PD-1 blockade plus capecitabine as curative-intent treatment for tumor mutational burden-high multi-metastatic pancreatic ductal adenocarcinoma: A case report

PD-1 blockade plus capecitabine as curative-intent treatment for tumor mutational burden-high multi-metastatic pancreatic ductal adenocarcinoma: A case report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report PD-1 blockade plus capecitabine as curative-intent treatment for tumor mutational burden-high multi-metastatic pancreatic ductal adenocarcinoma: A case report Luyao Ma, Yuejun Han, Xingxing Yu, Ketao Jin, Jinfang Xu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7202690/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The rising incidence and persistently dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for effective new systemic therapies. Cancer immunotherapy has increasingly garnered attention. Various methods, such as cell therapy, immune-checkpoint blockers (ICBs), and cancer vaccines, alone or in combination, have achieved satisfactory results in cancer therapy. Immunotherapy has shown significant benefits in solid organ tumors but has been disappointing in PDAC treatment. Despite promising preclinical studies, clinical translation has proven challenging, possibly because PDAC has a complex immunosuppressive tumor microenvironment (TME), which insulates the tumor from an effective cytotoxic immune response. Therefore, we aimed to investigate combined approaches to improve ICB efficacy. Here we present a case of a 69-year-old man diagnosed with multi-metastatic PDAC. Genetic analysis revealed a high tumor mutational burden of 9.02 mutations/megabase. The TME was positive for CD4 + and CD8 + T cells, suggesting potential immunotherapy success. Immune-checkpoint blockade treatment with sintilimab, a programmed cell death protein 1 (PD-1) monoclonal antibody, was initiated, leading to disease regression. The treatment response was confirmed using contrast-enhanced magnetic resonance imaging and computed tomography. Immune-checkpoint inhibitor Pancreatic ductal adenocarcinoma Sintilimab Capecitabine Case report Figures Figure 1 Figure 2 1 Introduction Pancreatic ductal adenocarcinoma (PDAC), a highly lethal human cancer, will likely become the second leading cause of cancer-related deaths by 2030 [ 1 ]. Despite advances in conventional systemic therapy, the 5-year overall survival rate for PDAC remains low at 11%, partly because it presents at an advanced stage, precludes therapeutic resection, and has a strong tendency to relapse. Despite the introduction of new regimens [ 2 ], the survival of patients with PDAC has not substantially improved over the last few decades. Therefore, new treatment strategies are required to treat PDAC. Advances in immunotherapy, particularly immune-checkpoint blockade (ICB), have improved treatment options for some historically chemotherapy-refractory malignancies. Over the past 10 years, ICBs have shown efficacy in the treatment of metastatic melanoma, renal cell carcinoma, colorectal cancer with microsatellite instability, non-small cell lung cancer, Hodgkin’s lymphoma, and other cancers [ 2 – 5 ]. Despite the success of ICB, PDAC has been largely refractory to ICB monotherapy, possibly because it has some intrinsic and extrinsic properties that sequester malignant cells from effective adaptive immune responses [ 6 ]. Therefore, it is worth investigating combined approaches to improve ICB efficacy. We present a case of multi-metastatic PDAC with a high tumor mutational burden (TMB), in which the tumor microenvironment (TME) was positive for CD4 + and CD8 + T cells, which suggested that immunotherapy was successful. Therefore, ICB treatment with sintilimab (Innovent Biologics Co., Ltd., Suzhou, China), a programmed cell death protein 1 (PD-1) monoclonal antibody (mAb), was added to an oral capecitabine regime, which led to disease regression. 2 Case report A 69-year-old man who complained of repeated left upper abdominal pain and discomfort for more than 1 year was admitted to our hospital in May 2022. The patient's medical history was unremarkable, with no documented family history of malignancy. Contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) of the abdomen showed a space-occupying lesion in the tail of the pancreas, with adjacent spleen and splenic arteriovenous invasion, multiple intrahepatic metastases, and multiple liver metastases (Fig. 1A1-2). Contrast-enhanced CT of the chest revealed multiple metastases to both lungs (Fig. 1A3). Histopathological examination of the liver metastases revealed adenocarcinoma, consistent with PDAC metastasis (Fig. 2 C). Serum carcinoembryonic antigen (CEA; up to 14.81 ng/mL) and carbohydrate antigen 19 − 9 (CA19-9; up to 208.89 U/mL) were elevated. The patient presented with newly diagnosed stage IV pancreatic ductal adenocarcinoma, demonstrating limited overall survival (OS) consistent