Abstract
We present a case of a 68-year-old male with advanced non-small cell lung cancer (NSCLC), PD-L1 negative and driver gene negative, who exhibited a significant abscopal effect following radiotherapy combined with systemic immunotherapy (sintilizumab) and chemotherapy. The patient achieved complete remission (CR) of intracranial metastases without cranial irradiation, suggesting a systemic immune response triggered by the combination of radiotherapy and immunotherapy. This case highlights the potential of radiotherapy combined with immuno-chemotherapy to induce abscopal effects, even in PD-L1 negative patients, and underscores the importance of further investigation into this therapeutic strategy. This case challenges traditional paradigms in NSCLC management and aligns with emerging theragnostic approaches that integrate localized treatment with systemic immune modulation.
Introduction
The management of brain metastases in NSCLC traditionally relies on cranial irradiation (), but emerging evidence supports synergistic effects of radiotherapy (RT) and immunotherapy. The abscopal effect, a phenomenon where localized RT induces systemic tumor regression at distant sites, has been increasingly reported in the era of immunotherapy (). This effect is thought to be mediated by the activation of the immune system, particularly through the release of tumor antigens and subsequent immune response (, ). While abscopal effects are rare, they have been observed in various cancers, including NSCLC (), especially when radiotherapy is combined with immune checkpoint inhibitors. Recent genomic studies highlight that homologous recombination deficiency (HRD) may enhance immunogenicity in driver-negative NSCLC (), while PD-L1 negativity typically correlates with reduced immunotherapy response. Here, we report a PD-L1 negative NSCLC case achieving rapid intracranial remission through abscopal effects.
Case presentation
In August 2020, a 68-year-old male patient presented with a right lower lobe pulmonary nodule. Following guidelines at the time, he underwent surgical resection of the primary tumor. The postoperative pathological diagnosis was stage IA (pT1N0M0) right lower lobe adenocarcinoma. No adjuvant therapy was administered. RNA sequencing testing revealed no detectable alterations in the tested driver genes (EGFR, ALK, ROS1, RET, KRAS, BRAF, MET, HER2, and NTRK were all negative). Due to limitations in economic resources and access to advanced clinical testing, extended molecular profiling—including Tumor Mutational Burden (TMB), Microsatellite Instability-High (MSI-H), or Mismatch Repair Deficiency (dMMR)—could not be performed. However, immunohistochemistry (IHC) confirmed negative PD-L1 expression (Supplementary Figure 1).
In February 2022, the patient developed left iliac bone metastasis and multiple intracranial metastases (Figure 1), with no new lesions detected at other sites. Given the patient’s left iliac bone pain but absence of central nervous system symptoms, we employed intensity-modulated radiation therapy (IMRT) targeting only the left iliac bone metastatic lesion with a total dose of 36 Gy in 12 fractions to alleviate pain symptoms. (Supplementary Figure 2). During the treatment of RT, the patient received one cycle of pemetrexed disodium(500mg/m2), cisplatin(75mg/m2), and sintilizumab (200mg,an anti-PD-1 antibody). Notably, follow-up MRI revealed complete remission (CR) of multiple brain metastases (Figure 1), despite the absence of cranial irradiation one month later.
Figure 1
Subsequently, the patient underwent two cycles of systemic treatment with pemetrexed disodium (500mg/m2), cisplatin (75mg/m2), and sintilimab (200mg), during which one episode of Grade 3 rash and gastrointestinal reaction occurred. The treatment was then switched to two cycles of carboplatin (AUC=5) combined with pemetrexed disodium (500mg/m2) and sintilimab (200mg). Finally, Patients received maintenance treatment with sintilimab (200mg) for 24 months until the last follow-up with or without pemetrexed disodium (500mg/m2) alternatively, during which no Grade 2 or higher adverse reactions have occurred. Until the last follow-up, the patient’s lung lesions (Supplementary Figure 3), bone metastases (Supplementary Figure 4), and brain metastases (Figure 1) remained stable, with the progression-free survival (PFS) of 35 months and an overall survival (OS) exceeding 40 months (Table 1). Prior to each treatment session, peripheral blood tumor markers—including carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1)-were routinely monitored. During the post-treatment surveillance phase after completing the two-year therapeutic regimen, assessment frequency was reduced to quarterly intervals. Results demonstrated progressive decline of these biomarkers, ultimately stabilizing at low levels (Figure 2). Concurrently, peripheral CD8+ T-cell counts were evaluated at identical time points using flow cytometry (BD FACSCanto II) with CD3+/CD8+ antibodies, with data indicating persistently elevated levels throughout the observation period (Figure 2). Next-generation sequencing of archival tumor tissue identified a TP53 mutation (VAF 4.8%).The sustained remission of both irradiated and non-irradiated lesions, particularly the brain metastases, underscores the potential of this combined approach to achieve durable disease control in advanced NSCLC, even in PD-L1 negative patients.
Table 1
| Timepoint | Brain Metastases (mm) | Lliac Bone Metastasis (status) | New Lesions | Overall Response |
|---|---|---|---|---|
| Baseline (February 2022) | 46.1 | Present | NO | NA |
| post-radiotherapy (March 2022) | 0 | Improved | NO | PR |
| Last follow-up (January 2025) | 0 | Improved | NO | PR |
The evolution of lesion status at key timepoints.
NA, Not Applicable; PR, Partial Response.
This table documents the longitudinal changes in tumor burden, with target lesions (brain metastases) quantified by the sum of the longest diameters (SLD, mm) of all measurable lesions, non-target lesions (iliac bone metastasis) described by their presence status, and overall response assessed per RECIST 1.1 criteria. Timepoints correspond to: baseline (pre-treatment), post-radiotherapy evaluation, and final follow-up.
