First case report of immune checkpoint inhibitor-related pneumonitis triggered by bispecific antibody (anti-PD-L1 and anti-CTLA-4) in a patient with non-small cell lung cancer: case report

Introduction

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of advanced non-small cell lung cancer (NSCLC), offering significant survival benefits. Nivolumab plus ipilimumab, targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4), respectively, is a classic dual ICI combination therapy. However, their use is associated with a broad spectrum of immune-related adverse events (irAEs) (1), among which immune checkpoint inhibitor-related pneumonitis (ICI-P) remains one of the most severe and potentially life-threatening toxicities (2). The clinical presentation of ICI-P is highly variable, and its diagnosis and management continue to pose significant challenges in clinical practice.

Bispecific antibodies targeting both PD-1/programmed death-ligand 1 (PD-L1) and CTLA-4, such as QL1706, AK104, and KN046, aim to improve efficacy while potentially reducing toxicity compared to conventional dual ICI therapy (3). Early data suggest that reduced CTLA-4 binding affinity may lower the risk of irAEs, including ICI-P, but clinical experience remains limited. Here, we report a rare case of grade 3 ICI-P triggered by a PD-L1/CTLA-4 bispecific antibody, which was refractory to corticosteroid therapy but responded to escalation with tocilizumab and adjunctive anti-fibrotic therapy with nintedanib. This case provides insight into the complex immunopathogenesis of ICI-P, highlights the need for early recognition and personalized management strategies, and raises important considerations regarding the potential role of anti-fibrotic agents in the setting of immune-mediated lung injury. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-479/rc).

Case presentation

In September 2019, a 64-year-old man with a smoking index of 1,600 and a history of emphysema was diagnosed with stage IV lung squamous cell carcinoma. He was enrolled in the phase II trial evaluating KN046, a PD-L1/CTLA-4 bispecific antibody, in combination with chemotherapy for advanced NSCLC (ClinicalTrials.gov: NCT04054531) (4). The treatment regimen included paclitaxel (175 mg/m² on day 2, every 3 weeks) and carboplatin (AUC 5 on day 2, every 3 weeks) combined with KN046 (5 mg/kg on day 1, every 3 weeks) for three cycles. After two cycles, the patient achieved stable disease.

On April 10, prior to the third cycle, a routine chest computed tomography (CT) was performed and he returned home afterward. The patient reported new-onset dyspnea when he presented for the next treatment cycle. Upon immediate review of the April 10 CT scan—which had just become available—new pulmonary abnormalities were noted, prompting urgent intervention. This scan was designated as the baseline for evaluating disease progression and guiding treatment decisions.

Approximately two weeks after the last dose of KN046, the patient developed a persistent cough and worsening dyspnea, with a pulse oximetry reading of 77%. Repeat chest CT revealed new, multifocal patchy and striated infiltrates in both lungs, suggestive of ICI-P. Laboratory tests showed elevated white blood cell and neutrophil counts, but a low procalcitonin level and negative microbiologic studies, helping to exclude bacterial pneumonia. Based on these findings, grade 3 ICI-P was diagnosed.

The patient was hospitalized and received low-flow oxygen therapy (3 L/min) and initiated on intravenous methylprednisolone at 80 mg once daily (approximately 1.5 mg/kg/day, body weight: 52.7 kg) in accordance with treatment guidelines for grade ≥3 ICI-P. However, 48 hours later, his respiratory symptoms had not improved. Chest radiography showed extensive patchy opacities and interstitial changes, and interleukin-6 (IL-6) levels were markedly elevated. IL-6 testing was proactively ordered at the time of admission (sample collected April 15; results returned April 16) in anticipation of possible steroid-refractory disease.

Given the elevated IL-6 level and continued clinical deterioration, tocilizumab was promptly added to the treatment regimen alongside nintedanib, enabling timely and effective immunosuppressive intervention. This combination resulted in rapid clinical improvement and resolution of pulmonary inflammation. The patient was discharged on April 24, 2020, and continued treatment with oral prednisone and moxifloxacin. A summary of the diagnostic and therapeutic timeline is provided in Figure 1. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Timeline of patient’s treatment and radiologic evaluation. On April 15, 2020, the patient started intravenous methylprednisolone. By April 17, chest X-rays showed persistent inflammation and new interstitial changes. As IL-6 had elevated to 160.8 pg/mL on April 16 and steroid response was poor, tocilizumab and nintedanib were added. Follow-up chest X-rays every 2–3 days showed gradual improvement in lung inflammation; on April 16, the IL-6 level had risen significantly to 160.8 pg/mL, continued to rise after tocilizumab administration, reaching 1,180 pg/mL at discharge. This is consistent with tocilizumab’s mechanism—blocking IL-6 receptor binding and reducing IL-6 clearance, leading to accumulation in the blood. Despite elevated IL-6, the patient’s symptoms and imaging improved, indicating effective inflammatory control. ICI-P, immune checkpoint inhibitor-related pneumonitis; IL-6, interleukin-6; SD, stable disease; TC, paclitaxel plus carboplatin chemotherapy.