with advanced disease prognosis. The patient refused systemic intravenous chemotherapy and received only oral capecitabine chemotherapy. After one capecitabine single agent (1500 mg, bid, po, d1-d14; Qilu Pharmaceutical Co. Ltd., Jinan, China) cycle, immunohistochemistry (IHC) showed a PD-L1 total positive score (TPS) of < 1%. Next-generation sequencing (NGS) of tumor tissue revealed a high TMB (9.02 mutations/megabase, 17.5%) and a microsatellite stable (MSS) state (Table I). IHC showed that the tumor immune microenvironment (TIME) was positive for CD4 + and CD8 + T cells (Fig. 2 D, E). Serum CEA and CA19-9 levels were elevated (up to 19.93 ng/mL and 308.37 U/mL, respectively). Sintilimab (200 mg every 3 weeks) was added to the ongoing capecitabine regimen. Except for grade capecitabine + sintilimab treatment (1 cycle of capecitabine and 17 cycles of capecitabine + sintilimab), contrast-enhanced MRI and CT demonstrated tumor shrinkage, and a partial response was observed (Fig. 1D1-3). Serum CEA (down to normal levels, 3.39 ng/mL) and CA19-9 (down to normal levels, 23.61 U/mL) were reduced (Fig. 2 A, B). The patient completed 18 cycles of treatment, and tolerated the treatment without any immune toxicity. The patient’s current condition was assessed as pathological response. Table 1 Analysis of next-generation sequencing (NGS) of tumor tissue Num Item Result 1 Tumor mutation burden, TMB 9.02 Mut/Mb 2 Micro satellite instability, MSI MSS 3 MLH1 - 4 MSH2 - 5 MSH6 - 6 PMS2 - 7 PD-L1 score TPS: <1% 8 TET2 P.I1873L 9 BRCA1 - 10 BRCA2 - 3 Discussion PDAC is associated with high morbidity and adverse clinical outcomes. To date, PDAC has been largely refractory to ICB monotherapy, and effective personalized immunotherapy is lacking. Here, we present the case of a 69-year-old man diagnosed with PDAC with liver and lung metastases. As the patient refused systemic intravenous chemotherapy, we could not treat him with the standard protocol. CEA and CA19-9 levels were elevated after a course of single-agent oral capecitabine chemotherapy. Therefore, after communicating with the patient and obtaining consent, we decided to combine this with immunotherapy to enhance the potency of the immune system to recognize and kill foreign targets and overcome the immunosuppressive TME. We emphasize the importance of genetic analysis of tumor tissue using NGS to screen for MSS, which may respond to immune-checkpoint inhibitors, and determine personalized immunotherapy characteristics. In this case, NGS showed an MSS status but a high TMB (9.02 mutations/megabase). A high TMB can be used as another predictor, in addition to microsatellite instability and mismatch-repair defects, for identifying patients with cancer who may benefit from ICB, with the underlying hypothesis of increasing the number of mutated proteins and producing antigenic peptides, thereby enhancing immunogenicity [ 7 ]. A previous study divided tumors into four categories based on PD-L1 expression and T cell infiltration (TIL, mainly CD8 + T cells) in the TIME: PD-L1 - /TIL - (type I), PD-L1 + /TIL + (type II), PD-L1 - /TIL + (type III), and PD-L1 + /TIL - (type IV); this study showed that type II tumors responded better to PD-1 treatment [ 8 ]. Tumor IHC of our patient showed infiltration of CD4 + and CD8 + T cells in the TME, which suggested that the tumor cells were recognized by the immune system and that immunotherapy was effective. However, PD-L1 results showed a TPS < 1%, that is, a PD-L1 status, which should be defined as a type III tumor according to the above classification. Nevertheless, our patient responded well to anti-PD-1 therapy clinically. Thus, this finding may be explained by the use of needle biopsy to sample the tumor tissue, which may have missed PD-L1 + areas, resulting in false-negative results. However, the PD-L1 + rate can be increased by performing multiple biopsies of the tumor tissue. PD-L1 expression can be assessed in a larger range of tumors by radioisotope labeling [ 9 ]. The processing of tumor tissue and type of antibodies used may lead to confusion regarding PD-L1 results [ 10 ]. Moreover, PD-L1 expression is inducible. This suggests that PD-L1 expression differs from the start of biopsy to the point of anti-PD-1 therapy. How much PD-L1 needs to be expressed in the TME to achieve anti-PD-1 effects is unknown; therefore, the effectiveness of anti-PD-1 therapy cannot be judged from the expression of PD-L1 alone. ICB monotherapy is less effective in patients with pancreatic cancer. However, combination regimens, including chemotherapy, have shown good preliminary results [ 11 ]. This case also verified that combination chemotherapy regimens are effective, and we believe that chemotherapy-induced cancer cell death can promote the release of tumor antigens and antigen presentation, stimulate immune effectors, and increase the efficacy of immunotherapy. Immune-checkpoint