{"paper_id":"1b6ae97d-72c9-42d2-bc35-5c6f736d5e60","body_text":"Anti-CD19 CAR-T Therapy for Central Lymphoma: A Case Study of Ocular Follicular Lymphoma and Emerging Therapeutic Strategies | 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 Anti-CD19 CAR-T Therapy for Central Lymphoma: A Case Study of Ocular Follicular Lymphoma and Emerging Therapeutic Strategies Hui Li, Ping Long, Xinyu Wei, Meng Zhou, Xiaohong Ming, Haichuan Zhu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6369375/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 Background: Central lymphomas, including rare and anatomically complex subtypes such as ocular follicular lymphoma (OFL), pose substantial therapeutic challenges due to their localization and unique microenvironment promoting immune evasion. OFL, a rare manifestation of follicular lymphoma (FL), often exhibits resistance to standard therapies, necessitating innovative approaches. Methods: This case report highlights the application of anti-CD19 CAR-T therapy in a patient with OFL. Treatment outcomes, including safety, cytokine release syndrome (CRS), and durability of remission, were assessed during an 18-month follow-up. Results: The patient achieved complete metabolic remission with no evidence of systemic relapse or significant long-term toxicities. Transient grade 1–2 CRS was observed but resolved with supportive care. No neurological toxicities were reported, and the patient has remained disease-free. Conclusions: Anti-CD19 CAR-T therapy demonstrated sustained efficacy and a favorable safety profile in this case of OFL, underscoring its potential as an innovative therapeutic approach for central lymphomas. Further research is warranted to explore its integration into first-line treatment settings and optimize its applicability across broader lymphoma subtypes. central lymphoma ocular follicular lymphoma CD19 CAR-T cell therapy non-Hodgkin lymphoma Figures Figure 1 Figure 2 Introduction Central lymphomas, including primary central nervous system lymphoma (PCNSL) and ocular follicular lymphoma (OFL), pose significant diagnostic and therapeutic challenges due to their involvement of critical anatomical sites. OFL, an extranodal subtype of follicular lymphoma (FL), typically manifests as painless proptosis or periorbital swelling. Early-stage diagnosis occurs in < 10% of cases, and systemic symptoms (e.g., B symptoms, elevated LDH) are uncommon (< 20%)[ 1 , 2 ]. FL pathogenesis is driven by hallmark t(14;18)-mediated BCL-2 overexpression and epigenetic mutations (e.g., KMT2D, CREBBP), conferring resistance to apoptosis[ 3 ][ 4 ]. Conventional therapies, including radiotherapy (RT) and rituximab-based chemoimmunotherapy, achieve 10-year OS rates of 60–80% in localized disease but fail to prevent relapses (40% recurrence rate)[ 5 ][ 6 ][ 7 ][ 8 ]. Prolonged anti-CD20 antibody use further risks immunosuppression and opportunistic infections[ 9 ]. Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has demonstrated transformative efficacy in aggressive B-cell malignancies[ 10 ]. Recent trials, such as ELARA, report > 80% response rates and 24-month PFS > 50% in relapsed/refractory FL, highlighting its potential for central lymphomas. CAR-T therapy induces durable remission with a single infusion, minimizing maintenance therapy burdens. However, challenges include high cost (> $ 500,000 per infusion), delayed cytopenias, and CRS/neurotoxicity risks[ 11 ]. Subtype-specific trials are needed to optimize CAR-T applications for anatomically complex lymphomas like OFL, balancing efficacy with accessibility and safety. Case report In August 2022, a 51-year-old male patient was found to have a protruding left eyeball and went to the hospital to refine orbital computed tomography (CT), enhancement, and three-dimensional imaging to reveal a left posterior ocular space-occupying lesion with suspicion of lymphoma. Immediately PET-CT considered irregular soft-tissue density mass behind the left eyeball(Figure 1 H), fusion of lymph nodes into a mass in the left neck, anterolateral border of the anterior deltoid fasciculus on the right, lateral border of the middle deltoid fasciculus on the right, anterior border of the right lesser round muscle, posterior gap of the right pectoralis minor muscle, subcutaneous fascia slightly above the left subscapularis margin, soft-tissue mass with metabolic increase in the left internal muscularis obturatoris, and consideration of lymphoma involvement, and the right anterior chest wall thickening of the medial border of the pectoralis major muscle, localized skin thickening, blurred subcutaneous fat, and slightly elevated metabolism, consider lymphoma involvement and localized biopsy after surgery༈Figure 1 I༉. The patient completed left orbital apical tumor removal + right chest wall tumor resection on September 6, 2022 at the First Affiliated Hospital of Zhengzhou University. Postoperative biopsy histopathology suggested: AE1/AE3(-), CD3(-), CD20(+), CD5(+), CD21(+), CD10(partial+), CD30(scattered+), PAX-5(+), Bc1-2(foci+), MUM-1(-), CyclinD1(-), Ki-67(20%+). Chest wall mass Immunohistochemistry results:CD19(+), CD38(-). In situ hybridization: EBER(-) (Fig. 1 A-D). A biopsy of the orbital lesion confirmed follicular lymphoma (grade 1–2), with immunophenotyping revealing CD20+, CD10+, BCL-2+, and a Ki-67 proliferation index of 20%. The fluorescence in situ hybridization (FISH) result is negative for BCL 2/IgH rearrangement; BCL6 rearrangement negative; C-MYC/IgH rearrangement negative; API2/MALT1 rearrangement negative (Fig. 1 E-H). Patient refused chemotherapy and requested targeted CD19 CART cell therapy. In the current case, after fully informing the patient and family about the risks of cell transfusion, immunotherapy, and insurance riders, and upon completing sign-off, CD19 cell immunotherapy was performed. Intervention After declining conventional systemic chemoimmunotherapy due to concerns about toxicity, the patient elected to undergo anti-CD19 