{"paper_id":"41231ed7-bdb4-42cd-b387-e9960101980a","body_text":"Characteristics and Developmental Trajectory of Clinical Trials Focused on Tumor-Infiltrating Lymphocytes for Cancer Treatment | 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 Article Characteristics and Developmental Trajectory of Clinical Trials Focused on Tumor-Infiltrating Lymphocytes for Cancer Treatment Jinyi Liu, Chun Xiao, Xinhong Li, Wei Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6990012/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Jan, 2026 Read the published version in Cancer Gene Therapy → Version 1 posted 12 You are reading this latest preprint version Abstract Background: Tumor-infiltrating lymphocytes (TILs) have shown promise in cancer immunotherapy, but their clinical application and developmental trajectory remain insufficiently characterized. This study aimed to systematically analyze the features and trends of TIL-related clinical trials to inform future trial designs and translational research. Methods: We conducted a cross-sectional analysis of interventional TIL trials for cancer treatment registered on ClinicalTrials.gov up to December 31, 2024. Trial characteristics, temporal trends, and treatment strategies were assessed. Results: Among 177 eligible trials, 98.3% were early-phase studies, and 53.1% enrolled no more than 20 patients. Malignant melanoma was the most frequently studied tumor (32.2%). North America led trial activity (49.2%), with growing industry sponsorship (37.9%). Cytokines (70.1%) and immune checkpoint inhibitors (ICIs; 23.2%) were the most common combination therapies. Since 2017, the proportion of trials using TIL monotherapy significantly increased (P<0.001), alongside a rise in TIL–ICI combinations (P=0.049). Genetically engineered TIL trials showed a lower use of cytokines (vs. autologous, P<0.001; vs. selectively expanded, P=0.007) and non-myeloablative chemotherapy (P=0.003; P=0.020). Selectively expanded TILs were more often combined with radiotherapy (P=0.033; P=0.009). Conclusion: Clinical trials of TIL for tumor treatment have primarily focused on early-phase studies. Cytokines and ICIs remain the predominant combination therapies utilized in TIL clinical trials. The use of TIL monotherapy has emerged as a growing trend. Further research efforts and clinical attention are essential to facilitate the broader application of TIL therapies in clinical practice. Biological sciences/Cancer/Tumour immunology Biological sciences/Immunology/Adaptive immunity/Cellular immunity Health sciences/Medical research/Drug development Biological sciences/Cell biology Tumor-infiltrating lymphocytes ClinicalTrials.gov Clinical trials Cancer Characteristics Trends Full Text Additional Declarations There is NO conflict of interest to disclose. Table 1 and 2 are available in the Supplementary Files section. Supplementary Files Table1.docx Table2.docx Suppl.Table1.docx Suppl.Table2.docx Cite Share Download PDF Status: Published Journal Publication published 14 Jan, 2026 Read the published version in Cancer Gene Therapy → Version 1 posted Editorial decision: revise 16 Jul, 2025 Review # 3 received at journal 14 Jul, 2025 Review # 4 received at journal 09 Jul, 2025 Reviewer # 4 agreed at journal 03 Jul, 2025 Reviewer # 3 agreed at journal 03 Jul, 2025 Reviewer # 2 agreed at journal 02 Jul, 2025 Reviewer # 1 agreed at journal 02 Jul, 2025 Reviewers invited by journal 02 Jul, 2025 Submission checks completed at journal 02 Jul, 2025 First submitted to journal 02 Jul, 2025 Unknown event 30 Jun, 2025 Editor assigned by journal 27 Jun, 2025 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-6990012\",\"acceptedTermsAndConditions\":true,\"allowDirectSubmit\":false,\"archivedVersions\":[],\"articleType\":\"Article\",\"associatedPublications\":[],\"authors\":[{\"id\":479723885,\"identity\":\"788103a1-7e68-4c9b-814b-34e4e3b999f0\",\"order_by\":0,\"name\":\"Jinyi 