenic combinations and sequencing for personalized TC therapy. Conclusion The field of TC immunotherapy faces challenges and opportunities. First, the rarity of TC makes large-scale clinical trials difficult. Second, TC shows heterogeneity in terms of histological subtypes and molecular features and lacks reliable biomarkers 68 . In addition, due to the unique immune environment of the thymus and the propensity of patients with TETs for autoimmune complications, patients with TC treated with ICIs may be at risk for irAEs. The challenges are how to detect and manage these events and reduce the risk of irAEs 69 . Despite these challenges, the field of TC immunotherapy remains promising. Combination therapy strategies, although promising, also bring new challenges. Overlapping toxicities, especially when combining ICIs with chemotherapy or antiangiogenic agents, can lead to compounded adverse effects that require careful management. Moreover, the optimal sequencing and patient selection for such therapies are not yet well defined. As such, there is a growing emphasis on precision medicine approaches, including the integration of biomarker screening—such as PD-L1 expression, TMB, and emerging targets like CD70 or B7-H4—to guide treatment decisions 41, 48 . These approaches aim to personalize therapy, minimize toxicity, and maximize therapeutic benefit. By addressing these challenges and seizing emerging opportunities, researchers and clinicians can develop more effective, personalized, and tolerable therapeutic options for patients with this rare and aggressive malignancy. \crefname equationبرابریequations \crefnamechapterفصلchapters \crefnamesectionبخشsections \crefnameappendixپیوستappendices \crefnameenumiموردitems \crefnamefootnoteزیرنویسfootnotes \crefnamefigureشکلfigures \crefnametableجدولtables \crefnametheoremقضیهtheorems \crefnamelemmaلمlemmas \crefnamecorollaryنتیجهcorollaries \crefnamepropositionگزارهpropositions \crefnamedefinitionتعریفdefinitions \crefnameresultنتیجهresults \crefnameexampleمثالexamples \crefnameremarkنکتهremarks \crefnamenoteیادداشتnotes \crefnameasumفرضAssumption Funding This work was supported by the National Natural Science Foundation of China (Grant No. 82072595, 82473191), the Natural Science Foundation of Tianjin (Grant No. 23JCZDJC00710), Tianjin Key Medical Discipline (Specialty) Construction Project (Grant No. TJYXZDXK-061B), and Tianjin Health Science and Technology Project (Grant No. TJWJ2022XK005). Beijing Science and Technology Innovation Medical Development Fund grant (KC2023-JX-0288-PZ78). Conflict of interests The authors have no conflict of interest. Ethics Statement - Approval of the research protocol by an Institutional Reviewer Board: N/A - Informed Consent: N/A - Registry and the Registration No. of the study/trial: N/A - Animal Studies: N/A Author Contributions Jinhui Li : conceptualization, methodology, writing, visualization-original draft. Fuling Mao : conceptualization, formal analysis, writing - review. Hongyu Liu : supervision, writing - review and editing. Jun Chen : supervision- review and editing. References 1. Tartarone A, Lerose R, Lettini AR, Tartarone M. Current Treatment Approaches for Thymic Epithelial Tumors. Life (Basel). May 12 2023;13(5). 2. Cafaro A, Bongiovanni A, Di Iorio V, Oboldi D, Masini C, Ibrahim T. Pembrolizumab in a Patient With Heavily Pre-Treated Squamous Cell Thymic Carcinoma and Cardiac Impairment: A Case Report and Literature Review. 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Keywords adverse drug reactions cancer drug allergy immunology immunotherapy oncology Authors Affiliations Jinhui Li 0009-0001-2803-7484 Tianjin Medical University General Hospital View all articles by this author Mao Fuling Tianjin Medical University General Hospital View all articles by this author Hongyu Liu Tianjin Medical University General Hospital Tianjin Lung Cancer Institute View all articles by this author Jun Chen [email protected] Tianjin Medical University General Hospital View all articles by this author Metrics & Citations Metrics Article Usage 395 views 156 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Jinhui Li, Mao Fuling, Hongyu Liu, et al. Immune checkpoint therapy for thymic carcinoma. Authorea . 14 May 2025. DOI: https://doi.org/10.22541/au.174724425.56401794/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. 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