CAR-T therapy. Preconditioning chemotherapy consisted of fludarabine (60 mg/day) and cyclophosphamide (1 g/day) for three consecutive days, followed by the infusion of 4 × 10⁶ anti-CD19 CAR-T cells on November 3, 2022. Under research compassionate use guidelines (Ethics Approval: TJ-IRB20210827), he received a 4-1BB-costimulated anti-CD19 CAR-T product (Bio-Raid, Bio-003). Primary endpoints included safety (incidence and severity of cytokine release syndrome [CRS] and neurotoxicity), efficacy (complete metabolic response assessed via PET-CT), and durability of response over 18 months of follow-up. Clinical trial number: not applicable. Results The patient experienced mild and self-limiting adverse effects following CAR-T cell infusion, including fever (initial temperature: 37.4°C; peak: 38.7°C, lasting 4 days) and tachycardia, which developed 48 hours post-infusion. A transient increase in serum ferritin (Fig. 2 E) and interleukin-6 (Fig. 2 F) was observed, with peak levels reaching 17.5-fold above baseline. Hematologic toxicity was most pronounced on day 3 post-infusion (Figs. 2 G-H); however, it resolved spontaneously without clinical intervention, and no central nervous system (CNS) toxicity was detected. Leukocyte and neutrophil counts normalized by day 7 post-infusion. Importantly, no red blood cell or platelet transfusions were required during the treatment course (Fig. 2 H). These findings indicate that the patient experienced only grade 1–2 cytokine release syndrome (CRS), demonstrating a favorable safety profile for CAR-T cell therapy. At 622 days post-infusion, positron emission tomography-computed tomography (PET-CT) demonstrated systemic disease remission without significant edema. Long-term follow-up assessments revealed no signs of disease progression, recurrence, or tumor metastasis (Fig. 2 I-L), further underscoring the sustained efficacy and safety of CAR-T cell therapy. Discussion Follicular lymphoma (FL), as the most common indolent lymphoma, presents unique therapeutic challenges despite its less aggressive nature compared to invasive lymphomas[ 12 ]. Follicular lymphoma (FL), the most common indolent lymphoma, is characterized by recurrent relapses despite high initial remission rates, necessitating therapies that provide durable responses. Current standards, such as rituximab-based chemoimmunotherapy and bendamustine-rituximab regimens, achieve short-term disease control but are limited by cumulative toxicities, immunosuppression-related infections, and inevitable relapses[ 13 ][ 14 ], but its long-term safety and efficacy are limited by drug toxicities and the inability to prevent eventual disease relapse. However, long-term use of CD20 monoclonal antibodies will inevitably lead to repeated hospitalizations, affecting the quality of life and causing many drawbacks such as easy infection. With the development of pathophysiology in follicular lymphoma, targeted therapy is the optimal choice, and many patients with quality of life requirements (including follicular lymphoma, especially those with advanced disease) will actively try new immunotherapy strategies. The diagnosis of follicular lymphoma requires the detection of characteristic t (14; 18) translocations [ 15 ], FL pathogenesis is driven by t(14;18)-mediated BCL-2 overexpression and recurrent epigenetic mutations (e.g., KMT2D, CREBBP, EZH2), which promote immune evasion and treatment resistance[[ 2 ][ 16 ][ 13 ][ 17 ]. The B cell receptor, RAS, mTOR, and JAK-STAT pathways have been found to be associated with immune escape mutations[ 18 ]. Emerging therapies, including antibody-drug conjugates (e.g., polatuzumab vedotin), CD47 inhibitors (e.g., magrolimab), and small molecule inhibitors targeting PI3K/BTK pathways, show promise but lack sustained efficacy in preventing relapse [ 14 ][ 19 ]. Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 represents a paradigm shift. While traditionally reserved for aggressive lymphomas, recent trials (e.g., ELARA) demonstrate > 80% response rates and durable remissions in relapsed/refractory FL[ 6 ]. The presented case of anti-CD19 CAR-T achieving sustained remission in treatment-naïve OFL highlights its potential in indolent subtypes. CAR-T therapy minimizes maintenance burdens and cumulative toxicities; however, challenges include high costs (> $ 500,000 per infusion), cytokine release syndrome (CRS), and delayed cytopenias[ 11 ]. Furthermore, its role in early-line therapy requires validation through subtype-specific trials, particularly for anatomically complex lymphomas like OFL, where tumor microenvironment interactions may influence outcomes. CAR-T was offered as compassionate use after multidisciplinary review. The patient acknowledged lymphodepletion risks and prioritized single-infusion efficacy over maintenance therapies. Conclusion Anti-CD19 CAR-T therapy induced sustained remission in this OFL case, underscoring its potential for central lymphomas. However, cost, toxicity, and indolent disease kinetics necessitate further studies before first-line adoption. Declarations Author Contribution M.Z., P.L, and XY.W. designed the experimental plans; HC.Z., MQ.Y., HX.W., M.Z., L.F., and M.L. performed the experiments. Q.W. performed the bioinformatic analysis; H.L. analyzed the data and drafted the manuscript. Y.X., and TC.Z. were involved in the revision of the manuscript. Acknowledgements This work was funded by grants from the Scientific Research Program for Young Talents of Hubei Provincial Department of Education (Q202111113), Wuhan Knowledge Innovation Project, Dawn Plan (20220220208001020313) and the Natural Science Foundation of Hubei Province (2023AFB606). Competing interests and Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki. All research involving human participants was approved by the institutional ethics committee, and the study adhered to appropriate national guidelines. The authors declare that they have no competing interests. The project has received approval