inhibitors have been successfully used in combination with standard chemotherapy for non-small cell lung cancer, small cell lung cancer, and triple-negative breast cancer [ 12 – 14 ]; however, their efficacy is limited or unsustainable. This may be owing to the significant immunosuppressive side effects of high-intensity chemotherapy, which compromise the immune system directly by inhibiting or killing effector cells or indirectly by causing anergy or immune paralysis. If chemotherapeutic agents are appropriately used in anti-PD therapy, T-cell immunity may be promoted by eliminating Tregs and increasing antigen release at the time of tumor cell death, thereby stimulating T-cell-mediated immune responses [ 15 , 16 ] and generating additional anti-tumor responses. After more than 13 months of treatment, the patient’s current condition was assessed as partial response. The next step is to consider when to discontinue the drug and whether to add targeted therapy to increase efficacy. PDACs possess several intrinsic and extrinsic properties that protect malignant cells from effective adaptive immune responses. To date, no single immunotherapy strategy has been proven effective, warranting the investigation of combination approaches to improve treatment efficacy. Our case showed that the use of PD-1 mAb immunotherapy and capecitabine might be a promising treatment option for patients with multi-metastatic PDAC with a high TMB who are positive for CD4 + and CD8 + T cells in the TIME. More clinical trials are needed to evaluate combination immunotherapy strategies to demonstrate the role of immunotherapy in PDAC treatment. Abbreviations PDAC = pancreatic ductal adenocarcinoma ICB = immune-checkpoint blocker TME = tumor microenvironment PD-1 = programmed cell death protein-1 MRI = magnetic resonance imaging CT = computed tomography CA19-9 = carbohydrate antigen 19-9 CEA = carcinoembryonic antigen OS = overall survival IHC = immunohistochemistry NGS = next-generation sequencing TIME = tumor immune microenvironment MSS = microsatellite stable Declarations Acknowledgements Not applicable. Author contributions LM wrote the main manuscript text and KJ prepared all figures. YH, XY and JX reviewed the manuscript. LM and KJ confirm the authenticity of all the raw data. All authors read and approved the final manuscript. Funding This work was supported by Science and Technology Department of the State Administration of Traditional Chinese Medicine of China - Zhejiang Province Joint Construction Project (Grant No. GZY-ZJ-KJ-24098 to KTJ), and Jinhua Municipal Science and Technology Projects (Grant No. 2021-3-040 to KTJ). Data availability The original contributions presented in this study are included in this article, further inquiries can be directed to the corresponding author. Clinical trial number Not applicable. Ethics approval and consent to participate The studies involving humans were approved by The Committee on Medical Ethics of the Affiliated Hospital of Shaoxing University. 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. Patient consent for publication Written informed consent was obtained from the patient specifically for the publication of potentially identifying information and/or images in an online open-access publication. A copy of the signed consent form is retained by the authors, and ethical and legal standards were adhered to throughout the publication process. Competing interests 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. References Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913-21. https://doi.org/10.1158/0008-5472.Can-14-0155. 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J Clin Oncol. 2022;40(24):2789-805. https://doi.org/10.1200/jco.21.02616. Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science. 2018;362(6411). https://doi.org/10.1126/science.aar3593. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37. https://doi.org/10.1126/scitranslmed.3003689. Niemeijer AN, Leung D, Huisman MC, et al. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018;9(1):4664. https://doi.org/10.1038/s41467-018-07131-y. Rimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 2017;3(8):1051-8. https://doi.org/10.1001/jamaoncol.2017.0013. Henriksen A, Dyhl-Polk A, Chen I, Nielsen D. Checkpoint inhibitors in pancreatic cancer. Cancer Treat Rev. 2019;78:17-30. https://doi.org/10.1016/j.ctrv.2019.06.005. Gadgeel S, Rodríguez-Abreu D, Speranza G, et al. Updated analysis from KEYNOTE-189: Pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-17. https://doi.org/10.1200/jco.19.03136. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-51. https://doi.org/10.1056/NEJMoa1810865. Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-28. https://doi.org/10.1016/s0140-6736(20)32531-9. Grimaldi A, Cammarata I, Martire C, et al. Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens. Commun Biol. 2020;3(1):85. https://doi.org/10.1038/s42003-020-0811-x. Ghiringhelli F, Menard C, Puig PE, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56(5):641-8. https://doi.org/10.1007/s00262-006-0225-8. Additional Declarations No competing interests reported. Supplementary Files DataofCEAandCA199.xls DataofGeneticTesting.pdf DataSupplementaryMaterials.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7202690","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":508164457,"identity":"848615f6-fcec-4a3d-8c5a-332e8b544722","order_by":0,"name":"Luyao Ma","email":"","orcid":"","institution":"Affiliated Hospital of Shaoxing University","correspondingAuthor":false,"prefix":"","firstName":"Luyao","middleName":"","lastName":"Ma","suffix":""},{"id":508164458,"identity":"e13e57b4-743b-4b22-91a4-6064134884ae","order_by":1,"name":"Yuejun Han","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":false,"prefix":"","firstName":"Yuejun","middleName":"","lastName":"Han","suffix":""},{"id":508164461,"identity":"a33453a7-f230-4a4e-9983-14f8a2b57a1d","order_by":2,"name":"Xingxing Yu","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xingxing","middleName":"","lastName":"Yu","suffix":""},{"id":508164464,"identity":"3adff8ea-43c1-4d21-86fd-90be7f195b1f","order_by":3,"name":"Ketao Jin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIie3RsWrDMBCA4RMGe1GTVR2avIKCoGQI7aucMGTyVuhSQwWCZDFk9Wtk6WxzoC55gAydO3VwNw8eatdTC1EyFqp/Ogl9SCCAUOgPxixE38M0YqZqIB5meQFBgOutrevyEtI3EnlwKfFxx0+i7RXJz/ZuBsdM0qqbaJPYFwH5m+dhk1SXmCpW9iTjsTbcPQpw7x7CFXGMtBUDET0R2a1ghvykw2e9GchS9mT+cZ6kgKQL7pAAh1v4ebIo1q9KJLaqiypWG75+WKI7TRa7gxLt6ml2T8w2bedudgntj03uIebn2o2fiScBwPzXOvecDYVCof/aF5cWUzhIyVaCAAAAAElFTkSuQmCC","orcid":"","institution":"The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)","correspondingAuthor":true,"prefix":"","firstName":"Ketao","middleName":"","lastName":"Jin","suffix":""},{"id":508164467,"identity":"6178ef99-7211-40ef-8fe5-2ed40c2a91d5","order_by":4,"name":"Jinfang Xu","email":"","orcid":"","institution":"Affiliated Hospital of Shaoxing University","correspondingAuthor":false,"prefix":"","firstName":"Jinfang","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2025-07-24 08:02:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7202690/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7202690/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90541284,"identity":"11393a00-676f-4a2c-9073-5fb046fc72a7","added_by":"auto","created_at":"2025-09-03 23:56:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1016211,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of imaging data before and after treatment (A1-3) Imaging data of the patient admitted on May 7, 2022. (A1) Upper abdominal magnetic resonance imaging (MRI). White arrows indicate pancreatic tail tumor, with invasion adjacent to the splenic artery and vein, as well as the spleen. (A2) Upper abdominal MRI. White areas indicate three metastatic nodules in the right liver, with a maximum diameter of approximately 13 mm. (A3) Lung computed tomography (CT). Black arrows indicate multiple metastatic nodules in both lungs, with a maximum diameter of approximately 12 mm. (B1-3) Imaging therapy after 4 months of capecitabine combined with nintedanib treatment. (B1-2) Upper abdominal MRI showed that pancreatic tumor lesions were smaller than those in May, liver metastases were smaller than before, with a maximum diameter of approximately 10 mm. (B3) Lung CT showed that bilateral lung metastases were smaller than before, with a maximum diameter of approximately 8 mm. (C1-3) Imaging therapy after 9 months of capecitabine combined with nintedanib treatment. (C1-2) Upper abdominal MRI showed that pancreatic tumor lesions were smaller than those in September. No obvious metastatic nodules were observed in the liver, and (C3) lung CT showed that bilateral lung metastases were smaller than before, with a maximum diameter of approximately 7 mm. (D1-3) Imaging therapy after 12 months of capecitabine combined with nintedanib treatment. (D1-2) Upper abdominal MRI showed that pancreatic tumor lesions were smaller than those in September. No obvious metastatic nodules were observed in the liver, and (D3) lung CT showed that bilateral lung metastases were smaller than before, with a maximum diameter of approximately 5 mm\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7202690/v1/2accea0af7d666d08eb118e3.png"},{"id":90541288,"identity":"9f577975-c8ae-44e1-9e6d-e232b390fb1a","added_by":"auto","created_at":"2025-09-03 23:56:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":631287,"visible":true,"origin":"","legend":"\u003cp\u003eTrend plots of tumor parameters after treatment: (A) CEA decreased from 14.81 ng/mL to 3.39 ng/mL and (B) CA19-9 decreased from 208.89 U/mL to 23.61 U/mL. (C) Hematoxylin and eosin (H\u0026amp;E) staining after fine needle aspiration of liver metastases showed pancreatic ductal adenocarcinoma metastasis at 200 × magnification. IHC