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05:30:48\",\"extension\":\"docx\",\"order_by\":9,\"title\":\"\",\"display\":\"\",\"copyAsset\":false,\"role\":\"supplement\",\"size\":34481,\"visible\":true,\"origin\":\"\",\"legend\":\"\",\"description\":\"\",\"filename\":\"Suppl.Table2.docx\",\"url\":\"https://assets-eu.researchsquare.com/files/rs-6990012/v1/1e882d59dea1bb016dc7334c.docx\"}],\"financialInterests\":\"\\u003cp\\u003eThere is \\u003cstrong\\u003eNO\\u003c/strong\\u003e conflict of interest to disclose.\\u003c/p\\u003e\\n\\u003cp\\u003eTable 1 and 2 are available in the Supplementary Files section.\\u003c/p\\u003e\",\"formattedTitle\":\"Characteristics and Developmental Trajectory of Clinical Trials Focused on Tumor-Infiltrating Lymphocytes for Cancer 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Therapy\",\"twitterHandle\":\"@cgtnature\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"ejp\",\"reportingPortfolio\":\"Nature AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false},\"keywords\":\"Tumor-infiltrating lymphocytes, ClinicalTrials.gov, Clinical trials, Cancer, Characteristics, Trends\",\"lastPublishedDoi\":\"10.21203/rs.3.rs-6990012/v1\",\"lastPublishedDoiUrl\":\"https://doi.org/10.21203/rs.3.rs-6990012/v1\",\"license\":{\"name\":\"CC BY 4.0\",\"url\":\"https://creativecommons.org/licenses/by/4.0/\"},\"manuscriptAbstract\":\"\\u003cp\\u003e\\u003cstrong\\u003eBackground: \\u003c/strong\\u003eTumor-infiltrating lymphocytes (TILs) have shown promise in cancer immunotherapy, but their clinical application and developmental trajectory remain insufficiently characterized. This study aimed to systematically analyze the features and trends of TIL-related clinical trials to inform future trial designs and translational research.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eMethods: \\u003c/strong\\u003eWe conducted a cross-sectional analysis of interventional TIL trials for cancer treatment registered on ClinicalTrials.gov up to December 31, 2024. Trial characteristics, temporal trends, and treatment strategies were assessed.\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eResults: \\u003c/strong\\u003eAmong 177 eligible trials, 98.3% were early-phase studies, and 53.1% enrolled no more than 20 patients. Malignant melanoma was the most frequently studied tumor (32.2%). North America led trial activity (49.2%), with growing industry sponsorship (37.9%). Cytokines (70.1%) and immune checkpoint inhibitors (ICIs; 23.2%) were the most common combination therapies. Since 2017, the proportion of trials using TIL monotherapy significantly increased (P\\u0026lt;0.001), alongside a rise in TIL–ICI combinations (P=0.049). Genetically engineered TIL trials showed a lower use of cytokines (vs. autologous, P\\u0026lt;0.001; vs. selectively expanded, P=0.007) and non-myeloablative chemotherapy (P=0.003; P=0.020). Selectively expanded TILs were more often combined with radiotherapy (P=0.033; P=0.009).\\u003c/p\\u003e\\n\\u003cp\\u003e\\u003cstrong\\u003eConclusion:\\u003c/strong\\u003e Clinical trials of TIL for tumor treatment have primarily focused on early-phase studies. Cytokines and ICIs remain the predominant combination therapies utilized in TIL clinical trials. The use of TIL monotherapy has emerged as a growing trend. Further research efforts and clinical attention are essential to facilitate the broader application of TIL therapies in clinical practice.\\u003c/p\\u003e\",\"manuscriptTitle\":\"Characteristics and Developmental Trajectory of Clinical Trials Focused on Tumor-Infiltrating Lymphocytes for Cancer Treatment\",\"msid\":\"\",\"msnumber\":\"\",\"nonDraftVersions\":[{\"code\":1,\"date\":\"2025-07-04 05:30:11\",\"doi\":\"10.21203/rs.3.rs-6990012/v1\",\"editorialEvents\":[{\"type\":\"communityComments\",\"content\":0},{\"type\":\"decision\",\"content\":\"revise\",\"date\":\"2025-07-16T15:47:40+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorInvitedReview\",\"content\":\"This content is not available.