from the Ethics Committee of Tianyou Hospital affiliated with Wuhan University of Science and Technology (LL-2023-05-09-01). We obtained the informed consent of the patient and family and performed compassionate treatment as agreed to by the patient and family. Informed consent was obtained from all study participants, including parents or legally authorized representatives of subjects under the age of 16. All participants were fully informed of the study's purpose, risks, and benefits before providing their consent. Consent for publication All statements in this case report were published with the consent of the patient and family. The work described has not been published before. It is not under consideration for publication anywhere else. Its publication has been approved by all co-authors, and the responsible authorities at the institute where the work has been carried out. All authors contributed equally to this manuscript. Prof. Yi Xiao and Prof. Tongcun Zhang were involved in the study design, manuscript writing, and final revisions. 1 All authors contribute equally to this article. Data Availability Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. The work described has not been published before. It is not under consideration for publication anywhere else. Its publication has been approved by all co-authors, and the responsible authorities at the institute where the work has been carried out. References Jacobsen E: Follicular lymphoma: 2023 update on diagnosis and management. American journal of hematology 2022, 97(12):1638–1651. Zhong J, Yang X, Chen J, He K, Gao X, Wu X, Zhang M, Zhou H, Xiao F, An L et al : Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands. Nature communications 2022, 13(1):4795. Schmatz AI, Streubel B, Kretschmer-Chott E, Püspök A, Jäger U, Mannhalter C, Tiemann M, Ott G, Fischbach W, Herzog P et al : Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2011, 29(11):1445–1451. Naresh KN, Medeiros LJ: Introduction to the Fifth Edition of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 2023, 36(12):100330. Kiaii S, Clear AJ, Ramsay AG, Davies D, Sangaralingam A, Lee A, Calaminici M, Neuberg DS, Gribben JG: Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2013, 31(21):2654–2661. Morschhauser F, Dahiya S, Palomba ML, Martin Garcia-Sancho A, Reguera Ortega JL, Kuruvilla J, Jäger U, Cartron G, Izutsu K, Dreyling M et al : Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nature medicine 2024. Borchmann S, Müller H, Haverkamp H, Baues C, Marková J, Hüttmann A, Glunz A, Fuchs M, Borchmann P, Engert A: Symptomatic osteonecrosis as a treatment complication in Hodgkin lymphoma: an analysis of the German Hodgkin Study Group (GHSG). Leukemia 2019, 33(2):439–446. MacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, Tsang R, Christie D, McClure B, Joseph D et al : Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2018, 36(29):2918–2925. Friedberg JW: Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2023, 41(2):151–152. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C et al : Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet (London, England) 2020, 396(10254):839–852. Schubert ML, Schmitt M, Wang L, Ramos CA, Jordan K, Müller-Tidow C, Dreger P: Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Annals of oncology: official journal of the European Society for Medical Oncology 2021, 32(1):34–48. Freedman A, Jacobsen E: Follicular lymphoma: 2020 update on diagnosis and management. American journal of hematology 2020, 95(3):316–327. Gordon MJ, Smith MR, Nastoupil LJ: Follicular lymphoma: The long and winding road leading to your cure? Blood reviews 2023, 57:100992. Flowers CR, Matasar MJ, Herrera AF, Hertzberg M, Assouline S, Demeter J, McMillan A, Mehta A, Opat S, Trnňný M et al : Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study. Haematologica 2024, 109(4):1194–1205. Roulland S, Kelly RS, Morgado E, Sungalee S, Solal-Celigny P, Colombat P, Jouve N, Palli D, Pala V, Tumino R et al : t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2014, 32(13):1347–1355. Amin R, Braza MS: The follicular lymphoma epigenome regulates its microenvironment. Journal of experimental & clinical cancer research: CR 2022, 41(1):21. Morschhauser F, Tilly H, Chaidos A, McKay P, Phillips T, Assouline S, Batlevi CL, Campbell P, Ribrag V, Damaj GL et al : Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. The Lancet Oncology 2020, 21(11):1433–1442. Weniger MA, Küppers R: Molecular biology of Hodgkin lymphoma. Leukemia 2021, 35(4):968–981. Song Y, Zhou K, Zou D, Zhou J, Hu J, Yang H, Zhang H, Ji J, Xu W, Jin J et al : Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood 2022, 139(21):3148–3158. Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.xlsx 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-6369375\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":true,\"archivedVersions\":[],\"articleType\":\"Case Report\",\"associatedPublications\":[],\"authors\":[{\"id\":475811757,\"identity\":\"2367fae4-8c66-4287-aaf4-bffc272f8065\",\"order_by\":0,\"name\":\"Hui Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Hui\",\"middleName\":\"\",\"lastName\":\"Li\",\"suffix\":\"\"},{\"id\":475811758,\"identity\":\"85674b8c-cbae-48f1-b8bf-af9ade9c0668\",\"order_by\":1,\"name\":\"Ping Long\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ping\",\"middleName\":\"\",\"lastName\":\"Long\",\"suffix\":\"\"},{\"id\":475811759,\"identity\":\"5e33e587-a574-4a87-af55-38333337da40\",\"order_by\":2,\"name\":\"Xinyu Wei\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xinyu\",\"middleName\":\"\",\"lastName\":\"Wei\",\"suffix\":\"\"},{\"id\":475811760,\"identity\":\"ee1aaa02-ea24-4c33-a0fb-bcb1dcfb4449\",\"order_by\":3,\"name\":\"Meng Zhou\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Meng\",\"middleName\":\"\",\"lastName\":\"Zhou\",\"suffix\":\"\"},{\"id\":475811761,\"identity\":\"cc6fc49e-d8e1-44a6-ade3-55d15cf0ba15\",\"order_by\":4,\"name\":\"Xiaohong