Figure 2
Discussion and conclusion
This case report describes a 68-year-old male with advanced, PD-L1 negative, driver gene-negative NSCLC who achieved complete remission of intracranial metastases after a single cycle of combined radiotherapy, immunotherapy (sintilizumab), and chemotherapy, without cranial irradiation. The treatment, which included IMRT to a left iliac bone metastasis, triggered a systemic immune response, leading to durable disease control and a PFS of 35 months. This notable outcome highlights the potential of combining radiotherapy with immuno-chemotherapy to induce abscopal effects, even in traditionally less responsive PD-L1 negative patients.
The case underscores the importance of multimodal approaches in achieving long-term survival and challenges current paradigms in the management of advanced NSCLC. While the abscopal effect—where localized RT induces systemic tumor regression—has been reported in NSCLC (–), the speed of intracranial response in this case is exceptional. The likely mechanism involves RT-induced immunogenic cell death, releasing tumor antigens and damage-associated molecular patterns (DAMPs) that activate dendritic cells and prime tumor-specific T cells (). The addition of sintilizumab, a PD-1 inhibitor, further amplified this immune response by reversing T cell exhaustion, enabling systemic tumor control, including in the brain (). Additionally, the patient’s TP53 mutation, which is associated with increased tumor mutational burden and immunogenicity, may have contributed to the robust abscopal effect by enhancing the presentation of neoantigens and promoting a stronger immune response post-radiotherapy ().Although the rapid intracranial response observed in this case strongly suggests an abscopal effect, we acknowledge that systemic immunotherapy (sintilimab) and chemotherapy may have contributed to the control of brain metastases. Previous studies indicate that PD-1 inhibitors can cross the blood-brain barrier and exert effects on brain metastases (, ). Furthermore, pemetrexed, when combined with platinum-based chemotherapy, has also been reported to exhibit limited intracranial activity (). However, the observation of a complete response within one month following radiotherapy and just one cycle of systemic therapy is more consistent with the characteristics of a radiation-induced abscopal effect—as the typical response time for systemic therapy alone is usually longer. This case highlights the synergistic potential of radiotherapy combined with immunochemotherapy in achieving rapid and durable systemic responses, even in challenging cases such as advanced non-small cell lung cancer with brain metastases.
The second highlight of this case is the remarkable PFS of 35 months, achieved through maintenance therapy with pemetrexed and sintilimab following initial treatment. The sustained high levels of CD8+ T cells in the patient’s peripheral blood, coupled with low tumor burden, likely contributed to this durable response. RT-induced immunogenic cell death and sintilizumab’s blockade of PD-1/PD-L1 signaling may have synergistically maintained CD8+ T cell activation, preventing T cell exhaustion and promoting continuous anti-tumor immunity (, –). Additionally, it is worth noting that pemetrexed may enhance immune efficacy through a triple mechanism: (1) up-regulating PD-L1 expression in tumor cells (); (2) Reduce Treg cell infiltration (, ); (3) enhance the sensitivity of tumor cells to T cell killing (). These mechanisms may work synergistically with radiotherapy and immunotherapy. Previous studies have shown that high peripheral CD8+ T cell levels correlate with improved survival in NSCLC patients receiving immunotherapy (, ), as these cells play a critical role in tumor cell recognition and elimination. This case underscores the importance of combining radiotherapy, immunotherapy, and chemotherapy to sustain immune activation and achieve long-term disease control, even in advanced NSCLC with high-risk features.
This case represents a rare and remarkable example of rapid intracranial remission and long-term survival in a PD-L1 negative, driver gene-negative NSCLC patient treated with a combination of RT and immuno-chemotherapy. The rapid speed of intracranial response and sustained disease control highlight the potential of multimodal therapy to induce systemic immune activation and achieve durable outcomes in traditionally challenging cases. The integration of localized RT with systemic immuno-chemotherapy exemplifies a theragnostic approach (), where molecular imaging (e.g., CXCR4-targeted PET) could non-invasively monitor immune activation during combined modality therapy. Such approaches may optimize RT/immunotherapy sequencing in PD-L1 negative NSCLC. Future studies could utilize patient-derived organoids (PDOs) to model such abscopal responses. As demonstrated in NSCLC PDOs (), these models can recapitulate tumor-immune interactions and predict combinatorial therapy efficacy, potentially identifying biomarkers for patient selection.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
Ethics statement
The studies involving humans were approved by the Ethics Committee of Jiangxi Cancer Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
QW: Writing – original draft, Data curation. WW: Data curation, Writing – original draft. KZ: Writing – original draft, Visualization. CP: Writing – review & editing, Methodology. ZL: Supervision, Writing – review & editing. LW: Writing – review & editing, Conceptualization.
Funding
The author(s) declare that no financial support was received for the research, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The author(s) declare that no Generative AI was used in the creation of this manuscript.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1613974/full#supplementary-material
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Summary
Keywords
NSCLC, brain metastases, abscopal effect, PD-L1 negative, immuno-chemotherapy
Citation
Wen Q, Wang W, Zhang K, Pan C, Liu Z and Wang L (2025) Case Report: Abscopal effect and long-term survival in a PD-L1 negative NSCLC patient treated with radiotherapy and immuno-chemotherapy. Front. Immunol. 16:1613974. doi: 10.3389/fimmu.2025.1613974
Received
18 April 2025
Accepted
06 August 2025
Published
22 August 2025
Volume
16 - 2025
Edited by
Savvas Lampridis, Imperial College London, United Kingdom
Reviewed by
Dechao Feng, University College London, United Kingdom
Carrie Anne Minnaar, Wits University Donald Gordon Medical Centre, South Africa
Updates
Copyright
© 2025 Wen, Wang, Zhang, Pan, Liu and Wang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lei Wang, wangleiy001@126.com
†These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.