\",\"date\":\"2025-07-14T13:07:54+00:00\",\"index\":3,\"fulltext\":\"This content is not available.\"},{\"type\":\"editorInvitedReview\",\"content\":\"This content is not available.\",\"date\":\"2025-07-09T19:49:40+00:00\",\"index\":4,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2025-07-03T16:36:47+00:00\",\"index\":4,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2025-07-03T06:48:54+00:00\",\"index\":3,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2025-07-02T20:08:10+00:00\",\"index\":2,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewerAgreed\",\"content\":\"This content is not available.\",\"date\":\"2025-07-02T17:11:04+00:00\",\"index\":1,\"fulltext\":\"This content is not available.\"},{\"type\":\"reviewersInvited\",\"content\":\"\",\"date\":\"2025-07-02T15:22:51+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksComplete\",\"content\":\"\",\"date\":\"2025-07-02T10:53:42+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"submitted\",\"content\":\"Cancer Gene Therapy\",\"date\":\"2025-07-02T07:35:21+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"checksFailed\",\"content\":\"\",\"date\":\"2025-06-30T11:24:46+00:00\",\"index\":\"\",\"fulltext\":\"\"},{\"type\":\"editorAssigned\",\"content\":\"\",\"date\":\"2025-06-27T09:16:27+00:00\",\"index\":\"\",\"fulltext\":\"\"}],\"status\":\"published\",\"journal\":{\"display\":true,\"email\":\"info@researchsquare.com\",\"identity\":\"cancer-gene-therapy\",\"isNatureJournal\":false,\"hasQc\":false,\"allowDirectSubmit\":false,\"externalIdentity\":\"cgt\",\"sideBox\":\"Learn more about [Cancer Gene Therapy](http://www.nature.com/cgt/)\",\"snPcode\":\"41417\",\"submissionUrl\":\"https://mts-cgt.nature.com/cgi-bin/main.plex\",\"title\":\"Cancer Gene Therapy\",\"twitterHandle\":\"@cgtnature\",\"acdcEnabled\":true,\"dfaEnabled\":true,\"editorialSystem\":\"ejp\",\"reportingPortfolio\":\"Nature AJ\",\"inReviewEnabled\":true,\"inReviewRevisionsEnabled\":false}}],\"origin\":\"\",\"ownerIdentity\":\"509549d0-f2aa-4802-bb5c-c400482eda32\",\"owner\":[],\"postedDate\":\"July 4th, 2025\",\"published\":true,\"recentEditorialEvents\":[],\"rejectedJournal\":[],\"revision\":\"\",\"amendment\":\"\",\"status\":\"published-in-journal\",\"subjectAreas\":[{\"id\":50942645,\"name\":\"Biological sciences/Cancer/Tumour immunology\"},{\"id\":50942646,\"name\":\"Biological sciences/Immunology/Adaptive immunity/Cellular immunity\"},{\"id\":50942647,\"name\":\"Health sciences/Medical research/Drug development\"},{\"id\":50942648,\"name\":\"Biological sciences/Cell biology\"}],\"tags\":[],\"updatedAt\":\"2026-01-15T08:10:16+00:00\",\"versionOfRecord\":{\"articleIdentity\":\"rs-6990012\",\"link\":\"https://doi.org/10.1038/s41417-026-00998-w\",\"journal\":{\"identity\":\"cancer-gene-therapy\",\"isVorOnly\":false,\"title\":\"Cancer Gene Therapy\"},\"publishedOn\":\"2026-01-14 05:00:00\",\"publishedOnDateReadable\":\"January 14th, 2026\"},\"versionCreatedAt\":\"2025-07-04 05:30:11\",\"video\":\"\",\"vorDoi\":\"10.1038/s41417-026-00998-w\",\"vorDoiUrl\":\"https://doi.org/10.1038/s41417-026-00998-w\",\"workflowStages\":[]},\"version\":\"v1\",\"identity\":\"rs-6990012\",\"journalConfig\":\"researchsquare\"},\"__N_SSP\":true},\"page\":\"/article/[identity]/[[...version]]\",\"query\":{\"redirect\":\"/article/rs-6990012\",\"identity\":\"rs-6990012\",\"version\":[\"v1\"]},\"buildId\":\"8U1c8b4HqxoKbykW_rLl7\",\"isFallback\":false,\"isExperimentalCompile\":false,\"dynamicIds\":[84888],\"gssp\":true,\"scriptLoader\":[]}","source_license":"CC-BY-4.0","license_restricted":false}