showed that the tumor immune microenvironment (TME) was positive for CD4\u003csup\u003e+\u003c/sup\u003e (D) and CD8\u003csup\u003e+\u003c/sup\u003e (E) T cells. IHC, Immunohistochemistry; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7202690/v1/5fdac0a7564cc9230800a470.png"},{"id":101413800,"identity":"33a4d9c6-cf42-44be-b9d0-e88c295a5fe7","added_by":"auto","created_at":"2026-01-29 12:12:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2075598,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7202690/v1/cf22e804-9351-4e10-ab64-216dc04daba0.pdf"},{"id":90541286,"identity":"df23a39f-8448-4295-a670-dfd0fa67a688","added_by":"auto","created_at":"2025-09-03 23:56:02","extension":"xls","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20480,"visible":true,"origin":"","legend":"","description":"","filename":"DataofCEAandCA199.xls","url":"https://assets-eu.researchsquare.com/files/rs-7202690/v1/7571d821c6751c78cfb287b7.xls"},{"id":90541292,"identity":"ff850af9-65e5-433e-8d1a-37ab3fe9a405","added_by":"auto","created_at":"2025-09-03 23:56:03","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":245184,"visible":true,"origin":"","legend":"","description":"","filename":"DataofGeneticTesting.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7202690/v1/26deca5f22672078000b482c.pdf"},{"id":90541293,"identity":"3f8237ef-c5ea-454b-b3c8-f6db828b30e2","added_by":"auto","created_at":"2025-09-03 23:56:03","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":2326357,"visible":true,"origin":"","legend":"","description":"","filename":"DataSupplementaryMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-7202690/v1/64c69aa2491ca8c9ef37f291.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"PD-1 blockade plus capecitabine as curative-intent treatment for tumor mutational burden-high multi-metastatic pancreatic ductal adenocarcinoma: A case report","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003ePancreatic ductal adenocarcinoma (PDAC), a highly lethal human cancer, will likely become the second leading cause of cancer-related deaths by 2030 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite advances in conventional systemic therapy, the 5-year overall survival rate for PDAC remains low at 11%, partly because it presents at an advanced stage, precludes therapeutic resection, and has a strong tendency to relapse. Despite the introduction of new regimens [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], the survival of patients with PDAC has not substantially improved over the last few decades. Therefore, new treatment strategies are required to treat PDAC.\u003c/p\u003e\u003cp\u003eAdvances in immunotherapy, particularly immune-checkpoint blockade (ICB), have improved treatment options for some historically chemotherapy-refractory malignancies. Over the past 10 years, ICBs have shown efficacy in the treatment of metastatic melanoma, renal cell carcinoma, colorectal cancer with microsatellite instability, non-small cell lung cancer, Hodgkin\u0026rsquo;s lymphoma, and other cancers [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Despite the success of ICB, PDAC has been largely refractory to ICB monotherapy, possibly because it has some intrinsic and extrinsic properties that sequester malignant cells from effective adaptive immune responses [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, it is worth investigating combined approaches to improve ICB efficacy.\u003c/p\u003e\u003cp\u003eWe present a case of multi-metastatic PDAC with a high tumor mutational burden (TMB), in which the tumor microenvironment (TME) was positive for CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells, which suggested that immunotherapy was successful. Therefore, ICB treatment with sintilimab (Innovent Biologics Co., Ltd., Suzhou, China), a programmed cell death protein 1 (PD-1) monoclonal antibody (mAb), was added to an oral capecitabine regime, which led to disease regression.\u003c/p\u003e"},{"header":"2 Case report","content":"\u003cp\u003eA 69-year-old man who complained of repeated left upper abdominal pain and discomfort for more than 1 year was admitted to our hospital in May 2022. The patient's medical history was unremarkable, with no documented family history of malignancy. Contrast-enhanced magnetic resonance imaging (MRI) and computed tomography (CT) of the abdomen showed a space-occupying lesion in the tail of the pancreas, with adjacent spleen and splenic arteriovenous invasion, multiple intrahepatic metastases, and multiple liver metastases (Fig.\u0026nbsp;1A1-2). Contrast-enhanced CT of the chest revealed multiple metastases to both lungs (Fig.