Ming\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Xiaohong\",\"middleName\":\"\",\"lastName\":\"Ming\",\"suffix\":\"\"},{\"id\":475811762,\"identity\":\"07c4735f-092b-4857-9c47-a65f1a864429\",\"order_by\":5,\"name\":\"Haichuan Zhu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Haichuan\",\"middleName\":\"\",\"lastName\":\"Zhu\",\"suffix\":\"\"},{\"id\":475811763,\"identity\":\"1e1893bc-069a-448a-a2dc-084fb948c5f1\",\"order_by\":6,\"name\":\"Ming Zhu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ming\",\"middleName\":\"\",\"lastName\":\"Zhu\",\"suffix\":\"\"},{\"id\":475811764,\"identity\":\"27223954-38d6-4902-9e49-300d5c8cef61\",\"order_by\":7,\"name\":\"Lei Feng\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Lei\",\"middleName\":\"\",\"lastName\":\"Feng\",\"suffix\":\"\"},{\"id\":475811765,\"identity\":\"8c3e5813-0da3-4fe5-be36-ba01f4a38fa5\",\"order_by\":8,\"name\":\"Ming Li\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Ming\",\"middleName\":\"\",\"lastName\":\"Li\",\"suffix\":\"\"},{\"id\":475811766,\"identity\":\"bdaf2313-beb5-43da-b85e-6c713c4d1595\",\"order_by\":9,\"name\":\"Qin Wu\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Qin\",\"middleName\":\"\",\"lastName\":\"Wu\",\"suffix\":\"\"},{\"id\":475811767,\"identity\":\"8b0676a4-976a-4776-a810-2102b232eaf1\",\"order_by\":10,\"name\":\"Tongcun Zhang\",\"email\":\"\",\"orcid\":\"\",\"institution\":\"Wuhan University of Science and Technology\",\"correspondingAuthor\":false,\"prefix\":\"\",\"firstName\":\"Tongcun\",\"middleName\":\"\",\"lastName\":\"Zhang\",\"suffix\":\"\"},{\"id\":475811768,\"identity\":\"6cd29a53-73c8-48f9-ba20-7a6cdf296127\",\"order_by\":11,\"name\":\"Yi Xiao\",\"email\":\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYDACZgaGAwwMNgyMM4AcCbBQAlFa0iSAWhgbiNMCAYclgDYwNjAQo8XgOI/hgR8V5+uYZzewP7DMOczAz55jwPBzBx4th9kSDvacuS3BOOcAY4PktsMMkj1vDBh7z+DTwnzgAG8bUMuMBIgWgxs5BsyMbfi0MDYc/Nt2DqHFnrAW5gOHedsOINkiQUCLJNAvh2XOJEs2zkhsnCG5LZ1H4syzgoO9eLTwnT9j/PFNhR2/4YzkA58lt1nL8bcnb3zwE48WhQNQhmEDYwMzMCp5QJwDONUDgXwDjAHEjB/wKR0Fo2AUjIIRCwDiHFQmBR6taAAAAABJRU5ErkJggg==\",\"orcid\":\"\",\"institution\":\"Huazhong University of Science and Technology\",\"correspondingAuthor\":true,\"prefix\":\"\",\"firstName\":\"Yi\",\"middleName\":\"\",\"lastName\":\"Xiao\",\"suffix\":\"\"}],\"badges\":[],\"createdAt\":\"2025-04-03 12:38:21\",\"currentVersionCode\":1,\"declarations\":\"\",\"doi\":\"10.21203/rs.3.rs-6369375/v1\",\"doiUrl\":\"https://doi.org/10.21203/rs.3.rs-6369375/v1\",\"draftVersion\":[],\"editorialEvents\":[],\"editorialNote\":\"\",\"failedWorkflow\":false,\"files\":[{\"id\":85753007,\"identity\":\"c821bd14-6182-44af-83fb-61ab953cd680\",\"added_by\":\"auto\",\"created_at\":\"2025-07-01 10:29:20\",\"extension\":\"png\",\"order_by\":1,\"title\":\"Figure 1\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":796256,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePatient's basic condition before treatment. a-d. Immunohistochemical staining results of chest wall tumor tissues. e-h. Fluorescence in situ hybridization (FISH) results of chest wall tumor tissues. i-h. 18FDG-PET scans of the patient's chest wall, posterior eyeballs, and whole body before treatment.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"1.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6369375/v1/de9910457f70d9d12deeb953.png\"},{\"id\":85752108,\"identity\":\"ee4dcec8-4efd-48a9-832e-27e77a96b167\",\"added_by\":\"auto\",\"created_at\":\"2025-07-01 10:21:20\",\"extension\":\"png\",\"order_by\":2,\"title\":\"Figure 2\",\"display\":\"\",\"copyAsset\":false,\"role\":\"figure\",\"size\":398382,\"visible\":true,\"origin\":\"\",\"legend\":\"\\u003cp\\u003ePatient's basic condition after treatment. a-c. Changes in the levels of inflammatory factors: C-reactive protein, IL-6, ferritin were significantly elevated during the treatment period and decreased to normal levels as the condition stabilized. d. Lactate dehydrogenase stayed within the normal levels during the treatment period. e-h. Changes in the leukocyte and platelet counts during the treatment period, with no significant hematologic toxicity seen. i-l. Anti-CD19 CART treatment Post-treatment 18FDG-PET scans of the patient's chest wall, behind the eyes, and whole body.\\u003c/p\\u003e\",\"description\":\"\",\"filename\":\"2.png\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6369375/v1/ea108fa0d0ee2a9a57de8f29.png\"},{\"id\":91857815,\"identity\":\"4187d1a9-03fd-4653-bd17-332c8004f2d7\",\"added_by\":\"auto\",\"created_at\":\"2025-09-22 12:10:32\",\"extension\":\"pdf\",\"order_by\":0,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"manuscript-pdf\",\"size\":1679840,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"manuscript.pdf\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6369375/v1/256a5729-8f9c-46d9-b0b7-fc42877ccce2.pdf\"},{\"id\":85752107,\"identity\":\"c0b86bda-a80b-4991-b095-9a7ccbdbd987\",\"added_by\":\"auto\",\"created_at\":\"2025-07-01 10:21:20\",\"extension\":\"xlsx\",\"order_by\":5,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":10578,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Table1.xlsx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6369375/v1/28535a283851cdfd03ed8070.xlsx\"}],\"financialInterests\":\"No competing interests reported.