Discussion

This case illustrated the complete clinical course of ICI-P triggered by a bispecific antibody targeting PD-L1 and CTLA-4, highlighting its characteristic rapid onset and progression. These features underscored the importance of timely diagnosis and appropriate intervention.

ICI-P is a rare but potentially fatal adverse event that may occur at any point during immunotherapy, with a median onset time of approximately 2.8 months (5). The incidence of ICI-P varies among different ICI regimens. Bispecific antibodies such as QL1706, AK104, and KN046, which co-target PD-1/PD-L1 and CTLA-4, have been reported to cause ICI-P less frequently than conventional dual ICI therapies like nivolumab plus ipilimumab, both in terms of overall and grade ≥3 ICI-P (Figure 2A) (2,6-8). This may attribute to their stronger affinity for PD-L1 and weaker binding to CTLA-4. Preclinical studies have shown that reduced CTLA-4 affinity correlates with a more favorable safety profile, potentially making bispecific antibodies a safer alternative. In addition to simplifying administration, they may also lower the risk of pulmonary toxicity. These differences could provide useful guidance for clinicians in choosing immunotherapy regimens.

Figure 2 Incidence of ICI-P in different treatment groups. (A) Patients receiving ICIs alone; (B) patients receiving ICIs combined with chemotherapy. Numbers in parentheses refer to ICI-P cases per total number of patients. Grade ≥3, Grade 3 or higher immune checkpoint inhibitor-related pneumonitis; ICI-P, immune checkpoint inhibitor-related pneumonitis; ICIs, immune checkpoint inhibitors; Nivo + Ipi, nivolumab plus ipilimumab.

Interestingly, some studies indicated that adding chemotherapy to dual ICI regimens reduced the incidence of ICI-P, consistent with findings from ICI monotherapy (9). One possible explanation was that chemotherapy induced systemic immunosuppression, thereby dampening immune overactivation. In addition, corticosteroid premedication, commonly used in chemotherapy regimens containing platinum, pemetrexed, or taxanes, may contribute to the reduced incidence of ICI-P. These effects may help explain why dual ICI combined with chemotherapy appears to carry lower pulmonary toxicity than dual ICI alone, although the exact mechanisms remain unclear. However, this trend was not observed with bispecific antibody regimens (Figure 2B) (2,4,10). We acknowledge that the JCOG2007 phase 3 trial raised serious safety concerns regarding dual ICI plus chemotherapy regimens, with 7% of patients in the nivolumab-ipilimumab-chemotherapy arm experiencing treatment-related deaths, including ILD-related fatalities, leading to early trial termination (11). These findings suggest that the effect of adding chemotherapy to dual ICI regimens on ICI-P risk is complex and may depend on factors such as patient population, ICI backbone, and trial design. Further large-scale prospective studies are needed to clarify the safety of combining chemotherapy with bispecific or dual ICI therapies in clinical practice.

Although idiopathic pulmonary fibrosis (IPF) and ICI-P differ in pathogenesis—IPF being a chronic fibrotic disease driven by fibroblast activation, and ICI-P an acute immune-mediated process involving cytokine release (e.g., IL-6, interferon-gamma, tumor necrosis factor-alpha) (12), both may ultimately progress to pulmonary fibrosis if not treated effectively. Nintedanib, approved for IPF, has demonstrated anti-inflammatory and anti-fibrotic effects by reducing cytokine production, pulmonary exudation, and fibroblast activity. While effective in IPF, its role in acute inflammatory settings like ICI-P remains unclear.

In our case, nintedanib was introduced following early radiologic signs of interstitial involvement in a patient with corticosteroid-refractory ICI-P, based on concern for fibrotic progression. Improvement following treatment with tocilizumab and nintedanib suggests that early anti-fibrotic intervention may help prevent irreversible lung damage, particularly in the subacute or recovery phase. Similar benefits were reported in two prior ICI-P cases treated with pembrolizumab or camrelizumab. These findings suggest that early anti-fibrotic intervention may help prevent irreversible remodeling, particularly in the subacute or recovery phase. Similar benefits were reported in two prior ICI-P cases treated with pembrolizumab or camrelizumab.

Although bronchoalveolar lavage and serum biomarkers such as Krebs von den Lungen-6 could have improved diagnostic accuracy, they were not performed due to the patient’s rapid deterioration and the need for urgent treatment. We recognize this as a limitation.

Conclusions

We reported the first documented case of ICI-P induced by a bispecific antibody targeting PD-L1 and CTLA-4. Based on a review of the literature, bispecific antibodies may offer a safer and more manageable profile compared to conventional dual ICI therapies. Our case demonstrated the potential role of nintedanib as an adjunct treatment for corticosteroid-refractory ICI-P, particularly in the presence of early interstitial changes suggestive of fibrotic progression. However, given the limited clinical experience, further studies are warranted to confirm the efficacy and safety of nintedanib in this context.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-479/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-479/prf

Funding: This work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0519700) and Chinese National Natural Science Foundation Project (Nos. 82173101, 82241232 and 82272789).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-479/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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