\u0026nbsp;1A3). Histopathological examination of the liver metastases revealed adenocarcinoma, consistent with PDAC metastasis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Serum carcinoembryonic antigen (CEA; up to 14.81 ng/mL) and carbohydrate antigen 19\u0026thinsp;\u0026minus;\u0026thinsp;9 (CA19-9; up to 208.89 U/mL) were elevated. The patient presented with newly diagnosed stage IV pancreatic ductal adenocarcinoma, demonstrating limited overall survival (OS) consistent with advanced disease prognosis. The patient refused systemic intravenous chemotherapy and received only oral capecitabine chemotherapy. After one capecitabine single agent (1500 mg, bid, po, d1-d14; Qilu Pharmaceutical Co. Ltd., Jinan, China) cycle, immunohistochemistry (IHC) showed a PD-L1 total positive score (TPS) of \u0026lt;\u0026thinsp;1%. Next-generation sequencing (NGS) of tumor tissue revealed a high TMB (9.02 mutations/megabase, 17.5%) and a microsatellite stable (MSS) state (Table I). IHC showed that the tumor immune microenvironment (TIME) was positive for CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD, E). Serum CEA and CA19-9 levels were elevated (up to 19.93 ng/mL and 308.37 U/mL, respectively).\u003c/p\u003e\u003cp\u003eSintilimab (200 mg every 3 weeks) was added to the ongoing capecitabine regimen. Except for grade capecitabine\u0026thinsp;+\u0026thinsp;sintilimab treatment (1 cycle of capecitabine and 17 cycles of capecitabine\u0026thinsp;+\u0026thinsp;sintilimab), contrast-enhanced MRI and CT demonstrated tumor shrinkage, and a partial response was observed (Fig.\u0026nbsp;1D1-3). Serum CEA (down to normal levels, 3.39 ng/mL) and CA19-9 (down to normal levels, 23.61 U/mL) were reduced (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, B). The patient completed 18 cycles of treatment, and tolerated the treatment without any immune toxicity. The patient\u0026rsquo;s current condition was assessed as pathological response.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAnalysis of next-generation sequencing (NGS) of tumor tissue\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNum\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eItem\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eResult\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTumor mutation burden, TMB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.02 Mut/Mb\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMicro satellite instability, MSI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMSS\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMLH1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMSH2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMSH6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePMS2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePD-L1 score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTPS: \u0026lt;1%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTET2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP.I1873L\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBRCA1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBRCA2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"3 Discussion","content":"\u003cp\u003ePDAC is associated with high morbidity and adverse clinical outcomes. To date, PDAC has been largely refractory to ICB monotherapy, and effective personalized immunotherapy is lacking. Here, we present the case of a 69-year-old man diagnosed with PDAC with liver and lung metastases. As the patient refused systemic intravenous chemotherapy, we could not treat him with the standard protocol. CEA and CA19-9 levels were elevated after a course of single-agent oral capecitabine chemotherapy. Therefore, after communicating with the patient and obtaining consent, we decided to combine this with immunotherapy to enhance the potency of the immune system to recognize and kill foreign targets and overcome the immunosuppressive TME.\u003c/p\u003e\u003cp\u003eWe emphasize the importance of genetic analysis of tumor tissue using NGS to screen for MSS, which may respond to immune-checkpoint inhibitors, and determine personalized immunotherapy characteristics. In this case, NGS showed an MSS status but a high TMB (9.02 mutations/megabase). A high TMB can be used as another predictor, in addition to microsatellite instability and mismatch-repair defects, for identifying patients with cancer who may benefit from ICB, with the underlying hypothesis of increasing the number of mutated proteins and producing antigenic peptides, thereby enhancing immunogenicity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA previous study divided tumors into four categories based on PD-L1 expression and T cell infiltration (TIL, mainly CD8\u003csup\u003e+\u003c/sup\u003e T cells) in the TIME: PD-L1\u003csup\u003e-\u003c/sup\u003e/TIL\u003csup\u003e-\u003c/sup\u003e (type I), PD-L1\u003csup\u003e+\u003c/sup\u003e/TIL\u003csup\u003e+\u003c/sup\u003e (type II), PD-L1\u003csup\u003e-\u003c/sup\u003e/TIL\u003csup\u003e+\u003c/sup\u003e (type III), and PD-L1\u003csup\u003e+\u003c/sup\u003e/TIL\u003csup\u003e-\u003c/sup\u003e (type IV); this study showed that type II tumors