\",\"formattedTitle\":\"Anti-CD19 CAR-T Therapy for Central Lymphoma: A Case Study of Ocular Follicular Lymphoma and Emerging Therapeutic Strategies\",\"fulltext\":[{\"header\":\"Introduction\",\"content\":\"\\u003cp\\u003e Central lymphomas, including primary central nervous system lymphoma (PCNSL) and ocular follicular lymphoma (OFL), pose significant diagnostic and therapeutic challenges due to their involvement of critical anatomical sites. OFL, an extranodal subtype of follicular lymphoma (FL), typically manifests as painless proptosis or periorbital swelling. Early-stage diagnosis occurs in \\u0026lt;\\u0026thinsp;10% of cases, and systemic symptoms (e.g., B symptoms, elevated LDH) are uncommon (\\u0026lt;\\u0026thinsp;20%)[ \\u003cspan citationid=\\\"CR1\\\" class=\\\"CitationRef\\\"\\u003e1\\u003c/span\\u003e , \\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e ]. FL pathogenesis is driven by hallmark t(14;18)-mediated BCL-2 overexpression and epigenetic mutations (e.g., KMT2D, CREBBP), conferring resistance to apoptosis[ \\u003cspan citationid=\\\"CR3\\\" class=\\\"CitationRef\\\"\\u003e3\\u003c/span\\u003e ][ \\u003cspan citationid=\\\"CR4\\\" class=\\\"CitationRef\\\"\\u003e4\\u003c/span\\u003e ]. Conventional therapies, including radiotherapy (RT) and rituximab-based chemoimmunotherapy, achieve 10-year OS rates of 60\\u0026ndash;80% in localized disease but fail to prevent relapses (40% recurrence rate)[ \\u003cspan citationid=\\\"CR5\\\" class=\\\"CitationRef\\\"\\u003e5\\u003c/span\\u003e ][ \\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e ][ \\u003cspan citationid=\\\"CR7\\\" class=\\\"CitationRef\\\"\\u003e7\\u003c/span\\u003e ][ \\u003cspan citationid=\\\"CR8\\\" class=\\\"CitationRef\\\"\\u003e8\\u003c/span\\u003e ]. Prolonged anti-CD20 antibody use further risks immunosuppression and opportunistic infections[ \\u003cspan citationid=\\\"CR9\\\" class=\\\"CitationRef\\\"\\u003e9\\u003c/span\\u003e ]. Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has demonstrated transformative efficacy in aggressive B-cell malignancies[ \\u003cspan citationid=\\\"CR10\\\" class=\\\"CitationRef\\\"\\u003e10\\u003c/span\\u003e ]. Recent trials, such as ELARA, report\\u0026thinsp;\\u0026gt;\\u0026thinsp;80% response rates and 24-month PFS\\u0026thinsp;\\u0026gt;\\u0026thinsp;50% in relapsed/refractory FL, highlighting its potential for central lymphomas. CAR-T therapy induces durable remission with a single infusion, minimizing maintenance therapy burdens. However, challenges include high cost (\\u0026gt;\\u003cspan\\u003e$\\u003c/span\\u003e500,000 per infusion), delayed cytopenias, and CRS/neurotoxicity risks[ \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e ]. Subtype-specific trials are needed to optimize CAR-T applications for anatomically complex lymphomas like OFL, balancing efficacy with accessibility and safety. \\u003c/p\\u003e \\u003cp\\u003eCase report\\u003c/p\\u003e \\u003cp\\u003eIn August 2022, a 51-year-old male patient was found to have a protruding left eyeball and went to the hospital to refine orbital computed tomography (CT), enhancement, and three-dimensional imaging to reveal a left posterior ocular space-occupying lesion with suspicion of lymphoma. Immediately PET-CT considered irregular soft-tissue density mass behind the left eyeball(Figure \\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eH), fusion of lymph nodes into a mass in the left neck, anterolateral border of the anterior deltoid fasciculus on the right, lateral border of the middle deltoid fasciculus on the right, anterior border of the right lesser round muscle, posterior gap of the right pectoralis minor muscle, subcutaneous fascia slightly above the left subscapularis margin, soft-tissue mass with metabolic increase in the left internal muscularis obturatoris, and consideration of lymphoma involvement, and the right anterior chest wall thickening of the medial border of the pectoralis major muscle, localized skin thickening, blurred subcutaneous fat, and slightly elevated metabolism, consider lymphoma involvement and localized biopsy after surgery༈Figure \\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eI༉. The patient completed left orbital apical tumor removal\\u0026thinsp;+\\u0026thinsp;right chest wall tumor resection on September 6, 2022 at the First Affiliated Hospital of Zhengzhou University. Postoperative biopsy histopathology suggested: AE1/AE3(-), CD3(-), CD20(+), CD5(+), CD21(+), CD10(partial+), CD30(scattered+), PAX-5(+), Bc1-2(foci+), MUM-1(-), CyclinD1(-), Ki-67(20%+). Chest wall mass Immunohistochemistry results:CD19(+), CD38(-). In situ hybridization: EBER(-) (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eA-D). A biopsy of the orbital lesion confirmed follicular lymphoma (grade 1\\u0026ndash;2), with immunophenotyping revealing CD20+, CD10+, BCL-2+, and a Ki-67 proliferation index of 20%. The fluorescence in situ hybridization (FISH) result is negative for BCL 2/IgH rearrangement; BCL6 rearrangement negative; C-MYC/IgH rearrangement negative; API2/MALT1 rearrangement negative (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig1\\\" class=\\\"InternalRef\\\"\\u003e1\\u003c/span\\u003eE-H).\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003ePatient refused chemotherapy and requested targeted CD19 CART cell therapy. In the current case, after fully informing the patient and family about the risks of cell transfusion, immunotherapy, and insurance riders, and upon completing sign-off, CD19 cell immunotherapy was performed.\\u003c/p\\u003e \\u003cp\\u003eIntervention\\u003c/p\\u003e \\u003cp\\u003eAfter declining conventional systemic chemoimmunotherapy due to concerns about toxicity, the patient elected to undergo anti-CD19 CAR-T therapy. Preconditioning chemotherapy consisted of fludarabine (60 mg/day) and cyclophosphamide (1 g/day) for three consecutive days, followed by the infusion of 4 \\u0026times; 10⁶ anti-CD19 CAR-T cells on November 3, 2022. Under research compassionate use guidelines (Ethics Approval: TJ-IRB20210827), he received a 4-1BB-costimulated anti-CD19 CAR-T product (Bio-Raid, Bio-003). Primary endpoints included safety (incidence and severity of cytokine release syndrome [CRS] and neurotoxicity), efficacy (complete metabolic response assessed via PET-CT), and durability of response over 18 months of follow-up. Clinical trial number: not applicable.\\u003c/p\\u003e\"},{\"header\":\"Results\",\"content\":\"\\u003cp\\u003eThe patient experienced mild and self-limiting adverse effects following CAR-T cell infusion, including fever (initial temperature: 37.4\\u0026deg;C; peak: 38.7\\u0026deg;C, lasting 4 days) and tachycardia, which developed 48 hours post-infusion. A transient increase in serum ferritin (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eE) and interleukin-6 (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eF) was observed, with peak levels reaching 17.5-fold above baseline. Hematologic toxicity was most pronounced on day 3 post-infusion (Figs.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eG-H); however, it resolved spontaneously without clinical intervention, and no central nervous system (CNS) toxicity was detected. Leukocyte and neutrophil counts normalized by day 7 post-infusion. Importantly, no red blood cell or platelet transfusions were required during the treatment course (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eH). These findings indicate that the patient experienced only grade 1\\u0026ndash;2 cytokine release syndrome (CRS), demonstrating a favorable safety profile for CAR-T cell therapy.\\u003c/p\\u003e \\u003cp\\u003e \\u003c/p\\u003e \\u003cp\\u003eAt 622 days post-infusion, positron emission tomography-computed tomography (PET-CT) demonstrated systemic disease remission without significant edema. Long-term follow-up assessments revealed no signs of disease progression, recurrence, or tumor metastasis (Fig.\\u0026nbsp;\\u003cspan refid=\\\"Fig2\\\" class=\\\"InternalRef\\\"\\u003e2\\u003c/span\\u003eI-L), further underscoring the sustained efficacy and safety of CAR-T cell therapy.\\u003c/p\\u003e\"},{\"header\":\"Discussion\",\"content\":\"\\u003cp\\u003eFollicular lymphoma (FL), as the most common indolent lymphoma, presents unique therapeutic challenges despite its less aggressive nature compared to invasive lymphomas[\\u003cspan citationid=\\\"CR12\\\" class=\\\"CitationRef\\\"\\u003e12\\u003c/span\\u003e]. Follicular lymphoma (FL), the most common indolent lymphoma, is characterized by recurrent relapses despite high initial remission rates, necessitating therapies that provide durable responses. Current standards, such as rituximab-based chemoimmunotherapy and bendamustine-rituximab regimens, achieve short-term disease control but are limited by cumulative toxicities, immunosuppression-related infections, and inevitable relapses[\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e][\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e], but its long-term safety and efficacy are limited by drug toxicities and the inability to prevent eventual disease relapse. However, long-term use of CD20 monoclonal antibodies will inevitably lead to repeated hospitalizations, affecting the quality of life and causing many drawbacks such as easy infection. With the development of pathophysiology in follicular lymphoma, targeted therapy is the optimal choice, and many patients with quality of life requirements (including follicular lymphoma, especially those with advanced disease) will actively try new immunotherapy strategies. The diagnosis of follicular lymphoma requires the detection of characteristic t (14; 18) translocations [\\u003cspan citationid=\\\"CR15\\\" class=\\\"CitationRef\\\"\\u003e15\\u003c/span\\u003e], FL pathogenesis is driven by t(14;18)-mediated BCL-2 overexpression and recurrent epigenetic mutations (e.g., KMT2D, CREBBP, EZH2), which promote immune evasion and treatment resistance[[\\u003cspan citationid=\\\"CR2\\\" class=\\\"CitationRef\\\"\\u003e2\\u003c/span\\u003e][\\u003cspan citationid=\\\"CR16\\\" class=\\\"CitationRef\\\"\\u003e16\\u003c/span\\u003e][\\u003cspan citationid=\\\"CR13\\\" class=\\\"CitationRef\\\"\\u003e13\\u003c/span\\u003e][\\u003cspan citationid=\\\"CR17\\\" class=\\\"CitationRef\\\"\\u003e17\\u003c/span\\u003e]. The B cell receptor, RAS, mTOR, and JAK-STAT pathways have been found to be associated with immune escape mutations[\\u003cspan citationid=\\\"CR18\\\" class=\\\"CitationRef\\\"\\u003e18\\u003c/span\\u003e]. Emerging therapies, including antibody-drug conjugates (e.g., polatuzumab vedotin), CD47 inhibitors (e.g., magrolimab), and small molecule inhibitors targeting PI3K/BTK pathways, show promise but lack sustained efficacy in preventing relapse [\\u003cspan citationid=\\\"CR14\\\" class=\\\"CitationRef\\\"\\u003e14\\u003c/span\\u003e][\\u003cspan citationid=\\\"CR19\\\" class=\\\"CitationRef\\\"\\u003e19\\u003c/span\\u003e].\\u003c/p\\u003e \\u003cp\\u003e Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 represents a paradigm shift. While traditionally reserved for aggressive lymphomas, recent trials (e.g., ELARA) demonstrate\\u0026thinsp;\\u0026gt;\\u0026thinsp;80% response rates and durable remissions in relapsed/refractory FL[ \\u003cspan citationid=\\\"CR6\\\" class=\\\"CitationRef\\\"\\u003e6\\u003c/span\\u003e ]. The presented case of anti-CD19 CAR-T achieving sustained remission in treatment-na\\u0026iuml;ve OFL highlights its potential in indolent subtypes. CAR-T therapy minimizes maintenance burdens and cumulative toxicities; however, challenges include high costs (\\u0026gt;\\u003cspan\\u003e$\\u003c/span\\u003e500,000 per infusion), cytokine release syndrome (CRS), and delayed cytopenias[ \\u003cspan citationid=\\\"CR11\\\" class=\\\"CitationRef\\\"\\u003e11\\u003c/span\\u003e ]. Furthermore, its role in early-line therapy requires validation through subtype-specific trials, particularly for anatomically complex lymphomas like OFL, where tumor microenvironment interactions may influence outcomes. CAR-T was offered as compassionate use after multidisciplinary review. The patient acknowledged lymphodepletion risks and prioritized single-infusion efficacy over maintenance therapies. \\u003c/p\\u003e\"},{\"header\":\"Conclusion\",\"content\":\"\\u003cp\\u003eAnti-CD19 CAR-T therapy induced sustained remission in this OFL case, underscoring its potential for central lymphomas. However, cost, toxicity, and indolent disease kinetics necessitate further studies before first-line adoption.