responded better to PD-1 treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Tumor IHC of our patient showed infiltration of CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells in the TME, which suggested that the tumor cells were recognized by the immune system and that immunotherapy was effective. However, PD-L1 results showed a TPS\u0026thinsp;\u0026lt;\u0026thinsp;1%, that is, a PD-L1 status, which should be defined as a type III tumor according to the above classification. Nevertheless, our patient responded well to anti-PD-1 therapy clinically. Thus, this finding may be explained by the use of needle biopsy to sample the tumor tissue, which may have missed PD-L1\u003csup\u003e+\u003c/sup\u003e areas, resulting in false-negative results. However, the PD-L1\u003csup\u003e+\u003c/sup\u003e rate can be increased by performing multiple biopsies of the tumor tissue. PD-L1 expression can be assessed in a larger range of tumors by radioisotope labeling [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The processing of tumor tissue and type of antibodies used may lead to confusion regarding PD-L1 results [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Moreover, PD-L1 expression is inducible. This suggests that PD-L1 expression differs from the start of biopsy to the point of anti-PD-1 therapy. How much PD-L1 needs to be expressed in the TME to achieve anti-PD-1 effects is unknown; therefore, the effectiveness of anti-PD-1 therapy cannot be judged from the expression of PD-L1 alone.\u003c/p\u003e\u003cp\u003eICB monotherapy is less effective in patients with pancreatic cancer. However, combination regimens, including chemotherapy, have shown good preliminary results [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This case also verified that combination chemotherapy regimens are effective, and we believe that chemotherapy-induced cancer cell death can promote the release of tumor antigens and antigen presentation, stimulate immune effectors, and increase the efficacy of immunotherapy. Immune-checkpoint inhibitors have been successfully used in combination with standard chemotherapy for non-small cell lung cancer, small cell lung cancer, and triple-negative breast cancer [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]; however, their efficacy is limited or unsustainable. This may be owing to the significant immunosuppressive side effects of high-intensity chemotherapy, which compromise the immune system directly by inhibiting or killing effector cells or indirectly by causing anergy or immune paralysis. If chemotherapeutic agents are appropriately used in anti-PD therapy, T-cell immunity may be promoted by eliminating Tregs and increasing antigen release at the time of tumor cell death, thereby stimulating T-cell-mediated immune responses [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and generating additional anti-tumor responses.\u003c/p\u003e\u003cp\u003eAfter more than 13 months of treatment, the patient\u0026rsquo;s current condition was assessed as partial response. The next step is to consider when to discontinue the drug and whether to add targeted therapy to increase efficacy.\u003c/p\u003e\u003cp\u003ePDACs possess several intrinsic and extrinsic properties that protect malignant cells from effective adaptive immune responses. To date, no single immunotherapy strategy has been proven effective, warranting the investigation of combination approaches to improve treatment efficacy. Our case showed that the use of PD-1 mAb immunotherapy and capecitabine might be a promising treatment option for patients with multi-metastatic PDAC with a high TMB who are positive for CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells in the TIME. More clinical trials are needed to evaluate combination immunotherapy strategies to demonstrate the role of immunotherapy in PDAC treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003ePDAC = pancreatic ductal adenocarcinoma\u003c/p\u003e\n\u003cp\u003eICB = immune-checkpoint blocker\u003c/p\u003e\n\u003cp\u003eTME = tumor microenvironment\u003c/p\u003e\n\u003cp\u003ePD-1 = programmed cell death protein-1\u003c/p\u003e\n\u003cp\u003eMRI = magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003eCT = computed tomography\u003c/p\u003e\n\u003cp\u003eCA19-9 = carbohydrate antigen 19-9\u003c/p\u003e\n\u003cp\u003eCEA\u0026nbsp;= carcinoembryonic antigen\u003c/p\u003e\n\u003cp\u003eOS = overall survival\u003c/p\u003e\n\u003cp\u003eIHC = immunohistochemistry\u003c/p\u003e\n\u003cp\u003eNGS = next-generation sequencing\u003c/p\u003e\n\u003cp\u003eTIME = tumor immune microenvironment\u003c/p\u003e\n\u003cp\u003eMSS = microsatellite stable\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eLM wrote the main manuscript text and KJ prepared all figures. YH, XY and JX reviewed the manuscript. LM and KJ confirm the authenticity of all the raw data. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by Science and Technology Department of the State Administration of Traditional Chinese Medicine of China - Zhejiang Province Joint Construction Project (Grant No. GZY-ZJ-KJ-24098 to KTJ), and Jinhua Municipal Science and Technology Projects (Grant No. 2021-3-040 to KTJ). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in this study are included in this article, further inquiries can be directed to the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eClinical trial number\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe studies involving humans were approved by The Committee on Medical Ethics of the Affiliated Hospital of Shaoxing University. 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. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient consent for publication\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient specifically for the publication of potentially identifying information and/or images in an online open-access publication. A copy of the signed consent form is retained by the authors, and ethical and legal standards were adhered to throughout the publication process.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe 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.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRahib L, Smith BD, Aizenberg R, et al. 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Sci Transl Med. 2012;4(127):127ra37. https://doi.org/10.1126/scitranslmed.3003689.\u003c/li\u003e\n\u003cli\u003eNiemeijer AN, Leung D, Huisman MC, et al. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018;9(1):4664. https://doi.org/10.1038/s41467-018-07131-y.\u003c/li\u003e\n\u003cli\u003eRimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non-small cell lung cancer. JAMA Oncol. 2017;3(8):1051-8. https://doi.org/10.1001/jamaoncol.2017.0013.\u003c/li\u003e\n\u003cli\u003eHenriksen A, Dyhl-Polk A, Chen I, Nielsen D. Checkpoint inhibitors in pancreatic cancer. Cancer Treat Rev. 2019;78:17-30. https://doi.org/10.1016/j.ctrv.2019.06.005.\u003c/li\u003e\n\u003cli\u003eGadgeel S, Rodr\u0026iacute;guez-Abreu D, Speranza G, et al. 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Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens. Commun Biol. 2020;3(1):85. https://doi.org/10.1038/s42003-020-0811-x.\u003c/li\u003e\n\u003cli\u003eGhiringhelli F, Menard C, Puig PE, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56(5):641-8. https://doi.org/10.1007/s00262-006-0225-8.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Immune-checkpoint inhibitor, Pancreatic ductal adenocarcinoma, Sintilimab, Capecitabine, Case report","lastPublishedDoi":"10.21203/rs.3.rs-7202690/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7202690/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe rising incidence and persistently dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for effective new systemic therapies. Cancer immunotherapy has increasingly garnered attention. Various methods, such as cell therapy, immune-checkpoint blockers (ICBs), and cancer vaccines, alone or in combination, have achieved satisfactory results in cancer therapy. Immunotherapy has shown significant benefits in solid organ tumors but has been disappointing in PDAC treatment. Despite promising preclinical studies, clinical translation has proven challenging, possibly because PDAC has a complex immunosuppressive tumor microenvironment (TME), which insulates the tumor from an effective cytotoxic immune response. Therefore, we aimed to investigate combined approaches to improve ICB efficacy. Here we present a case of a 69-year-old man diagnosed with multi-metastatic PDAC. Genetic analysis revealed a high tumor mutational burden of 9.02 mutations/megabase. The TME was positive for CD4\u003csup\u003e+\u003c/sup\u003e and CD8\u003csup\u003e+\u003c/sup\u003e T cells, suggesting potential immunotherapy success. Immune-checkpoint blockade treatment with sintilimab, a programmed cell death protein 1 (PD-1) monoclonal antibody, was initiated, leading to disease regression. The treatment response was confirmed using contrast-enhanced magnetic resonance imaging and computed tomography.\u003c/p\u003e","manuscriptTitle":"PD-1 blockade plus capecitabine as curative-intent treatment for tumor mutational burden-high multi-metastatic pancreatic ductal adenocarcinoma: A case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-03 23:55:58","doi":"10.21203/rs.3.rs-7202690/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6dd73e1d-76c4-4c47-a795-68c8fa5e4378","owner":[],"postedDate":"September 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-29T12:11:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-03 23:55:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7202690","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7202690","identity":"rs-7202690","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}