\\u003c/p\\u003e\"},{\"header\":\"Declarations\",\"content\":\"\\u003ch2\\u003eAuthor Contribution\\u003c/h2\\u003e\\u003cp\\u003eM.Z., P.L, and XY.W. designed the experimental plans; HC.Z., MQ.Y., HX.W., M.Z., L.F., and M.L. performed the experiments. Q.W. performed the bioinformatic analysis; H.L. analyzed the data and drafted the manuscript. Y.X., and TC.Z. were involved in the revision of the manuscript.\\u003c/p\\u003e\\u003ch2\\u003eAcknowledgements\\u003c/h2\\u003e \\u003cp\\u003eThis work was funded by grants from the Scientific Research Program for Young Talents of Hubei Provincial Department of Education (Q202111113), Wuhan Knowledge Innovation Project, Dawn Plan (20220220208001020313) and the Natural Science Foundation of Hubei Province (2023AFB606).\\u003c/p\\u003e \\u003cp\\u003eCompeting interests and Ethics approval and consent to participate This study was conducted in accordance with the Declaration of Helsinki. All research involving human participants was approved by the institutional ethics committee, and the study adhered to appropriate national guidelines. The authors declare that they have no competing interests.\\u003c/p\\u003e \\u003cp\\u003eThe project has received approval from the Ethics Committee of Tianyou Hospital affiliated with Wuhan University of Science and Technology (LL-2023-05-09-01). We obtained the informed consent of the patient and family and performed compassionate treatment as agreed to by the patient and family. Informed consent was obtained from all study participants, including parents or legally authorized representatives of subjects under the age of 16. All participants were fully informed of the study's purpose, risks, and benefits before providing their consent.\\u003c/p\\u003e \\u003cp\\u003eConsent for publication\\u003c/p\\u003e \\u003cp\\u003eAll statements in this case report were published with the consent of the patient and family. The work described has not been published before. It is not under consideration for publication anywhere else. Its publication has been approved by all co-authors, and the responsible authorities at the institute where the work has been carried out. All authors contributed equally to this manuscript. Prof. Yi Xiao and Prof. Tongcun Zhang were involved in the study design, manuscript writing, and final revisions.\\u003c/p\\u003e \\u003cp\\u003e \\u003csup\\u003e1\\u003c/sup\\u003eAll authors contribute equally to this article.\\u003c/p\\u003e\\u003ch2\\u003eData Availability\\u003c/h2\\u003e\\u003cp\\u003eData sharing is not applicable to this article as no datasets were generated or analyzed during the current study. The work described has not been published before. It is not under consideration for publication anywhere else. Its publication has been approved by all co-authors, and the responsible authorities at the institute where the work has been carried out.\\u003c/p\\u003e \"},{\"header\":\"References\",\"content\":\"\\u003col\\u003e\\u003cli\\u003e\\u003cspan\\u003eJacobsen E: Follicular lymphoma: 2023 update on diagnosis and management. \\u003cem\\u003eAmerican journal of hematology\\u003c/em\\u003e 2022, 97(12):1638\\u0026ndash;1651.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eZhong J, Yang X, Chen J, He K, Gao X, Wu X, Zhang M, Zhou H, Xiao F, An L \\u003cem\\u003eet al\\u003c/em\\u003e: Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands. \\u003cem\\u003eNature communications\\u003c/em\\u003e 2022, 13(1):4795.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSchmatz AI, Streubel B, Kretschmer-Chott E, P\\u0026uuml;sp\\u0026ouml;k A, J\\u0026auml;ger U, Mannhalter C, Tiemann M, Ott G, Fischbach W, Herzog P \\u003cem\\u003eet al\\u003c/em\\u003e: Primary follicular lymphoma of the duodenum is a distinct mucosal/submucosal variant of follicular lymphoma: a retrospective study of 63 cases. \\u003cem\\u003eJournal of clinical oncology: official journal of the American Society of Clinical Oncology\\u003c/em\\u003e 2011, 29(11):1445\\u0026ndash;1451.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eNaresh KN, Medeiros LJ: Introduction to the Fifth Edition of the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissues. \\u003cem\\u003eModern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc\\u003c/em\\u003e 2023, 36(12):100330.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eKiaii S, Clear AJ, Ramsay AG, Davies D, Sangaralingam A, Lee A, Calaminici M, Neuberg DS, Gribben JG: Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation. \\u003cem\\u003eJournal of clinical oncology: official journal of the American Society of Clinical Oncology\\u003c/em\\u003e 2013, 31(21):2654\\u0026ndash;2661.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMorschhauser F, Dahiya S, Palomba ML, Martin Garcia-Sancho A, Reguera Ortega JL, Kuruvilla J, J\\u0026auml;ger U, Cartron G, Izutsu K, Dreyling M \\u003cem\\u003eet al\\u003c/em\\u003e: Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. \\u003cem\\u003eNature medicine\\u003c/em\\u003e 2024.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eBorchmann S, M\\u0026uuml;ller H, Haverkamp H, Baues C, Markov\\u0026aacute; J, H\\u0026uuml;ttmann A, Glunz A, Fuchs M, Borchmann P, Engert A: Symptomatic osteonecrosis as a treatment complication in Hodgkin lymphoma: an analysis of the German Hodgkin Study Group (GHSG). \\u003cem\\u003eLeukemia\\u003c/em\\u003e 2019, 33(2):439\\u0026ndash;446.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, Tsang R, Christie D, McClure B, Joseph D \\u003cem\\u003eet al\\u003c/em\\u003e: Randomized Trial of Systemic Therapy After Involved-Field Radiotherapy in Patients With Early-Stage Follicular Lymphoma: TROG 99.03. \\u003cem\\u003eJournal of clinical oncology: official journal of the American Society of Clinical Oncology\\u003c/em\\u003e 2018, 36(29):2918\\u0026ndash;2925.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFriedberg JW: Flashback Foreword: Chimeric Anti-CD20 Monoclonal Antibody Therapy. \\u003cem\\u003eJournal of clinical oncology: official journal of the American Society of Clinical Oncology\\u003c/em\\u003e 2023, 41(2):151\\u0026ndash;152.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAbramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C \\u003cem\\u003eet al\\u003c/em\\u003e: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. \\u003cem\\u003eLancet (London, England)\\u003c/em\\u003e 2020, 396(10254):839\\u0026ndash;852.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSchubert ML, Schmitt M, Wang L, Ramos CA, Jordan K, M\\u0026uuml;ller-Tidow C, Dreger P: Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. \\u003cem\\u003eAnnals of oncology: official journal of the European Society for Medical Oncology\\u003c/em\\u003e 2021, 32(1):34\\u0026ndash;48.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFreedman A, Jacobsen E: Follicular lymphoma: 2020 update on diagnosis and management. \\u003cem\\u003eAmerican journal of hematology\\u003c/em\\u003e 2020, 95(3):316\\u0026ndash;327.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eGordon MJ, Smith MR, Nastoupil LJ: Follicular lymphoma: The long and winding road leading to your cure? \\u003cem\\u003eBlood reviews\\u003c/em\\u003e 2023, 57:100992.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eFlowers CR, Matasar MJ, Herrera AF, Hertzberg M, Assouline S, Demeter J, McMillan A, Mehta A, Opat S, Trnňn\\u0026yacute; M \\u003cem\\u003eet al\\u003c/em\\u003e: Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study. \\u003cem\\u003eHaematologica\\u003c/em\\u003e 2024, 109(4):1194\\u0026ndash;1205.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eRoulland S, Kelly RS, Morgado E, Sungalee S, Solal-Celigny P, Colombat P, Jouve N, Palli D, Pala V, Tumino R \\u003cem\\u003eet al\\u003c/em\\u003e: t(14;18) Translocation: A predictive blood biomarker for follicular lymphoma. \\u003cem\\u003eJournal of clinical oncology: official journal of the American Society of Clinical Oncology\\u003c/em\\u003e 2014, 32(13):1347\\u0026ndash;1355.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eAmin R, Braza MS: The follicular lymphoma epigenome regulates its microenvironment. \\u003cem\\u003eJournal of experimental \\u0026amp; clinical cancer research: CR\\u003c/em\\u003e 2022, 41(1):21.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eMorschhauser F, Tilly H, Chaidos A, McKay P, Phillips T, Assouline S, Batlevi CL, Campbell P, Ribrag V, Damaj GL \\u003cem\\u003eet al\\u003c/em\\u003e: Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. \\u003cem\\u003eThe Lancet Oncology\\u003c/em\\u003e 2020, 21(11):1433\\u0026ndash;1442.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eWeniger MA, K\\u0026uuml;ppers R: Molecular biology of Hodgkin lymphoma. \\u003cem\\u003eLeukemia\\u003c/em\\u003e 2021, 35(4):968\\u0026ndash;981.\\u003c/span\\u003e\\u003c/li\\u003e \\u003cli\\u003e\\u003cspan\\u003eSong Y, Zhou K, Zou D, Zhou J, Hu J, Yang H, Zhang H, Ji J, Xu W, Jin J \\u003cem\\u003eet al\\u003c/em\\u003e: Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. \\u003cem\\u003eBlood\\u003c/em\\u003e 2022, 139(21):3148\\u0026ndash;3158.\\u003c/span\\u003e\\u003c/li\\u003e\\u003c/ol\\u003e\"},{\"header\":\"Table\",\"content\":\"\\u003cp\\u003eTable 1 is available in the Supplementary Files section.\\u003c/p\\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\":\"info@researchsquare.com\",\"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\":\"central lymphoma, ocular follicular lymphoma, CD19 CAR-T, cell therapy, non-Hodgkin lymphoma\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6369375/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6369375/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground: \\u003c/strong\\u003eCentral lymphomas, including rare and anatomically complex subtypes such as ocular follicular lymphoma (OFL), pose substantial therapeutic challenges due to their localization and unique microenvironment promoting immune evasion. OFL, a rare manifestation of follicular lymphoma (FL), often exhibits resistance to standard therapies, necessitating innovative approaches.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods: \\u003c/strong\\u003eThis case report highlights the application of anti-CD19 CAR-T therapy in a patient with OFL. Treatment outcomes, including safety, cytokine release syndrome (CRS), and durability of remission, were assessed during an 18-month follow-up.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults: \\u003c/strong\\u003eThe patient achieved complete metabolic remission with no evidence of systemic relapse or significant long-term toxicities. Transient grade 1–2 CRS was observed but resolved with supportive care. No neurological toxicities were reported, and the patient has remained disease-free.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusions: \\u003c/strong\\u003eAnti-CD19 CAR-T therapy demonstrated sustained efficacy and a favorable safety profile in this case of OFL, underscoring its potential as an innovative therapeutic approach for central lymphomas. Further research is warranted to explore its integration into first-line treatment settings and optimize its applicability across broader lymphoma subtypes.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Anti-CD19 CAR-T Therapy for Central Lymphoma: A Case Study of Ocular Follicular Lymphoma and Emerging Therapeutic Strategies\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-01 10:21:15\",\"doi\":\"10.21203/rs.3.rs-6369375/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"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\":\"b1936754-805b-459b-9279-99db998d649b\",\"owner\":[],\"postedDate\":\"July 1st, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"posted\",\"subjectAreas\":[],\"tags\":[],\"updatedAt\":\"2025-09-22T12:08:44+00:00\",\"versionOfRecord\":[],\"versionCreatedAt\":\"2025-07-01 10:21:15\",\"video\":\"\",\"vorDoi\":\"\",\"vorDoiUrl\":\"\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6369375\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6369375\",\"identity\":\"rs-6369375\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}